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Sample records for acute graft-versus-host disease

  1. A randomized study of the prevention of acute graft-versus-host disease

    International Nuclear Information System (INIS)

    Ramsay, N.K.C.; Kersey, J.H.; Robison, L.L.; McGlave, P.B.; Woods, W.G.; Krivit, W.; Kim, T.H.; Goldman, A.I.; Nesbit, M.E. Jr.

    1982-01-01

    Acute graft-versus-host disease is a major problem in allogeneic bone-marrow transplantation. We performed a randomized study to compare the effectiveness of two regimens in the prevention of acute graft-versus-host disease. Thirty-five patients received methotrexate alone, and 32 received methotrexate, antithymocyte globulin, and prednisone. Of the patients who received methotrexate alone, 48 percent had acute graft-versus-host disease, as compared with 21 per cent of those who received methotrexate, antithymocyte globulin, and prednisone (P = 0.01). The age of the recipient was a significant factor in the development of acute graft-versus-host disease: Older patients had a higher incidence of the disease (P = 0.001). We conclude that the combination of methotrexate, antithymocyte globulin, and prednisone significantly decreased the incidence of acute graft-versus-host disease and should be used to prevent this disorder in patients receiving allogeneic marrow transplants

  2. Etanercept on steroid-refractary acute graft-versus-host disease

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    Silvia González Munguía

    2015-02-01

    Full Text Available Objetive: To describe etanercept use and effectiveness on steroid- refractary acute graft-versus-host disease after hematopoietic cell transplantation. Method: Patients treated with etanercept as off label use for steroid-refractary acute graft-versus-host disease were selected and each patient’s medical history was reviewed to assess the clinical response. Results: The study included five patients: four presented with digestive manifestations and one presented pulmonary and liver manifestations. 80% of patients showed a clinical response: 60% a partial response and 20% a total response. In four cases etanercept 25mg was administered twice a week with variable duration of treatment, achieving no response in 1 case (3 weeks, partial response in two 2 cases (4 weeks and 8 weeks and a complete response in 1 case (8 week period. Only one case was treated with etanercept 50mg administered twice a week for 5 weeks with a partial treatment response. Conclusions: The clinical response rate is consistent with the previously published data. This updates the scarce bibliographic information about etanecept use in steroid-refractary acute graft-versus-host disease. Due to clinical design limitations and the small patient population, future clinical studies should be conducted to assess the efficacy and security of etanercept in these patients.

  3. Subacute radiation dermatitis: a histologic imitator of acute cutaneous graft-versus-host disease

    International Nuclear Information System (INIS)

    LeBoit, P.E.

    1989-01-01

    The histopathologic changes of radiation dermatitis have been classified either as early effects (necrotic keratinocytes, fibrin thrombi, and hemorrhage) or as late effects (vacuolar changes at the dermal-epidermal junction, atypical radiation fibroblasts, and fibrosis). Two patients, one exposed to radiation therapeutically and one accidentally, are described. Skin biopsy specimens showed an interface dermatitis characterized by numerous dyskeratotic epidermal cells with lymphocytes in close apposition (satellite cell necrosis); that is, the epidermal changes were similar to those in acute graft-versus-host disease. Because recipients of bone marrow transplants frequently receive total body irradiation as part of their preparatory regimen, the ability of radiation to cause persistent epidermal changes similar to those in acute graft-versus-host disease could complicate the interpretation of posttransplant skin biopsy specimens

  4. Acute Graft Versus Host Disease: A Comprehensive Review.

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    Nassereddine, Samah; Rafei, Hind; Elbahesh, Ehab; Tabbara, Imad

    2017-04-01

    Acute graft versus host disease (aGVHD) remains the second leading cause of death following allogeneic hematopoietic stem cell transplant (AHSCT). Over the last five years, the progress in understanding the pathophysiology of this immune based-process helped redefine graft versus host reaction and opened new possibilities for novel preventive and therapeutic approaches. The evolution in the field of immunology widened the horizons for hematopoietic stem cell transplant leading to the availability of different stem cell sources for potential graft and incorporation of novel conditioning regimens. There is conflicting data about the impact of the graft source and the conditioning regimen used in the process of AHSCT on the incidence of aGVHD. Many studies have reported increased risk of chronic GVHD (cGVHD) and to a less extent aGVHD with the use of peripheral blood stem cell and bone marrow compared to umbilical cord stem cell. The conditioning regimen, either myeloablative, non-myeloablative or reduced intensity may have different impact on the incidence of GVHD. Several preventive modalities have been adopted by different transplant centers but, to date, there is no standardized regimen. As for treatment, immunosuppression using steroids remains the first line of intervention. Several novel therapeutic options are being investigated for treatment of steroid-refractory aGVHD including the use of mesenchymal stem cells, anti thymocyte globulin and extra corporeal photophoresis. This review discusses the pathophysiology, risk factors, clinical features, and advances in the diagnosis, prevention and treatment of aGVHD. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  5. Oral chronic graft-versus-host disease: analysis of dendritic cells subpopulations*

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    Botari, Clara Marino Espricigo; Nunes, Adauto José Ferreira; de Souza, Mair Pedro; Orti-Raduan, Érica Sinara Lenharo; Salvio, Ana Gabriela

    2014-01-01

    The graft-versus-host disease is the major cause of morbidity and mortality in patients who have undergone hematopoietic stem cell transplantation. Aiming at contributing to the understanding of the role of myeloid and plasmacytoid dendritic cells, and natural killer cells in chronic graft-versus-host disease, we examined biopsies of jugal mucosa of 26 patients with acute myeloid leukemia who had undergone allogenic hematopoietic stem cell transplantation. Half of these patients developed oral chronic graft-versus-host disease. Microscopic sections were immunohistochemically stained for anti-CD1a, anti-CD123 and anti-CD56. We calculated the number of immunostained cells in the corium per square millimeter and applied the Mann-Whitney test. Results showed a statistically significant increase of myeloid dendritic cells (CD1a+; p=0,02) and natural killer cells (CD56; p=0,04) in patients with oral chronic graft-versus-host disease. CD123 immunostaining showed no statistical difference between groups. It was concluded that myeloid dendritic cells and natural killer cells participate in the development of oral chronic graft-versus-host disease. PMID:25054751

  6. Oral chronic graft-versus-host disease: analysis of dendritic cells subpopulations.

    Science.gov (United States)

    Botari, Clara Marino Espricigo; Nunes, Adauto José Ferreira; Souza, Mair Pedro de; Orti-Raduan, Erica Sinara Lenharo; Salvio, Ana Gabriela

    2014-01-01

    The graft-versus-host disease is the major cause of morbidity and mortality in patients who have undergone hematopoietic stem cell transplantation. Aiming at contributing to the understanding of the role of myeloid and plasmacytoid dendritic cells, and natural killer cells in chronic graft-versus-host disease, we examined biopsies of jugal mucosa of 26 patients with acute myeloid leukemia who had undergone allogenic hematopoietic stem cell transplantation. Half of these patients developed oral chronic graft-versus-host disease. Microscopic sections were immunohistochemically stained for anti-CD1a, anti-CD123 and anti-CD56. We calculated the number of immunostained cells in the corium per square millimeter and applied the Mann-Whitney test. Results showed a statistically significant increase of myeloid dendritic cells (CD1a+; p=0,02) and natural killer cells (CD56; p=0,04) in patients with oral chronic graft-versus-host disease. CD123 immunostaining showed no statistical difference between groups. It was concluded that myeloid dendritic cells and natural killer cells participate in the development of oral chronic graft-versus-host disease.

  7. Pathogenic mechanisms of Acute Graft versus Host Disease

    Directory of Open Access Journals (Sweden)

    Ferrara James L.M.

    2002-01-01

    Full Text Available Graft-versus-host-disease (GVHD is the major complication of allogeneic Bone Marrow Transplant (BMT. Older BMT recipients are a greater risk for acute GVHD after allogeneic BMT, but the causes of this association are poorly understood. Using well-characterized murine BMT models we have explored the mechanisms of increased GVHD in older mice. GVHD mortality and morbidity, and pathologic and biochemical indices were all worse in old recipients. Donor T cell responses were significantly increased in old recipients both in vivo and in vitro when stimulated by antigen-presenting cells (APCs from old mice. In a haploidential GVHD model, CD4+ donor T cells mediated more severe GVHD in old mice. We confirmed the role of aged APCs in GVHD using bone marrow chimera recipient created with either old or young bone marrow. APCs from these mice also stimulated greater responses from allogeneic cells in vitro. In a separate set of experiments we evaluated whether alloantigen expression on host target epithelium is essential for tissue damage induced by GVHD. Using bone marrow chimeras recipients in which either MHC II or MHC I alloantigen was expressed only on APCs, we found that acute GVHD does not require alloantigen expression on host target epithelium and that neutralization of tumor necrosis factor-alpha and interleukin-1 prevents acute GVHD. These results pertain to CD4-mediated GVHD and to a lesser extent in CD8-mediated GVHD, and confirm the central role of most APCs as well as inflammatory cytokines.

  8. Fulminant transfusion-associated graft-versus-host disease in a premature infant

    International Nuclear Information System (INIS)

    Berger, R.S.; Dixon, S.L.

    1989-01-01

    A fatal case of transfusion-associated graft-versus-host disease developed in a premature infant after receiving several blood products, including nonirradiated white blood cells. Transfusion-associated graft-versus-host disease can be prevented. Irradiation of blood products is the least controversial and most effective method. Treatment was unsuccessful in most reported cases of transfusion-associated graft-versus-host disease. Therefore irradiation of blood products before transfusing to patients susceptible to transfusion-associated graft-versus-host disease is strongly recommended

  9. Inhibition of protein geranylgeranylation and farnesylation protects against graft-versus-host disease via effects on CD4 effector T cells.

    Science.gov (United States)

    Hechinger, Anne-Kathrin; Maas, Kristina; Dürr, Christoph; Leonhardt, Franziska; Prinz, Gabriele; Marks, Reinhard; Gerlach, Ulrike; Hofmann, Maike; Fisch, Paul; Finke, Jürgen; Pircher, Hanspeter; Zeiser, Robert

    2013-01-01

    Despite advances in immunosuppressive regimens, acute graft-versus-host disease remains a frequent complication of allogeneic hematopoietic cell transplantation. Pathogenic donor T cells are dependent on correct attachment of small GTPases to the cell membrane, mediated by farnesyl- or geranylgeranyl residues, which, therefore, constitute potential targets for graft-versus-host disease prophylaxis. A mouse model was used to study the impact of a farnesyl-transferase inhibitor and a geranylgeranyl-transferase inhibitor on acute graft-versus-host disease, anti-cytomegalovirus T-cell responses and graft-versus-leukemia activity. Treatment of mice undergoing allogeneic hematopoietic cell transplantation with farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor reduced the histological severity of graft-versus-host disease and prolonged survival significantly. Mechanistically, farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor treatment resulted in reduced alloantigen-driven expansion of CD4 T cells. In vivo treatment led to increased thymic cellularity and polyclonality of the T-cell receptor repertoire by reducing thymic graft-versus-host disease. These effects were absent when squalene production was blocked. The farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor did not compromise CD8 function against leukemia cells or reconstitution of T cells that were subsequently responsible for anti-murine cytomegalovirus responses. In summary, we observed an immunomodulatory effect of inhibitors of farnesyl-transferase and geranylgeranyl-transferase on graft-versus-host disease, with enhanced functional immune reconstitution. In the light of the modest toxicity of farnesyl-transferase inhibitors such as tipifarnib in patients and the potent reduction of graft-versus-host disease in mice, farnesyl-transferase and geranylgeranyl-transferase inhibitors could help to reduce graft-versus-host disease significantly without

  10. Mesenchymal Stromal Cells: What Is the Mechanism in Acute Graft-Versus-Host Disease?

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    Neil Dunavin

    2017-07-01

    Full Text Available After more than a decade of preclinical and clinical development, therapeutic infusion of mesenchymal stromal cells is now a leading investigational strategy for the treatment of acute graft-versus-host disease (GVHD. While their clinical use continues to expand, it is still unknown which of their immunomodulatory properties contributes most to their therapeutic activity. Herein we describe the proposed mechanisms, focusing on the inhibitory activity of mesenchymal stromal cells (MSCs at immunologic checkpoints. A deeper understanding of the mechanism of action will allow us to design more effective treatment strategies.

  11. Steroid treatment of acute graft-versus-host disease grade I: a randomized trial

    OpenAIRE

    Bacigalupo, Andrea; Milone, Giuseppe; Cupri, Alessandra; Severino, Antonio; Fagioli, Franca; Berger, Massimo; Santarone, Stella; Chiusolo, Patrizia; Sica, Simona; Mammoliti, Sonia; Sorasio, Roberto; Massi, Daniela; Van Lint, Maria Teresa; Raiola, Anna Maria; Gualandi, Francesca

    2017-01-01

    Patients with acute graft-versus-host disease (GvHD) grade I were randomized to an observation arm (n=85) or to a treatment arm (n=86) consisting of 6-methylprednisolone 1 mg/kg/day, after stratification for age and donor type. The primary end point was development of grade II–IV GvHD. The cumulative incidence of grade II–IV GvHD was 50% in the observation arm and 33% in the treatment arm (P=0.005). However, grade III–IV GvHD was comparable (13% vs. 10%, respectively; P=0.6), and this was tru...

  12. New Insight for the Diagnosis of Gastrointestinal Acute Graft-versus-Host Disease

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    Florent Malard

    2014-01-01

    Full Text Available Allogeneic stem cell transplantation (allo-SCT is a curative therapy for different life-threatening malignant and nonmalignant hematologic disorders. Graft-versus-host disease (GVHD remains a major source of morbidity and mortality following allo-SCT, which limits the use of this treatment in a broader spectrum of patients. Early diagnostic of GVHD is essential to initiate treatment as soon as possible. Unfortunately, the diagnosis of GVHD may be difficult to establish, because of the nonspecific nature of the associated symptoms and of the numerous differential diagnosis. This is particularly true regarding gastrointestinal (GI acute GVHD. In the recent years many progress has been made in medical imaging test and endoscopic techniques. The interest of these different techniques in the diagnosis of GI acute GVHD has been evaluated in several studies. With this background we review the contributions, limitations, and future prospect of these techniques in the diagnosis of GI acute GVHD.

  13. Acute graft-versus-host disease of the gut: considerations for the gastroenterologist.

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    Naymagon, Steven; Naymagon, Leonard; Wong, Serre-Yu; Ko, Huaibin Mabel; Renteria, Anne; Levine, John; Colombel, Jean-Frederic; Ferrara, James

    2017-12-01

    Haematopoietic stem cell transplantation (HSCT) is central to the management of many haematological disorders. A frequent complication of HSCT is acute graft-versus-host disease (GVHD), a condition in which immune cells from the donor attack healthy recipient tissues. The gastrointestinal system is among the most common sites affected by acute GVHD, and severe manifestations of acute GVHD of the gut portends a poor prognosis in patients after HSCT. Acute GVHD of the gastrointestinal tract presents both diagnostic and therapeutic challenges. Although the clinical manifestations are nonspecific and overlap with those of infection and drug toxicity, diagnosis is ultimately based on clinical criteria. As reliable serum biomarkers have not yet been validated outside of clinical trials, endoscopic and histopathological evaluation continue to be utilized in diagnosis. Once a diagnosis of gastrointestinal acute GVHD is established, therapy with systemic corticosteroids is typically initiated, and non-responders can be treated with a wide range of second-line therapies. In addition to treating the underlying disease, the management of complications including profuse diarrhoea, severe malnutrition and gastrointestinal bleeding is paramount. In this Review, we discuss strategies for the diagnosis and management of acute GVHD of the gastrointestinal tract as they pertain to the practising gastroenterologist.

  14. IL-35 mitigates murine acute graft-versus-host disease with retention of graft-versus-leukemia effects.

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    Liu, Y; Wu, Y; Wang, Y; Cai, Y; Hu, B; Bao, G; Fang, H; Zhao, L; Ma, S; Cheng, Q; Song, Y; Liu, Y; Zhu, Z; Chang, H; Yu, X; Sun, A; Zhang, Y; Vignali, D A A; Wu, D; Liu, H

    2015-04-01

    IL-35 is a newly discovered inhibitory cytokine secreted by regulatory T cells (Tregs) and may have therapeutic potential in several inflammatory disorders. Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation and caused by donor T cells and inflammatory cytokines. The role of IL-35 in aGVHD is still unknown. Here we demonstrate that IL-35 overexpression suppresses CD4(+) effector T-cell activation, leading to a reduction in alloreactive T-cell responses and aGVHD severity. It also leads to the expansion of CD4(+)Foxp3(+) Tregs in the aGVHD target organs. Furthermore, IL-35 overexpression results in a selective decrease in the frequency of Th1 cells and an increase of IL-10-producing CD4(+) T cells in aGVHD target tissues. Serum levels of TNF-α, IFN-γ, IL-6, IL-22 and IL-23 decrease and IL-10 increases in response to IL-35. Most importantly, IL-35 preserves graft-versus-leukemia effect. Finally, aGVHD grade 2-4 patients have decreased serum IL-35 levels comparing with time-matched patients with aGVHD grade 0-1. Our findings indicate that IL-35 has an important role in reducing aGVHD through promoting the expansion of Tregs and repressing Th1 responses, and should be investigated as the therapeutic strategy for aGVHD.

  15. Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia

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    Baron, F; Labopin, M; Niederwieser, D

    2012-01-01

    This report investigated the impact of graft-versus-host disease (GVHD) on transplantation outcomes in 1859 acute myeloid leukemia patients given allogeneic peripheral blood stem cells after reduced-intensity conditioning (RIC allo-SCT). Grade I acute GVHD was associated with a lower risk...... of relapse (hazards ratio (HR)=0.7, P=0.02) translating into a trend for better overall survival (OS; HR=1.3; P=0.07). Grade II acute GVHD had no net impact on OS, while grade III-IV acute GVHD was associated with a worse OS (HR=0.4, P...

  16. Ibrutinib Effective against Graft-Versus-Host Disease

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    A Cancer Currents blog post on results from a small clinical trial showing that ibrutinib can effectively treat graft-versus-host-disease, a common and serious complication of allogeneic stem cell transplants.

  17. Fototerapia na doença enxerto contra hospedeiro Phototherapy in the graft versus host disease

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    Ida Duarte

    2008-10-01

    Full Text Available FUNDAMENTOS: A doença enxerto contra hospedeiro é um dos obstáculos ao sucesso do transplante de medula óssea, e o envolvimento cutâneo é freqüente. A fototerapia é utilizada devido à intensa atividade imunomoduladora local, sendo opção terapêutica adjuvante para as lesões cutâneas resistentes à terapia convencional. OBJETIVO: Realizar análise descritiva do tratamento da doença enxerto contra hospedeiro com fototerapia (Puva ou UVB de faixa estreita. MÉTODOS: Foram atendidos nove pacientes com manifestação cutânea da doença enxerto contra hospedeiro aguda ou crônica. Seis foram tratados com Puva, terapia de primeira escolha, e três com UVB de faixa estreita. As sessões foram realizadas três vezes por semana, e a resposta terapêutica avaliada após 12 sessões. RESULTADOS: Todos os pacientes com doença enxerto contra hospedeiro aguda mostraram melhora, com desaparecimento do eritema e do edema. Naqueles com doença crônica, observaram-se involução das lesões liquenóides e melhora da mobilidade daqueles com a forma esclerodermiforme. Dois pacientes apresentaram doença de evolução grave e foram a óbito. CONCLUSÃO: A fototerapia mostrou-se efetiva no tratamento das manifestações cutâneas da doença enxerto contra hospedeiro aguda e crônica. A Puva permite o controle da doença, podendo a UVB de faixa estreita ser opção para pacientes impossibilitados de usar medicação sistêmica.BACKGROUND: Graft versus host disease is one of the obstacles to successful bone marrow transplantation. It often affects the skin. Phototherapy has been used because of its strong local immunomodulatory activity and it is an option for adjuvant therapy for skin lesions of graft versus host disease resistant to conventional therapy. OBJECTIVE: To make a descriptive analysis of treating graft versus host disease with phototherapy (PUVA or narrowband UVB. Methods - Nine patients with cutaneous manifestation of acute or chronic

  18. The Role of Programmed Cell Death Ligand-1 (PD-L1/CD274) in the Development of Graft versus Host Disease

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    Al-Chaqmaqchi, Heevy; Sadeghi, Behnam; Abedi-Valugerdi, Manuchehr; Al-Hashmi, Sulaiman; Fares, Mona; Kuiper, Raoul; Lundahl, Joachim

    2013-01-01

    Programmed cell death ligand-1 (PD-L1/CD274) is an immunomodulatory molecule involved in cancer and complications of bone marrow transplantation, such as graft rejection and graft-versus-host disease. The present study was designed to assess the dynamic expression of this molecule after hematopoietic stem cell transplantation in relation to acute graft-versus-host disease. Female BALB/c mice were conditioned with busulfan and cyclophosphamide and transplanted with either syngeneic or allogeneic (male C57BL/6 mice) bone marrow and splenic cells. The expression of PD-L1 was evaluated at different time points employing qPCR, western blot and immunohistochemistry. Allogeneic- but not syngeneic-transplanted animals exhibited a marked up-regulation of PD-L1 expression in the muscle and kidney, but not the liver, at days 5 and 7 post transplantation. In mice transplanted with allogeneic bone marrow cells, the enhanced expression of PD-L1 was associated with high serum levels of IFNγ and TNFα at corresponding intervals. Our findings demonstrate that PD-L1 is differently induced and expressed after allogeneic transplantation than it is after syngeneic transplantation, and that it is in favor of target rather than non-target organs at the early stages of acute graft-versus-host disease. This is the first study to correlate the dynamics of PD-L1 at the gene-, protein- and activity levels with the early development of acute graft-versus-host disease. Our results suggest that the higher expression of PD-L1 in the muscle and kidney (non-target tissues) plays a protective role in skeletal muscle during acute graft-versus-host disease. PMID:23593203

  19. Pharmacogenetics of steroid-responsive acute graft-versus-host disease.

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    Arora, Mukta; Weisdorf, Daniel J; Shanley, Ryan M; Thyagarajan, Bharat

    2017-05-01

    Glucocorticoids are central to effective therapy of acute graft-versus-host disease (GVHD). However, only about half of the patients respond to steroids in initial therapy. Based on postulated mechanisms for anti-inflammatory effectiveness, we explored genetic variations in glucocorticoid receptor, co-chaperone proteins, membrane transporters, inflammatory mediators, and variants in the T-cell receptor complex in hematopoietic cell transplant recipients with acute GVHD requiring treatment with steroids and their donors toward response at day 28 after initiation of therapy. A total of 300 recipient and donor samples were analyzed. Twenty-three SNPs in 17 genes affecting glucocorticoid pathways were included in the analysis. In multiple regression analysis, donor SNP rs3192177 in the ZAP70 gene (O.R. 2.8, 95% CI: 1.3-6.0, P=.008) and donor SNP rs34471628 in the DUSPI gene (O.R. 0.3, 95% CI: 0.1-1.0, P=.048) were significantly associated with complete or partial response. However, after adjustment for multiple testing, these SNPs did not remain statistically significant. Our results, on this small, exploratory, hypothesis generating analysis suggest that common genetic variation in glucocorticoid pathways may help identify subjects with differential response to glucocorticoids. This needs further assessment in larger datasets and if validated could help identify subjects for alternative treatments and design targeted treatments to overcome steroid resistance. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Hydrogen, a potential safeguard for graft-versus-host disease and graft ischemia-reperfusion injury?

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    Yuan, Lijuan; Shen, Jianliang

    2016-01-01

    Post-transplant complications such as graft-versus-host disease and graft ischemia-reperfusion injury are crucial challenges in transplantation. Hydrogen can act as a potential antioxidant, playing a preventive role against post-transplant complications in animal models of multiple organ transplantation. Herein, the authors review the current literature regarding the effects of hydrogen on graft ischemia-reperfusion injury and graft-versus-host disease. Existing data on the effects of hydrogen on ischemia-reperfusion injury related to organ transplantation are specifically reviewed and coupled with further suggestions for future work. The reviewed studies showed that hydrogen (inhaled or dissolved in saline) improved the outcomes of organ transplantation by decreasing oxidative stress and inflammation at both the transplanted organ and the systemic levels. In conclusion, a substantial body of experimental evidence suggests that hydrogen can significantly alleviate transplantation-related ischemia-reperfusion injury and have a therapeutic effect on graft-versus-host disease, mainly via inhibition of inflammatory cytokine secretion and reduction of oxidative stress through several underlying mechanisms. Further animal experiments and preliminary human clinical trials will lay the foundation for hydrogen use as a drug in the clinic. PMID:27652837

  1. T-cell chimerism is valuable in predicting early mortality in steroid-resistant acute graft-versus-host disease after myeloablative allogeneic cell transplantation

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    Minculescu, Lia; Madsen, Hans O.; Sengeløv, Henrik

    2014-01-01

    The main aim of this study was to evaluate the impact of early T-cell chimerism status on the incidence and clinical course of acute graft-versus-host disease (aGVHD) in allogeneic transplant recipients after myeloablative conditioning. Of 62 patients, 38 (61%) had complete T-cell donor chimerism...

  2. Pneumatosis cystoides interstitialis: A complication of graft-versus-host disease. A report of two cases.

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    Laskowska, Katarzyna; Burzyńska-Makuch, Małgorzata; Krenska, Anna; Kołtan, Sylwia; Chrupek, Małgorzata; Nawrocka, Elżbieta; Lasek, Władysław; Serafin, Zbigniew

    2012-04-01

    Pneumatosis cystoides intestinalis (PCI) is a rare disorder characterized by the presence of multiple gas collections in the subserosal or submucosal intestinal wall of the large or small intestine. We report two cases of PCI in the course of chronic graft-versus-host disease. A 5-year-old girl was treated for acute lymphoblastic leukemia. Twenty-four months after the hematopoietic stem cell transplantation, in the course of graft-versus-host disease, she developed subcutaneous emphysema of the right inguinal and pudendal region. PCI was diagnosed based on a CT examination. A 3-year-old boy was treated for juvenile myelomonocytic leukemia. Fourteen months after the hematopoietic stem cell transplantation he presented with an increased severity of intestinal symptoms, including intermittent bleeding from large intestine. PCI was diagnosed based on a CT exam and was confirmed by a colonoscopy. Pneumatosis cystoides interstitialis in the course of chronic graft-versus-host disease has a heterogeneous clinical presentation that does not correlate with results of imaging. CT is a method of choice to diagnose PCI. In patients with PCI, the presence of free air in the peritoneal cavity does not confirm an intestinal perforation.

  3. Pneumatosis cystoides interstitialis: A complication of graft-versus-host disease. A report of two cases

    International Nuclear Information System (INIS)

    Laskowska, Katarzyna; Burzyńska-Makuch, Małgorzata; Krenska, Anna; Kołtan, Sylwia; Chrupek, Małgorzata; Nawrocka, Elżbieta; Lasek, Władysław; Serafin, Zbigniew

    2012-01-01

    Pneumatosis cystoides intestinalis (PCI) is a rare disorder characterized by the presence of multiple gas collections in the subserosal or submucosal intestinal wall of the large or small intestine. We report two cases of PCI in the course of chronic graft-versus-host disease. A 5-year-old girl was treated for acute lymphoblastic leukemia. Twenty-four months after the hematopoietic stem cell transplantation, in the course of graft-versus-host disease, she developed subcutaneous emphysema of the right inguinal and pudendal region. PCI was diagnosed based on a CT examination. A 3-year-old boy was treated for juvenile myelomonocytic leukemia. Fourteen months after the hematopoietic stem cell transplantation he presented with an increased severity of intestinal symptoms, including intermittent bleeding from large intestine. PCI was diagnosed based on a CT exam and was confirmed by a colonoscopy. Pneumatosis cystoides interstitialis in the course of chronic graft-versus-host disease has a heterogeneous clinical presentation that does not correlate with results of imaging. CT is a method of choice to diagnose PCI. In patients with PCI, the presence of free air in the peritoneal cavity does not confirm an intestinal perforation

  4. Characterization of Regulatory Dendritic Cells That Mitigate Acute Graft-versus-Host Disease in Older Mice Following Allogeneic Bone Marrow Transplantation

    OpenAIRE

    Scroggins, Sabrina M.; Olivier, Alicia K.; Meyerholz, David K.; Schlueter, Annette J.

    2013-01-01

    Despite improvements in human leukocyte antigen matching and pharmacologic prophylaxis, acute graft-versus-host disease (GVHD) is often a fatal complication following hematopoietic stem cell transplant (HSCT). Older HSCT recipients experience significantly increased morbidity and mortality compared to young recipients. Prophylaxis with syngeneic regulatory dendritic cells (DCreg) in young bone marrow transplanted (BMT) mice has been shown to decrease GVHD-associated mortality. To evaluate thi...

  5. Homecare-based motor rehabilitation in musculoskeletal chronic graft versus host disease

    Directory of Open Access Journals (Sweden)

    A Tendas

    2011-01-01

    Full Text Available Chronic graft versus host disease (cGVHD is a frequent complication of allogeneic stem cell transplantation. Extensive musculoskeletal and skin involvement may induce severe functional impairment, disability and quality of life deterioration. Physical rehabilitation is recommended as ancillary therapy in these forms, but experiences are sparse. A 39-year-old man affected by musculoskeletal and skin chronic graft versus host disease (cGVHD was treated with a homecare-based motor rehabilitation program during palliation for disease progression. Significant functional improvement was obtained. Motor rehabilitation should be strongly considered for patients with musculoskeletal cGVHD, both in the palliative and in the curative phase of disease.

  6. Steroid treatment of acute graft-versus-host disease grade I: a randomized trial.

    Science.gov (United States)

    Bacigalupo, Andrea; Milone, Giuseppe; Cupri, Alessandra; Severino, Antonio; Fagioli, Franca; Berger, Massimo; Santarone, Stella; Chiusolo, Patrizia; Sica, Simona; Mammoliti, Sonia; Sorasio, Roberto; Massi, Daniela; Van Lint, Maria Teresa; Raiola, Anna Maria; Gualandi, Francesca; Selleri, Carmine; Sormani, Maria Pia; Signori, Alessio; Risitano, Antonio; Bonifazi, Francesca

    2017-12-01

    Patients with acute graft- versus -host disease (GvHD) grade I were randomized to an observation arm (n=85) or to a treatment arm (n=86) consisting of 6-methylprednisolone 1 mg/kg/day, after stratification for age and donor type. The primary end point was development of grade II-IV GvHD. The cumulative incidence of grade II-IV GvHD was 50% in the observation arm and 33% in the treatment arm ( P =0.005). However, grade III-IV GvHD was comparable (13% vs 10%, respectively; P =0.6), and this was true for sibling and alternative donor transplants. Moderate/severe chronic GvHD was also comparable (17% vs 9%). In multivariate analysis, an early interval between transplant and randomization (versus 26% ( P =0.2), relapse-related mortality 25% versus 21%, and actuarial survival was 51% versus 41% ( P =0.3) in the observation and treatment arms, respectively. In multivariate analysis, advanced disease phase, older age and an early onset of GvHD were significant negative predictors of survival, independent of the randomization arm. In conclusion, steroid treatment of acute grade I GvHD prevents progression to grade II but not to grade III-IV GvHD, and there is no effect on non-relapse mortality and survival. Patients treated with steroids are at a higher risk of developing infections and have more adverse events. ( Trial registered as EUDTRACT 2008-000413-29 ). Copyright© 2017 Ferrata Storti Foundation.

  7. Wireless capsule endoscopy for diagnosis of acute intestinal graft-versus-host disease.

    Science.gov (United States)

    Neumann, Susanne; Schoppmeyer, Konrad; Lange, Thoralf; Wiedmann, Marcus; Golsong, Johannes; Tannapfel, Andrea; Mossner, Joachim; Niederwieser, Dietger; Caca, Karel

    2007-03-01

    The small intestine is the most common location of intestinal graft-versus-host disease (GVHD). EGD with duodenal biopsies yields the highest diagnostic sensitivity, but the jejunum and ileum are not accessible by regular endoscopy. In contrast, wireless capsule endoscopy (WCE) is a noninvasive imaging procedure offering complete evaluation of the small intestine. The objective was to compare the diagnostic value of EGD, including biopsies, with the results of WCE in patients with acute intestinal symptoms who received allogeneic blood stem cell transplantation and to analyze the appearance and distribution of acute intestinal GVHD lesions in these patients. An investigator-blinded, single-center prospective study. Patients with acute intestinal symptoms after allogeneic stem cell transplantation underwent both EGD and WCE within 24 hours. Clinical data were recorded during 2 months of follow-up. Fourteen consecutive patients with clinical symptoms of acute intestinal GVHD were recruited. In 1 patient, the capsule remained in the stomach and was removed endoscopically. In 7 of 13 patients who could be evaluated, acute intestinal GVHD was diagnosed by EGD with biopsies, but 3 of these would have been missed by EGD alone. In all 7 patients with histologically confirmed acute intestinal GVHD, WCE revealed typical signs of GVHD. Lesions were scattered throughout the small intestine, but were most accentuated in the ileum. This study had a small number of patients. WCE, which is less invasive than EGD with biopsies, showed a comparable sensitivity and a high negative predictive value for diagnosing acute intestinal GVHD. It may be helpful to avoid repeated endoscopic procedures in patients who have undergone stem cell transplantation.

  8. Graft irradiation abrogates graft-versus-host disease in combined pancreas-spleen transplantation

    International Nuclear Information System (INIS)

    Schulak, J.A.; Sharp, W.J.

    1986-01-01

    A model of combined pancreas-spleen transplantation (PST) was studied in LBN F1 recipients of Lewis grafts in order to evaluate the efficacy of pretransplant graft irradiation in preventing lethal graft-versus-host disease (GVHD). Recipients of unmodified PST uniformly developed severe GVHD and died (MST = 16.7 +/- 3.8 days). Whole body donor irradiation with either 500 or 250 rad prevented lethal GVHD. Similarly, ex vivo graft irradiation with either 1000 or 500 rad also resulted in normal weight gain, graft function, and host survival for the 6-week study period. Conversely, delay of graft irradiation until 3 days after transplantation failed to prevent this complication (MST = 15.8 +/- 3.7 days). Recipients of irradiated grafts displayed glucose tolerance tests that were identical to those in the control group indicating that the doses of radiation employed in these experiments were not deleterious to islet function. Irradiated spleen grafts appeared histologically normal at 6 weeks after transplantation. Cells derived from these grafts failed to stimulate lymph node enlargement in a popliteal lymph node assay for GVHD, suggesting that these spleens may have become repopulated with host cells. These experiments confirm that PST has the potential to cause lethal GVHD and suggest that pretransplant graft irradiation may be used to prevent its occurrence

  9. Vulvovaginal Graft-Versus-Host Disease.

    Science.gov (United States)

    Kornik, Rachel I; Rustagi, Alison S

    2017-09-01

    Vulvovaginal chronic graft-versus-host disease (cGVHD) is an underrecognized complication of stem cell transplantation. Early recognition may prevent severe sequelae. Genital involvement is associated with oral, ocular, and skin manifestations. Treatment includes topical immunosuppression, dilator use, and adjuvant topical estrogen. Clinical and histologic features may mimic other inflammatory vulvar conditions. In the right clinical context, these findings are diagnostic of chronic GVHD. Female recipients of allo-hematopoietic stem cell transplantation (HCT) are at higher risk of condylomas, cervical dysplasia, and neoplasia. The National Institutes of Health publishes guidelines for the diagnosis, grading, management, and supportive care for HCT patients by organ system. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Early and late oral features of chronic graft-versus-host disease

    Directory of Open Access Journals (Sweden)

    Alessandra Oliveira Ferrari Gomes

    2014-01-01

    Full Text Available Background: Chronic graft-versus-host disease is a serious complication of allogeneic hematopoietic cell transplantation, and the mouth is one of the affected sites. Objective: The aim of this study was to evaluate the oral features of this disease after hematopoietic cell transplantation. Methods: This was a cross-sectional multicenter study that enrolled patients submitted to transplantation. Oral evaluations used the National Institutes of Health criteria, salivary flow rates, and the range of mouth opening. Pain and xerostomia were evaluated through a visual analogue scale. Patients were divided into two groups based on the transplantation time (up to one year and more than one year. Results: Of the 57 evaluated recipients, 44 had chronic graft-versus-host disease: ten (22.72% in the group with less than one year after transplantation, and 34 (77.27% in the group with more than one year after transplantation. Lichenoid/hyperkeratotic plaques, erythematous lesions, xerostomia, and hyposalivation were the most commonly reported oral features. Lichenoid/hyperkeratotic plaques were significantly more common in patients within the first year after the transplant. The labial mucosa was affected more in the first year. No significant changes occurred in the frequency of xerostomia, hyposalivation, and reduced mouth opening regarding time after transplantation. Conclusion: Oral chronic graft-versus-host disease lesions were identified early in the course of the disease. The changes observed in salivary gland function and in the range of mouth opening were not correlated with the time after transplantation.

  11. Transfusion-associated graft-versus-host disease

    International Nuclear Information System (INIS)

    Rappeport, J.M.

    1990-01-01

    The clinical pathologic syndrome of graft-versus-host disease (GVHD) is usually a sequela of bone marrow transplantation. This disorder occurs as a result of recognition by engrafted donor-derived lymphocytes of foreign recipient transplantation antigens. GVHD may also result from engraftment of lymphocytes from other sources, including (1) transfusion of lymphocytes containing blood components, (2) transplacental maternal fetal transfusion, and (3) passive transfer of lymphocytes in solid organ transplantation. The recipients are usually severely immunodeficient and thus incapable of rejecting the transfused lymphocytes. This syndrome may, however, also develop in immunologically competent patients receiving blood products from individuals with histocompatibility antigens not recognized as foreign. 58 refs

  12. Pentraxin 3 plasma levels at graft-versus-host disease onset predict disease severity and response to therapy in children given haematopoietic stem cell transplantation

    OpenAIRE

    Dander, Erica; De Lorenzo, Paola; Bottazzi, Barbara; Quarello, Paola; Vinci, Paola; Balduzzi, Adriana; Masciocchi, Francesca; Bonanomi, Sonia; Cappuzzello, Claudia; Prunotto, Giulia; Pavan, Fabio; Pasqualini, Fabio; Sironi, Marina; Cuccovillo, Ivan; Leone, Roberto

    2016-01-01

    Acute Graft-versus-Host Disease (GvHD) remains a major complication of allogeneic haematopoietic stem cell transplantation, with a significant proportion of patients failing to respond to first-line systemic corticosteroids. Reliable biomarkers predicting disease severity and response to treatment are warranted to improve its management. Thus, we sought to determine whether pentraxin 3 (PTX3), an acute-phase protein produced locally at the site of inflammation, could represent a novel acute G...

  13. Cyclosporin-Methotrexate Compared with Cyclosporin-Methotrexate-Methylprednisolone Therapy for the Prophylaxis of Acute Graft-Versus Host Disease

    International Nuclear Information System (INIS)

    Khattab, N.F.

    2010-01-01

    Acute graft-versus host (GVHD) disease is a common immunologic complication, which occurs in 40-50% of the recipients of allogenic stem cell transplantation (SCT). The role of corticosteroid in the prevention of GVHD is not well established. We report here a study to determine whether the addition of methylprednisolone to the combination of cyclosporine (CSA) and methotrexate (MTX), methylp-rednisolone (MP) for the prophylaxis of acute GVHD would further decrease the incidence of acute GVHD. A group of patients (25 patients with acute myeloid leukemia (AML) and 12 patients with acute lymphocytic leukemia (ALL) that received CSA/MTX/MP started from 2004 to 2008, were compared to a historical group of patients (19 patient with acute myeloid leukemia (AML) and 12 patients with acute lymphocytic leukemia (ALL) that received GVHD prophylaxis in the form of CSA/MTX only from 1999 to 2003). The primary endpoint in this study was the develop-ment of GVHD and the secondary end point was overall and disease free survival. Both groups of patients were matched for age, sex, donor recipient sex, low risk patients and high risk patients. Although the incidence of acute GVHD in the MP -ve group was 35% versus 24% in the MP+ve group, there was no significant difference between them. The overall survival showed a significant difference between the 2 groups (p<0.05). It was 48% for the 2 drug regimen (CSA/MTX) vs. 81% for the three drug regimen (CSA/MTX/MP). There was a significant decrease in the relapse rate in patients on CSA/MTX/MP (p<0.05). In conclusion, the addition of MP (methylprednis-olone) to the combination of CSA/MTX did not affect the incidence of acute GVHD significantly in allogeneic SCT but surprisingly the incidence of survival and relapse was markedly increased and decreased respectively

  14. Viral infections in acute graft-versus-host disease: a review of diagnostic and therapeutic approaches.

    Science.gov (United States)

    Tong, Lana X; Worswick, Scott D

    2015-04-01

    While immunosuppressive therapy for acute graft-versus-host disease (aGVHD) advances, viral reactivation has been found to be an increasingly common complication in these patients. Dermatologists may often be consulted on inpatient services for evaluation. We investigated the literature for the role of viral infections in aGVHD and review the current evidence regarding management. Articles in the public domain regarding aGVHD, cytomegalovirus, Epstein-Barr virus, varicella zoster virus, hepatitis viruses, parvovirus B19, and respiratory viruses were included. Dermatologic findings vary between different viral antigens, and some infections may be a marker for the development of aGVHD or worsen prognosis. The heterogeneous cohorts of the studies reviewed often preclude direct comparison between results. The relationship between viral reactivation and aGVHD may be bidirectional and is worthy of further exploration. Additional studies are needed to determine appropriate prophylaxis and treatment. Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  15. A Critical Appraisal of Extracorporeal Photopheresis as a Treatment Modality for Acute and Chronic Graft-Versus-Host Disease

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    Hind Rafei

    2017-10-01

    Full Text Available Although significant advances have been made in the biologic understanding of graft-versus-host disease (GVHD and its treatment options, GVHD remains the single most challenging obstacle to the success of allogeneic hematopoietic cell transplantation (HCT due to high risk of disabling morbidity and mortality. Extracorporeal photopheresis (ECP has promising effects in controlling steroid-refractory GVHD, both acute and chronic, and it has been studied extensively. Its putative immunomodulatory mechanisms, while not immunosuppressive, position ECP as an attractive treatment strategy for GVHD patients who are already receiving global immunosuppression. However, ECP is relatively underutilized due in part to limited access and time commitment. Here, we review the recent findings on the ECP efficacy in both acute and chronic GVHD, primarily for steroid-refractory status, and we critically appraise its benefits. We also explore salient considerations on the optimal use of ECP in the treatment of refractory GVHD.

  16. Does defibrotide prophylaxis decrease the risk of acute graft versus host disease following allogeneic hematopoietic cell transplantation?

    Science.gov (United States)

    Tekgündüz, Emre; Kaya, Ali Hakan; Bozdağ, Sinem Civriz; Koçubaba, Şerife; Kayıkçı, Ömür; Namdaroğlu, Sinem; Uğur, Bilge; Akpınar, Seval; Batgi, Hikmetullah; Bekdemir, Filiz; Altuntaş, Fevzi

    2016-02-01

    There is some preliminary evidence, that veno-occlusive disease prophylaxis with defibrotide (DF) may also have a role in decreasing risk of acute graft-versus-host disease (aGvHD) by preventing tissue damage. In this study, we aimed to investigate the role of DF prophylaxis on the development of aGvHD at D+180. One hundred ninety-five consecutive adult patients receiving allogeneic HCT were retrospectively evaluated in 3 groups: no DF, DF/post-HCT (DF D+1 to D+14) and DF/pre-HCT (DF for 14 days concurrently with conditioning). The total (p: 0.057) and grades III/IV (p: 0.051) aGvHD rates at D+180 were 46.5%, 40%, 25.5% and 15.5%, 11.2%, 0% in patients on no DF, DF/post-HCT and DF/pre-HCT. DF may have a role in decreasing incidence and severity of aGvHD, especially if used concurrently with conditioning regimen. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Altered T-cell entry and egress in the absence of Coronin 1A attenuates murine acute graft versus host disease.

    Science.gov (United States)

    Fulton, LeShara M; Taylor, Nicholas A; Coghill, James M; West, Michelle L; Föger, Niko; Bear, James E; Baldwin, Albert S; Panoskaltsis-Mortari, Angela; Serody, Jonathan S

    2014-06-01

    Acute graft-versus-host disease (aGvHD) is a major limitation to the use of allogeneic stem cell transplantation for the treatment of patients with relapsed malignant disease. Previous work using animals lacking secondary lymphoid tissue (SLT) suggested that activation of donor T cells in SLT is critically important for the pathogenesis of aGvHD. However, these studies did not determine if impaired migration into, and more importantly, out of SLT, would ameliorate aGvHD. Here, we show that T cells from mice lacking Coronin 1A (Coro 1A(-/-)), an actin-associated protein shown to be important for thymocyte egress, do not mediate acute GvHD. The attenuation of aGvHD was associated with decreased expression of the critical trafficking proteins C-C chemokines receptor type 7 (CCR7) and sphingosine 1 phosphate receptor on donor T cells. This was mediated in part by impaired activation of the canonical NF-κB pathway in the absence of Coro 1A. As a result of these alterations, donor T cells from Coro 1A(-/-) mice were not able to initially traffic to SLT or exit SLT after BM transplantation. However, this alteration did not abrogate the graft-versus-leukemia response. Our data suggest that blocking T-cell migration into and out of SLT is a valid approach to prevent aGvHD. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Brazilian status in blood irradiation in Graft-Versus-Host Disease (GVHD) prevention

    International Nuclear Information System (INIS)

    Goes, E.G. de; Borges, J.C.; Ghilardi Netto, T.

    1996-01-01

    A short overview of the Brazilian reality concerning Graft-Versus-Host Disease (GVHD) is presented. Suggestions of policies and procedures to optimise GVHD prevention are reported. A national irradiator device using cobalt teletherapy unit is proposed for irradiation of blood and cellular components

  19. Chronic graft versus host disease and nephrotic syndrome

    Directory of Open Access Journals (Sweden)

    Samia Barbouch

    2014-01-01

    Full Text Available Disturbed kidney function is a common complication after bone marrow transplantation. Recently, attention has been given to immune-mediated glomerular damage related to graft versus host disease (GVHD. We describe a 19-year-old woman who developed membranous glomerulonephritis after bone marrow transplantation (BMT. Six months later, she developed soft palate, skin and liver lesions considered to be chronic GVHD. Fifteen months after undergoing BMT, this patient presented with nephrotic syndrome. A renal biopsy showed mem-branous glomerulonephritis associated with a focal segmental glomerulosclerosis. She was started on corticosteroid treatment with good outcome.

  20. Use of the National Institutes of Health Consensus Guidelines Improves the Diagnostic Sensitivity of Gastrointestinal Graft-Versus-Host Disease.

    Science.gov (United States)

    Cardona, Diana M; Detweiler, Claire J; Shealy, Michael J; Sung, Anthony D; Wild, Daniel M; Poleski, Martin H; Balmadrid, Bryan L; Cirrincione, Constance T; Howell, David N; Sullivan, Keith M

    2018-04-26

    - Graft-versus-host disease of the gastrointestinal tract is a common complication of hematopoietic stem cell transplant associated with significant morbidity and mortality. Accurate diagnosis can be difficult and is a truly clinicopathologic endeavor. - To assess the diagnostic sensitivity of gastrointestinal graft-versus-host disease using the 2015 National Institutes of Health (NIH) histology consensus guidelines and to analyze histologic findings that support the guidelines. - Patients with allogeneic hematopoietic stem cell transplants were identified via a retrospective search of our electronic medical record from January 1, 2005, to January 1, 2011. Endoscopies with available histology were reviewed by 2 pathologists using the 2015 NIH guidelines. The clinical diagnosis was used as the gold standard. A nontransplant set of endoscopic biopsies was used as a control. - Of the 250 total endoscopies, 217 (87%) had a clinical diagnosis of gastrointestinal graft-versus-host disease. Use of the NIH consensus guidelines showed a sensitivity of 86% and a specificity of 65%. Thirty-seven of 58 (64%) cases with an initial false-negative histopathologic diagnosis were diagnosed as graft-versus-host disease on our review. - Use of the NIH histology consensus guidelines results in a high sensitivity and specificity, thereby decreasing false-negatives. Additionally, use of the NIH guidelines aids in creating uniformity and diagnostic clarity. Correlation with clinical and laboratory findings is critical in evaluating the differential diagnosis and to avoid false-positives. As expected, increased apoptosis with decreased inflammation was associated with a pathologic diagnosis of graft-versus-host disease and supports the NIH guidelines.

  1. Economic evaluation of posaconazole versus fluconazole prophylaxis in patients with graft-versus-host disease (GVHD) in the Netherlands

    NARCIS (Netherlands)

    J.P. Jansen (Jeroen); A.K. O'Sullivan (Amy); P.J. Lugtenburg (Pieternella); L.F.R. Span (Lambert); J.J.W.M. Janssen (Jeroen); W.B. Stam (Wiro)

    2010-01-01

    textabstractThe objective of this study was to evaluate the cost-effectiveness of posaconazole versus fluconazole for the prevention of invasive fungal infections (IFI) in graft-versus-host disease (GVHD) patients in the Netherlands. A decision analytic model was developed based on a double-blind

  2. GRAFT VERSUS HOST DISEASE- ORAL PRESENTATION

    Directory of Open Access Journals (Sweden)

    Pradeep P. S

    2017-09-01

    Full Text Available BACKGROUND Graft-versus-host disease (GVHD is described as a potentially life-threatening complication caused by allogeneic haematopoietic cell transplantation. It is an exaggerated manifestation of a normal inflammatory mechanism in which donor lymphocytes encounter foreign antigens in an atmosphere that promote inflammation. 90% of the patients show oral features in case of cGVHD. Oral mucosal lesions and salivary gland dysfunction are the main oral features of chronic GVHD. Trismus or reduction of the mouth opening due to the perioral deposition of collagen is also commonly seen. Purpose of this review is to understand pathophysiology of oral presentations of GVHD. MATERIALS AND METHODS Review related to GVHD pathophysiology, oral lesions after haematopoietic cell transplant encompassed literature from 1966 through 2015. Review of Medline/PubMed Journals were done. RESULTS It is difficult to describe the pathophysiology of oral manifestations because there is no well accepted definition. CONCLUSION Larger well-designed clinical studies are needed to understand the pathobiology of oral cGVHD and determine best treatments for this disease.

  3. [Extracorporeal photopheresis as an alternative therapy for drug-resistant graft versus host disease: three cases].

    Science.gov (United States)

    D'incan, M; Kanold, J; Halle, P; De Lumley, L; Souteyrand, P; Deméocq, F

    2000-02-01

    Graft versus host reaction is a life-threatening complication of allogenic bone marrow transplantation. Extracorporeal photopheresis has been used for some years in the treatment of graft versus host reaction. We report on three children treated with extracorporeal photopheresis for a graft versus host reaction resistant to immunosuppresive drugs. Three children with a graft versus host reaction were submitted to 18, 30 and 46 extracorporeal photopheresis courses respectively. In the same time, the other immunosuppressive treatments were tapered or definitively stopped (ciclosporin). A dramatic improvement of cutaneous status and biological data was observed after the first courses. However, the extracorporeal photopheresis treatment did not improve the mucous lesions. No serious adverse effect was encountered. As published elsewhere, extracorporeal photopheresis was effective on the graft versus host reaction lichenoid cutaneous lesions and in case of visceral involvement. In all of our cases, the immunosuppressive drug could have been tapered. No adverse event was observed. Thus, extracorporeal photopheresis should be indicated in case of resistance to immunosuppressive drugs.

  4. Ceacam1 separates graft-versus-host-disease from graft-versus-tumor activity after experimental allogeneic bone marrow transplantation.

    Directory of Open Access Journals (Sweden)

    Sydney X Lu

    Full Text Available Allogeneic bone marrow transplantation (allo-BMT is a potentially curative therapy for a variety of hematologic diseases, but benefits, including graft-versus-tumor (GVT activity are limited by graft-versus-host-disease (GVHD. Carcinoembryonic antigen related cell adhesion molecule 1 (Ceacam1 is a transmembrane glycoprotein found on epithelium, T cells, and many tumors. It regulates a variety of physiologic and pathological processes such as tumor biology, leukocyte activation, and energy homeostasis. Previous studies suggest that Ceacam1 negatively regulates inflammation in inflammatory bowel disease models.We studied Ceacam1 as a regulator of GVHD and GVT after allogeneic bone marrow transplantation (allo-BMT in mouse models. In vivo, Ceacam1(-/- T cells caused increased GVHD mortality and GVHD of the colon, and greater numbers of donor T cells were positive for activation markers (CD25(hi, CD62L(lo. Additionally, Ceacam1(-/- CD8 T cells had greater expression of the gut-trafficking integrin α(4β(7, though both CD4 and CD8 T cells were found increased numbers in the gut post-transplant. Ceacam1(-/- recipients also experienced increased GVHD mortality and GVHD of the colon, and alloreactive T cells displayed increased activation. Additionally, Ceacam1(-/- mice had increased mortality and decreased numbers of regenerating small intestinal crypts upon radiation exposure. Conversely, Ceacam1-overexpressing T cells caused attenuated target-organ and systemic GVHD, which correlated with decreased donor T cell numbers in target tissues, and mortality. Finally, graft-versus-tumor survival in a Ceacam1(+ lymphoma model was improved in animals receiving Ceacam1(-/- vs. control T cells.We conclude that Ceacam1 regulates T cell activation, GVHD target organ damage, and numbers of donor T cells in lymphoid organs and GVHD target tissues. In recipients of allo-BMT, Ceacam1 may also regulate tissue radiosensitivity. Because of its expression on both the

  5. The Role of MicroRNAs in Myeloid Cells during Graft-versus-Host Disease

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    Sophia Chen

    2018-01-01

    Full Text Available The successful treatment of various hematologic diseases with allogeneic hematopoietic cell transplantation is often limited by the occurrence of graft-versus-host disease (GvHD. Several microRNAs (miRs have recently been shown to impact the biology of GvHD by regulating pro- as well as anti-inflammatory target genes. There is increasing evidence that a single miR can have different effects by preferentially targeting certain genes depending on the cell type that the miR is analyzed in. This review will focus on the role of miRs in myeloid cells during the development of acute and chronic GvHD and autoimmune diseases. Because miRs act on the expression of multiple target genes and may thereby influence the immune system at different functional levels, they are potentially attractive targets for the modification of allogeneic immune responses using miR mimics and inhibitors.

  6. Late acute graft-versus-host disease: a prospective analysis of clinical outcomes and circulating angiogenic factors.

    Science.gov (United States)

    Holtan, Shernan G; Khera, Nandita; Levine, John E; Chai, Xiaoyu; Storer, Barry; Liu, Hien D; Inamoto, Yoshihiro; Chen, George L; Mayer, Sebastian; Arora, Mukta; Palmer, Jeanne; Flowers, Mary E D; Cutler, Corey S; Lukez, Alexander; Arai, Sally; Lazaryan, Aleksandr; Newell, Laura F; Krupski, Christa; Jagasia, Madan H; Pusic, Iskra; Wood, William; Renteria, Anne S; Yanik, Gregory; Hogan, William J; Hexner, Elizabeth; Ayuk, Francis; Holler, Ernst; Watanaboonyongcharoen, Phandee; Efebera, Yvonne A; Ferrara, James L M; Panoskaltsis-Mortari, Angela; Weisdorf, Daniel; Lee, Stephanie J; Pidala, Joseph

    2016-11-10

    Late acute (LA) graft-versus-host disease (GVHD) is persistent, recurrent, or new-onset acute GVHD symptoms occurring >100 days after allogeneic hematopoietic cell transplantation (HCT). The aim of this analysis is to describe the onset, course, morbidity, and mortality of and examine angiogenic factors associated with LA GVHD. A prospective cohort of patients (n = 909) was enrolled as part of an observational study within the Chronic GVHD Consortium. Eighty-three patients (11%) developed LA GVHD at a median of 160 (interquartile range, 128-204) days after HCT. Although 51 out of 83 (61%) achieved complete or partial response to initial therapy by 28 days, median failure-free survival was only 7.1 months (95% confidence interval, 3.4-19.1 months), and estimated overall survival (OS) at 2 years was 56%. Given recently described alterations of circulating angiogenic factors in classic acute GVHD, we examined whether alterations in such factors could be identified in LA GVHD. We first tested cases (n = 55) and controls (n = 50) from the Chronic GVHD Consortium and then validated the findings in 37 cases from Mount Sinai Acute GVHD International Consortium. Plasma amphiregulin (AREG; an epidermal growth factor [EGF] receptor ligand) was elevated, and an AREG/EGF ratio at or above the median was associated with inferior OS and increased nonrelapse mortality in both cohorts. Elevation of AREG was detected in classic acute GVHD, but not chronic GVHD. These prospective data characterize the clinical course of LA GVHD and demonstrate alterations in angiogenic factors that make LA GVHD biologically distinct from chronic GVHD. © 2016 by The American Society of Hematology.

  7. International, multi-center standardization of acute graft-versus-host disease clinical data collection: a report from the MAGIC consortium

    Science.gov (United States)

    Harris, Andrew C.; Young, Rachel; Devine, Steven; Hogan, William J.; Ayuk, Francis; Bunworasate, Udomsak; Chanswangphuwana, Chantiya; Efebera, Yvonne A.; Holler, Ernst; Litzow, Mark; Ordemann, Rainer; Qayed, Muna; Renteria, Anne S.; Reshef, Ran; Wölfl, Matthias; Chen, Yi-Bin; Goldstein, Steven; Jagasia, Madan; Locatelli, Franco; Mielke, Stephan; Porter, David; Schechter, Tal; Shekhovtsova, Zhanna; Ferrara, James L.M.; Levine, John E.

    2015-01-01

    Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and non-relapse mortality following allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed upon by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multi-center clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance was following discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture which may improve the reproducibility of GVHD clinical trials after further prospective validation. PMID:26386318

  8. International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium.

    Science.gov (United States)

    Harris, Andrew C; Young, Rachel; Devine, Steven; Hogan, William J; Ayuk, Francis; Bunworasate, Udomsak; Chanswangphuwana, Chantiya; Efebera, Yvonne A; Holler, Ernst; Litzow, Mark; Ordemann, Rainer; Qayed, Muna; Renteria, Anne S; Reshef, Ran; Wölfl, Matthias; Chen, Yi-Bin; Goldstein, Steven; Jagasia, Madan; Locatelli, Franco; Mielke, Stephan; Porter, David; Schechter, Tal; Shekhovtsova, Zhanna; Ferrara, James L M; Levine, John E

    2016-01-01

    Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed on by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multicenter clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance followed discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture, which may improve the reproducibility of GVHD clinical trials after further prospective validation. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  9. Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial

    NARCIS (Netherlands)

    Choi, S.W.; Braun, T.; Chang, L.; Ferrara, J.L.; Pawarode, A.; Magenau, J.M.; Hou, G.; Beumer, J.H.; Levine, J.E.; Goldstein, S.; Couriel, D.R.; Stockerl-Goldstein, K.; Krijanovski, O.I.; Kitko, C.; Yanik, G.A.; Lehmann, M.H.; Tawara, I.; Sun, Y; Paczesny, S.; Mapara, M.Y.; Dinarello, C.A.; Dipersio, J.F.; Reddy, P.

    2014-01-01

    BACKGROUND: Acute graft-versus-host disease (GVHD) remains a barrier to more widespread application of allogeneic haemopoietic stem-cell transplantation. Vorinostat is an inhibitor of histone deacetylases and was shown to attenuate GVHD in preclinical models. We aimed to study the safety and

  10. OSI-027 modulates acute graft-versus-host disease after liver transplantation in a rat model.

    Science.gov (United States)

    Zhi, Xiao; Xue, Fei; Chen, Wei; Liang, Chao; Liu, Hao; Ma, Tao; Xia, Xuefeng; Hu, Liqiang; Bai, Xueli; Liang, Tingbo

    2017-09-01

    Despite its rarity (1%-2%), acute graft-versus-host disease after liver transplantation (LT-aGVHD) has a high mortality rate (85%). A gradual decrease in regulatory T cells (Tregs) correlates with disease progression in a rat LT-GVHD model, and treatments which increase Tregs exert therapeutic effects on LT-aGVHD. In this study, LT-aGVHD model rats were treated with rapamycin (RAPA), OSI-027, or an equal quantity of vehicle. Rats treated with OSI-027 survived longer (>100 days) than those in the RAPA (70 ± 8 days) or control (24 ± 3 days) groups. Flow cytometric analysis showed that the Treg ratios in peripheral blood mononuclear cells in the OSI-027 group were higher than those in the RAPA or control groups. The proportions of donor-derived lymphocytes in the OSI-027 group were lower than those in the RAPA or control groups. Hematoxylin-eosin staining of skin tissue demonstrated less severe lymphocyte infiltration in the OSI-027 group than that in the RAPA or control groups. In vitro, OSI-027 induced differentiation of CD4 + CD25 - T cells into CD4 + CD25 + forkhead box P3 + Tregs. Furthermore, injection of OSI-027-induced donor-derived CD4 + CD25 + T cells into the peripheral blood of LT-aGVHD model rats prevented LT-aGVHD. Thus, OSI-027 is implicated as a novel method for the treatment of LT-aGVHD. Liver Transplantation 23 1186-1198 2017 AASLD. © 2017 by the American Association for the Study of Liver Diseases.

  11. Idelalisib-induced colitis and skin eruption mimicking graft-versus-host disease.

    Science.gov (United States)

    Hammami, Muhammad Bader; Al-Taee, Ahmad; Meeks, Marshall; Fesler, Mark; Hurley, M Yadira; Cao, Dengfeng; Lai, Jin-Ping

    2017-04-01

    Idelalisib is a selective inhibitor of the delta isoform of phosphatidylinositol 3-kinase which was approved by the United States Federal Drug Administration in 2014 for the treatment of relapsed chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma. Drug-induced injury of the gastrointestinal tract is a relatively frequent but usually under-recognized disease entity. We report the case of a 56-year-old male with a history of relapsed follicular lymphoma status post allogenic bone marrow transplant who developed severe diarrhea with a skin eruption mimicking graft-versus-host disease (GVHD) 6 months after starting idelalisib. He underwent a colonoscopy demonstrating a grossly normal-appearing colon and terminal ileum. Biopsies taken during the procedure revealed mild active ileitis, colitis, and proctitis with frequent epithelial apoptosis, and focal intra-epithelial lymphocytosis. Skin biopsies revealed sub-acute spongiotic dermatitis suggestive of either contact dermatitis or an eczematous drug reaction. Symptoms were attributed to idelalisib given their resolution with withdrawal of the drug in conjunction with the skin and colonic biopsies. High clinical suspicion and awareness of the histological features of idelalisib-associated colitis is important to distinguish it from potential mimickers such as GVHD and infectious colitis.

  12. Advance in Targeted Immunotherapy for Graft-Versus-Host Disease

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    Lingling Zhang

    2018-05-01

    Full Text Available Graft-versus-host disease (GVHD is a serious and deadly complication of patients, who undergo hematopoietic stem cell transplantation (HSCT. Despite prophylactic treatment with immunosuppressive agents, 20–80% of recipients develop acute GVHD after HSCT. And the incidence rates of chronic GVHD range from 6 to 80%. Standard therapeutic strategies are still lacking, although considerable advances have been gained in knowing of the predisposing factors, pathology, and diagnosis of GVHD. Targeting immune cells, such as regulatory T cells, as well as tolerogenic dendritic cells or mesenchymal stromal cells (MSCs display considerable benefit in the relief of GVHD through the deletion of alloactivated T cells. Monoclonal antibodies targeting cytokines or signaling molecules have been demonstrated to be beneficial for the prevention of GVHD. However, these remain to be verified in clinical therapy. It is also important and necessary to consider adopting individualized treatment based on GVHD subtypes, pathological mechanisms involved and stages. In the future, it is hoped that the identification of novel therapeutic targets and systematic research strategies may yield novel safe and effective approaches in clinic to improve outcomes of GVHD further. In this article, we reviewed the current advances in targeted immunotherapy for the prevention of GVHD.

  13. A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant.

    Science.gov (United States)

    Ronald, John A; Kim, Byung-Su; Gowrishankar, Gayatri; Namavari, Mohammad; Alam, Israt S; D'Souza, Aloma; Nishikii, Hidekazu; Chuang, Hui-Yen; Ilovich, Ohad; Lin, Chih-Feng; Reeves, Robert; Shuhendler, Adam; Hoehne, Aileen; Chan, Carmel T; Baker, Jeanette; Yaghoubi, Shahriar S; VanBrocklin, Henry F; Hawkins, Randall; Franc, Benjamin L; Jivan, Salma; Slater, James B; Verdin, Emily F; Gao, Kenneth T; Benjamin, Jonathan; Negrin, Robert; Gambhir, Sanjiv Sam

    2017-06-01

    A major barrier to successful use of allogeneic hematopoietic cell transplantation is acute graft-versus-host disease (aGVHD), a devastating condition that arises when donor T cells attack host tissues. With current technologies, aGVHD diagnosis is typically made after end-organ injury and often requires invasive tests and tissue biopsies. This affects patient prognosis as treatments are dramatically less effective at late disease stages. Here, we show that a novel PET radiotracer, 2'-deoxy-2'-[18F]fluoro-9-β-D-arabinofuranosylguanine ([18F]F-AraG), targeted toward two salvage kinase pathways preferentially accumulates in activated primary T cells. [18F]F-AraG PET imaging of a murine aGVHD model enabled visualization of secondary lymphoid organs harboring activated donor T cells prior to clinical symptoms. Tracer biodistribution in healthy humans showed favorable kinetics. This new PET strategy has great potential for early aGVHD diagnosis, enabling timely treatments and improved patient outcomes. [18F]F-AraG may be useful for imaging activated T cells in various biomedical applications. Cancer Res; 77(11); 2893-902. ©2017 AACR . ©2017 American Association for Cancer Research.

  14. Osteopontin attenuates acute gastrointestinal graft-versus-host disease by preventing apoptosis of intestinal epithelial cells

    International Nuclear Information System (INIS)

    Kawakami, Kentaro; Minami, Naoki; Matsuura, Minoru; Iida, Tomoya; Toyonaga, Takahiko; Nagaishi, Kanna; Arimura, Yoshiaki; Fujimiya, Mineko; Uede, Toshimitsu; Nakase, Hiroshi

    2017-01-01

    Background and aims: Acute graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation, which often targets gastrointestinal (GI) tract. Osteopontin (OPN) plays an important physiological role in the efficient development of Th1 immune responses and cell survival by inhibiting apoptosis. The role of OPN in acute GI-GVHD is poorly understood. In the present study, we investigated the role of OPN in donor T cells in the pathogenicity of acute GI-GVHD. Methods: OPN knockout (KO) mice and C57BL/6 (B6) mice were used as donors, and (C57BL/6 × DBA/2) F1 (BDF1) mice were used as allograft recipients. Mice with acute GI-GVHD were divided into three groups: the control group (BDF1→BDF1), B6 group (B6→BDF1), and OPN-KO group (OPN-KO→BDF1). Bone marrow cells and spleen cells from donors were transplanted to lethally irradiated recipients. Clinical GVHD scores were assessed daily. Recipients were euthanized on day 7 after transplantation, and colons and small intestines were collected for various analyses. Results: The clinical GVHD score in the OPN-KO group was significantly increased compared with the B6 and control groups. We observed a difference in the severity of colonic GVHD between the OPN-KO group and B6 group, but not small intestinal-GVHD between these groups. Interferon-γ, Tumor necrosis factor-α, Interleukin-17A, and Interleukin-18 gene expression in the OPN-KO group was differed between the colon and small intestine. Flow cytometric analysis revealed that the fluorescence intensity of splenic and colonic CD8 T cells expressing Fas Ligand was increased in the OPN-KO group compared with the B6 group. Conclusion: We demonstrated that the importance of OPN in T cells in the onset of acute GI-GVHD involves regulating apoptosis of the intestinal cell via the Fas-Fas Ligand pathway. - Highlights: • A lack of osteopontin in donor cells exacerbated clinical gastrointestinal GVHD. • Donor cells lacking

  15. Demonstration and suppression of a radioresistant host-versus-graft reaction

    International Nuclear Information System (INIS)

    Thierfelder, S.; Roessler, R. v.; Ruppelt, W.

    1975-01-01

    The possibilities of suppressing and measuring a radioresistant host-versus-graft reaction are described. According to the authors, the host-versus-graft immune reaction may outlast whole-body irradiation at high doses. (BSC/AK) [de

  16. Unraveling the Mechanisms of Cutaneous Graft-Versus-Host Disease

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    Pedro Santos e Sousa

    2018-05-01

    Full Text Available The skin is the most common target organ affected by graft-versus-host disease (GVHD, with severity and response to therapy representing important predictors of patient survival. Although many of the initiating events in GVHD pathogenesis have been defined, less is known about why treatment resistance occurs or why there is often a permanent failure to restore tissue homeostasis. Emerging data suggest that the unique immune microenvironment in the skin is responsible for defining location- and context-specific mechanisms of injury that are distinct from those involved in other target organs. In this review, we address recent advances in our understanding of GVHD biology in the skin and outline the new research themes that will ultimately enable design of precision therapies.

  17. Chronic graft-versus-host disease in the rat radiation chimera. III. Immunology and immunopathology in rapidly induced models

    International Nuclear Information System (INIS)

    Beschorner, W.E.; Tutschka, P.J.; Santos, G.W.

    1983-01-01

    Although chronic graft-versus-host disease (GVHD) frequently develops in the long-term rat radiation chimera, we present three additional models in which a histologically similar disease is rapidly induced. These include adoptive transfer of spleen and bone marrow from rats with spontaneous chronic GVHD into lethally irradiated rats of the primary host strain; sublethal irradiation of stable chimeras followed by a booster transplant; and transfer of spleen cells of chimeras recovering from acute GVHD into second-party (primary recipient strain) or third-party hosts. Some immunopathologic and immune abnormalities associated with spontaneous chronic GVHD were not observed in one or more of the induced models. Thus, IgM deposition in the skin, antinuclear antibodies, and vasculitis appear to be paraphenomena. On the other hand, lymphoid hypocellularity of the thymic medulla, immaturity of splenic follicles, and nonspecific suppressor cells were consistently present in the long term chimeras, and in all models. These abnormalities therefore may be pathogenetically important, or closely related to the development of chronic GVHD

  18. An update on the clinical utility of extracorporeal photopheresis in the treatment of graft-versus-host disease

    Directory of Open Access Journals (Sweden)

    Salem B

    2017-03-01

    Full Text Available Baheyeldin Salem,1,2 Jennifer Webb,3 David Alex Jacobsohn1,2 1Blood and Marrow Transplant Program, 2Department of Paediatrics, 3Department of Transfusion Medicine, Children’s National Health System, Washington, DC, USA Abstract: Graft-versus-host disease (GVHD continues to be a major complication following allogeneic hematopoietic cell transplantation (allo-HCT with high morbidity and mortality. Corticosteroids are the first-line treatment for GVHD; however, a substantial number of patients go on to require second-line treatment where no single therapeutic modality has been proven to be the most effective. Extracorporeal photopheresis (ECP is an efficient and established therapy for cutaneous T-cell lymphoma, GVHD, rejection after solid organ transplantation and various autoimmune diseases. Although large randomized trials are limited, there is compelling cumulative data on the efficacy of ECP for GVHD, and the response rates, especially for cutaneous involvement, are encouraging. ECP has an excellent safety profile, a well-documented steroid-sparing effect, proven survival benefit and overall quality-of-life improvement. In many institutions, ECP is commonly regarded as the preferred second-line treatment for GVHD. Keywords: GVHD, ECP, immunosuppressive therapy, IST, apheresis, steroid-refractory ­graft-versus-host disease, hematopoietic cell transplantation, graft versus leukemia effect

  19. Thoracic air-leakage syndrome in allogeneic stem cell transplant recipients as a late complication of chronic graft-versus-host disease: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jae Wook; Kim, Song Soo; Jo, Daeg Yeon; Yun, Hwan Jung; Lee, Hyo Jin; Kim, Jin Hwan [Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon (Korea, Republic of)

    2016-08-15

    Air-leakage syndrome associated with graft-versus-host disease (GVHD) is a rare complication, but it is also reported as an independent predictor of a worse survival rate after stem cell transplantation. We report two cases of air-leakage syndrome associated with GVHD after allogeneic stem cell transplantation in acute leukemia patients who presented with spontaneous pneumomediastinum and subcutaneous emphysema, and finally death due to respiratory failure seven to eight months later.

  20. Clinical-Grade-Expanded Regulatory T Cells Prevent Graft-versus-Host Disease While Allowing a Powerful T Cell-Dependent Graft-versus-Leukemia Effect in Murine Models.

    Science.gov (United States)

    Del Papa, Beatrice; Ruggeri, Loredana; Urbani, Elena; Baldoni, Stefano; Cecchini, Debora; Zei, Tiziana; Iacucci Ostini, Roberta; Crescenzi, Barbara; Carotti, Alessandra; Pierini, Antonio; Sportoletti, Paolo; Di Bartolomeo, Paolo; Falzetti, Franca; Mecucci, Cristina; Velardi, Andrea; Martelli, Massimo F; Di Ianni, Mauro

    2017-11-01

    We developed a good manufacturing practices-compatible expansion protocol to improve number and purity of regulatory T cells (Tregs) available for clinical trials. Six clinical-grade separation procedures were performed, followed by expansion with high-dose interleukin (IL)-2, anti-CD3/anti-CD28 TCR stimulation, and rapamycin for 19 days achieving a median of 8.5-fold (range, 6.25 to 13.7) expansion. FOXP3 expression was stably maintained over the culture period, while the percentage of CD127 was significantly reduced. The in vitro suppression assay showed a strong Mixed Lymphocytes Reaction inhibition. In vitro amplification did not induce any karyotypic modification. To evaluate the graft-versus-host disease (GVHD)/graft-versus-leukemia (GVL) bifunctional axis, expanded Tregs and conventional T cells (Tcons) were tested in NOD/SCID/IL2Rgnull mice injected with primary acute myeloid leukemia (AML) cells, AML cell line, acute lymphoid leukemia Philadelphia cell line, or Burkitt-like lymphoma cell line. All mice that received leukemia cells together with expanded Tregs and Tcons were rescued from leukemia and survived without GVHD, showing that Treg expansion procedure did not compromise GVHD control and the strong Tcon-mediated GVL activity. This report might represent the basis for treating high-risk leukemia and/or relapsed/refractory leukemia patients with high-dose Treg/Tcons. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  1. Recipient Immune Modulation with Atorvastatin for Acute Graft-versus-Host Disease Prophylaxis after Allogeneic Transplantation.

    Science.gov (United States)

    Kanate, Abraham S; Hari, Parameswaran N; Pasquini, Marcelo C; Visotcky, Alexis; Ahn, Kwang W; Boyd, Jennifer; Guru Murthy, Guru Subramanian; Rizzo, J Douglas; Saber, Wael; Drobyski, William; Michaelis, Laura; Atallah, Ehab; Carlson, Karen S; D'Souza, Anita; Fenske, Timothy S; Cumpston, Aaron; Bunner, Pamela; Craig, Michael; Horowitz, Mary M; Hamadani, Mehdi

    2017-08-01

    Atorvastatin administration to both the donors and recipients of matched related donor (MRD) allogeneic hematopoietic cell transplantation (allo-HCT) as acute graft-versus-host disease (GVHD) prophylaxis has been shown to be safe and effective. However, its efficacy as acute GVHD prophylaxis when given only to allo-HCT recipients is unknown. We conducted a phase II study to evaluate the safety and efficacy of atorvastatin-based acute GVHD prophylaxis given only to the recipients of MRD (n = 30) or matched unrelated donor (MUD) (n = 39) allo-HCT, enrolled in 2 separate cohorts. Atorvastatin (40 mg/day) was administered along with standard GVHD prophylaxis consisting of tacrolimus and methotrexate. All patients were evaluable for acute GVHD. The cumulative incidences of grade II to IV acute GVHD at day +100 in the MRD and MUD cohorts were 9.9% (95% confidence interval [CI], 0 to 20%) and 29.6% (95% CI,15.6% to 43.6%), respectively. The cumulative incidences of grade III and IV acute GVHD at day +100 in the MRD and MUD cohorts were 3.4% (95% CI, 0 to 9.7%) and 18.3% (95% CI, 6.3% to 30.4%), respectively. The corresponding rates of moderate/severe chronic GVHD at 1 year were 28.1% (95% CI, 11% to 45.2%) and 38.9% (95% CI, 20.9% to 57%), respectively. In the MRD cohort, the 1-year nonrelapse mortality, relapse rate, progression-free survival, and overall survival were 6.7% (95% CI, 0 to 15.4%), 43.3% (95% CI, 24.9% to 61.7%), 50% (95% CI, 32.1% to 67.9%), and 66.7% (95% CI, 49.8% to 83.6%), respectively. The respective figures for the MUD cohort were 10.3% (95% CI, 8% to 19.7%), 20.5% (95% CI, 7.9% to 33.1%), 69.2% (95% CI, 54.7% to 83.7%), and 79.5% (95% CI, 66.8% to 92.2%), respectively. No grade 4 toxicities attributable to atorvastatin were seen. In conclusion, the addition of atorvastatin to standard GVHD prophylaxis in only the recipients of MRD and MUD allo-HCT appears to be feasible and safe. The preliminary efficacy seen here warrants confirmation in

  2. A murine model of graft-versus-host disease induced by allogeneic bone marrow transplantation

    International Nuclear Information System (INIS)

    Hu Jiangwei; Jin Jiangang; Ning Hongmei; Yu Liquan; Feng Kai; Chen Hu; Wang Lisha

    2007-01-01

    Objective: To establish the model of graft-versus-host disease (GVHD) in mice with allogeneic bone marrow transplantation. Methods: Bone marrow cells were combined with spleen cells of male donor C57BL/6 mice according to different proportions, then were transfused into female postradiation recipient BALB/c mice. General state, life span and histopathology of the recipient mice and detected chimera were observed. Results and Conclusion:The recipient mice groups which accepted above 5 x 10 6 donor spleen cells developed acute GVHD after different peroids of time. The GVHD model in mice after allo-BMT was successfully established. The transfusion of 5 x 10 6 -5 x 10 7 spleen cells may be adequate to establish the murine model of GVHD for the prevention and treatment of GVHD. The number of murine spleen cells can be chosen according to the experimental requirement. (authors)

  3. Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: a meta-analysis.

    Science.gov (United States)

    Cutler, C; Giri, S; Jeyapalan, S; Paniagua, D; Viswanathan, A; Antin, J H

    2001-08-15

    Controversy exists as to whether the incidence of graft-versus-host disease (GVHD) is increased after peripheral-blood stem-cell transplantation (PBSCT) when compared with bone marrow transplantation (BMT). We performed a meta-analysis of all trials comparing the incidence of acute and chronic GVHD after PBSCT and BMT reported as of June, 2000. Secondary analyses examined relapse rates after the two procedures. An extensive MEDLINE search of the literature was undertaken. Primary authors were contacted for clarification and completion of missing information. A review of cited references was also undertaken. Sixteen studies (five randomized controlled trials and 11 cohort studies) were included in this analysis. Data was extracted by two pairs of reviewers and analyzed for the outcomes of interest. Meta-analyses, regression analyses, and assessments of publication bias were performed. Using a random effects model, the pooled relative risk (RR) for acute GVHD after PBSCT was 1.16 (95% confidence interval [CI], 1.04 to 1.28; P=.006) when compared with traditional BMT. The pooled RR for chronic GVHD after PBSCT was 1.53 (95% CI, 1.25 to 1.88; P <.001) when compared with BMT. The RR of developing clinically extensive chronic GVHD was 1.66 (95% CI, 1.35 to 2.05; P <.001). The excess risk of chronic GVHD was explained by differences in the T-cell dose delivered with the graft in a meta-regression model that did not reach statistical significance. There was a trend towards a decrease in the rate of relapse after PBSCT (RR = 0.81; 95% CI, 0.62 to 1.05). Both acute and chronic GVHD are more common after PBSCT than BMT, and this may be associated with lower rates of malignant relapse. The magnitude of the transfused T-cell load may explain the differences in chronic GVHD risk.

  4. Defecation of a colon cast as a rare presentation of acute graft-versus-host disease

    International Nuclear Information System (INIS)

    Al Ashgar, Hamad; Peedikayil, Musthafa; Chaudhri, Naeem; AlGhamdi, Abdulmonem

    2009-01-01

    Diffuse involvement of the gastrointestinal tract by graft versus host disease (GVHD) is a common complication of allogeneic hematopoietic stem cell transplant (HSCT). Gastrointestinal GVHD usually presents 3 or more weeks after HSCT and is characterized by profuse diarrhea, anorexia, nausea, vomiting, abdominal pain and gastrointestinal bleeding. We report a case of a 23 year old male who had undergone allogeneic HSCT and presented with bloody diarrhea on the 90th day post-HSCT. On the fourth day of admission, the patient passed per rectum a 27-cm long pinkish colored fleshy material recognized as a colon cast. Sigmoidoscopy showed a congested and erythematous rectum with the remaining portion of the colon cast attached to the proximal part of the sigmoid colon. A biopsy from the rectal wall was suggestive of grade 4 GVHD. The patient was treated with methylprednisolone, cyclosporine and mycophenolate mofetil, with a partial response (diarrhea and abdominal pain improved), but then he developed multiple other medical complications and died after 3 months. (author)

  5. Utility of Endoscopic Examination in the Diagnosis of Acute Graft-versus-Host Disease in the Lower Gastrointestinal Tract

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    Kosuke Nomura

    2017-01-01

    Full Text Available Background and Aims. We retrospectively investigated the incidence of acute graft-versus-host disease (GVHD in the lower gastrointestinal (GI tract and the diagnostic accuracy of endoscopy. Methods. Of 1231 patients who underwent allogeneic hematopoietic stem cell transplantation between January 2005 and December 2014, 186 of whom underwent colonoscopy and biopsy and had no cytomegalovirus infection. The endoscopic findings and histologic diagnosis from these 186 patients were retrospectively analyzed. Results. Based on the histopathological findings, 171 patients were diagnosed with GVHD, accounting for 13.9% of all transplant recipients. Useful endoscopic findings for the diagnosis of GVHD were atrophy of the ileocecal valve and villous atrophy in the terminal ileum and tortoise shell-like mucosae, edema, and low vascular permeability in the colon. Even when no mucosal abnormality was observed, the incidence of GVHD was 78.9% in the terminal ileum and 75.0% in the colon. Furthermore, patients with mucosal exfoliation, although infrequent, were all diagnosed with grade 3/4 GVHD. Conclusions. It is important to perform endoscopy proactively for the early diagnosis of GVHD, and biopsy should be performed even when no abnormality is observed. In addition, because patients with mucosal exfoliation are extremely likely to have grade 3/4 GVHD, early treatment should be initiated.

  6. Quality of life of patients with graft-versus-host disease (GvHD post-hematopoietic stem cell transplantation

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    Sibéli de Fátima Ferraz Simão Proença

    Full Text Available Abstract OBJECTIVE Assessing the quality of life of adult patients with hematological cancer in the 100 days after transplantation of hematopoietic stem cells and verifying whether the variable graft-versus-host disease (GvHD is predictive of worse results. METHOD An observational correlational and quantitative study with 36 adult participants diagnosed with hematologic cancer who underwent hematopoietic stem cell transplantation from September 2013 to June 2015. RESULT The mean age was 37 years, 52.78% were female, and 61.11% were diagnosed with leukemia. Quality of life scores showed a significant impact between pre-transplantation and pre-hospital discharge, and also within the 100 days post-transplantation. The statistical analysis between the scores for the groups with and without GvHD showed a significant difference between the presence of the complication and worse results. CONCLUSION Quality of life is altered as a result of hematopoietic stem cells transplantation, especially in patients who have graft-versus-host disease.

  7. Therapeutic effects of hydrogen on chronic graft-versus-host disease.

    Science.gov (United States)

    Qian, Liren; Liu, Xiaopeng; Shen, Jianliang; Zhao, Defeng; Yin, Wenjie

    2017-10-01

    The incidence of chronic graft-versus-host disease (cGVHD) is rising recent years, which has been the leading cause of non-transplantation mortality post allogenetic hematopoietic stem cell transplantation (HSCT). Imbalance of inflammatory cytokines and fibrosis plays critical roles in the pathogenesis of cGVHD. Recent studies showed that molecular hydrogen has anti-inflammatory, antioxidant, anti-fibrosis effects. Therefore, we hypothesized that molecular hydrogen may have therapeutic effects on cGVHD. To determine whether hydrogen could protect mice from cGVHD in an MHC-incompatible murine bone marrow transplantation (BMT) model, survival rates of mice were calculated, and skin lesions were also evaluated after BMT. This article demonstrated that administration of hydrogen-rich saline increased survival rate of cGVHD mice. Administration of hydrogen-rich saline after transplantation also reduced skin lesions of cGVHD mice. Previously, we reported the therapeutic effects of hydrogen on acute GVHD. However, there was no report on the therapeutic effects of hydrogen on cGVHD mice. It is suggested that hydrogen has a potential as an effective and safe therapeutic agent on cGVHD. This study will provide new ideas on the treatment of cGVHD and has important theoretical values. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  8. High incidence of chronic graft-versus-host disease after myeloablative allogeneic stem cell transplantation for chronic lymphocytic leukemia in Sweden: graft-versus-leukemia effect protects against relapse.

    Science.gov (United States)

    Machaczka, Maciej; Johansson, Jan-Erik; Remberger, Mats; Hallböök, Helene; Lazarevic, Vladimir Lj; Wahlin, Björn Engelbrekt; Omar, Hamdy; Wahlin, Anders; Juliusson, Gunnar; Kimby, Eva; Hägglund, Hans

    2013-12-01

    Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potentially curative treatment option for eligible patients with chronic lymphocytic leukemia (CLL). However, it is known that cure of CLL is only possible if a graft-versus-leukemia effect is present. Between 1994 and 2007, 48 adults underwent allo-SCT for poor-risk CLL in Sweden. Of these, ten (21%) patients aged 24-53 years (median: 46 years) received myeloablative conditioning (MAC), based on TBI and cyclophosphamide. All MAC patients had refractory, poorly controlled CLL before allo-SCT (partial remission in 9/10 patients and progressive disease in one). The cumulative incidence of acute graft-versus-host disease (GVHD) grades II-IV was 30%. Nine patients developed chronic GVHD; extensive in four. Rates of nonrelapse mortality at 1, 3 and 10 years were 0, 10 and 20%, respectively. Two patients relapsed 36 and 53 months after transplantation. Six patients were still alive after a median follow-up time of 11.5 years (range 5.9-13.7). The probabilities of relapse-free and overall survival from 1, 3 and 5 years after transplantation were 100, 90 and 70%, and 100, 90 and 80%, respectively. Nevertheless, our analysis of long-term outcome after MAC allo-SCT for CLL suggests that younger patients with poorly controlled CLL may benefit from MAC allo-SCT.

  9. Modified extracorporeal photopheresis with cells from a healthy donor for acute graft-versus-host disease in a mouse model.

    Directory of Open Access Journals (Sweden)

    Holger Budde

    Full Text Available Graft-versus-host disease (GvHD is a major challenge after hematopoietic stem cell transplantation but treatment options for patients are still limited. In many cases first-line treatment with glucocorticoids is not successful. Among second-line therapies the extracorporeal photopheresis (ECP is frequently performed, due to induction of selective tolerance instead of general immunosuppression. However, for some patients with severe acute GvHD the leukapheresis step of the ECP procedure is physically exhausting and limits the number of ECP cycles.We hypothesized that leukocytes from healthy cell donors could be used as a replacement for ECP leukocytes gained from the GvHD patient. For this purpose we used a well established mouse model of acute GvHD. The ECP therapy was based on cells with the genetic background of the initial donor of the stem cell transplantation. As a precondition we developed a protocol representing conventional ECP in mice equivalent to clinical used ECP setup.We could demonstrate that conventional, clinically derived ECP setup is able to alleviate acute GvHD. By using leukocytes obtained from healthy mice with the bone marrow donor's genetic background we could not observe a statistically significant therapeutic effect.Conventional human ECP setup is effective in the mouse model of severe acute GvHD. In addition we could not prove that ECP cells from healthy mice with bone marrow donor's genetic background are as effective as ECP cells derived from GvHD mice. Based on our findings, new questions arise for further studies, in which the cellular characteristics for ECP mediated immune tolerance are a matter of investigation.

  10. Syngeneic graft-versus-host disease: a report of two cases and literature review.

    Science.gov (United States)

    Latif, T; Pohlman, B; Kalaycio, M; Sobecks, R; Hsi, E D; Andresen, S; Bolwell, B J

    2003-09-01

    Rappeport et al first reported the clinical syndrome of graft-versus-host disease (GVHD) in syngeneic bone marrow transplant patients. Recently, there have been more reports of a GVHD-like syndrome in syngeneic bone marrow transplant patients (SGVHD) that may result in significant clinical morbidity. A total of 17 cases of SGVHD in syngeneic bone marrow transplant patients have been reported to date in the medical literature. The current report reviews these cases and presents two additional cases of severe SGVHD that have occurred at our institution.

  11. [NKT cells and graft-versus-host disease-review].

    Science.gov (United States)

    Zhao, Lei; Hao, Sha; Yuan, Wei-Ping; Cheng, Tao

    2013-10-01

    NKT cells (nature killer T cells), as a regulatory cellular compartment in the immune system, express cell surface markers of T cells and NK cells. It secretes a variety of cytokines that stimulate specific antigens. Through regulating the balance of Th1/Th2, the NKT cells play an important role in prevention and treatment of graft-versus-host disease (GVHD). Its antitumor and anti-infectious effects serve as a basis of its application in allogeneic hematopoietic stem cell transplantation. A better understanding of the biological and immunological features of NKT cell, as well as its specific immune regulatory mechanisms, will further justify the rationales of using NKT cells in the management of GVHD for patients. In this review, the biologic properties, classification, differentiation and development, immune activation of NKT cells as well as the NKT cells and GVHD including the related mechanisms of prevention and treatment of GVHD with NKT cells, NKT cells and tumors, NKT cells and infection, and NKT cells and clinical GVHD are summarized.

  12. Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors.

    Science.gov (United States)

    Carnevale-Schianca, Fabrizio; Caravelli, Daniela; Gallo, Susanna; Coha, Valentina; D'Ambrosio, Lorenzo; Vassallo, Elena; Fizzotti, Marco; Nesi, Francesca; Gioeni, Luisa; Berger, Massimo; Polo, Alessandra; Gammaitoni, Loretta; Becco, Paolo; Giraudo, Lidia; Mangioni, Monica; Sangiolo, Dario; Grignani, Giovanni; Rota-Scalabrini, Delia; Sottile, Antonino; Fagioli, Franca; Aglietta, Massimo

    2017-03-01

    Allogeneic hematopoietic cell transplant (HCT) remains the only curative therapy for many hematologic malignancies but it is limited by high nonrelapse mortality (NRM), primarily from unpredictable control of graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide demonstrated improved GVHD control in allogeneic bone marrow HCT. Here we explore cyclophosphamide in allogeneic peripheral blood stem cell transplantation (alloPBSCT). Patients with high-risk hematologic malignancies received alloPBSCT from HLA-matched unrelated/related donors. GVHD prophylaxis included combination post-HCT cyclophosphamide 50 mg/kg (days +3 and +4) and tacrolimus/mofetil mycophenolate (T/MMF) (day +5 forward). The primary objective was the cumulative incidence of acute and chronic GVHD. Between March 2011 and May 2015, 35 consecutive patients received the proposed regimen. MMF was stopped in all patients at day +28; the median discontinuation of tacrolimus was day +113. Acute and chronic GVHD cumulative incidences were 17% and 7%, respectively, with no grade IV GVHD events, only 2 patients requiring chronic GVHD immunosuppression control, and no deaths from GVHD. Two-year NRM, overall survival, event-free survival, and chronic GVHD event-free survival rates were 3%, 77%, 54%, and 49%, respectively. The graft-versus-tumor effect was maintained as 5 of 15 patients (33%) who received HCT with evidence of disease experienced further disease response. A post-transplant cyclophosphamide + T/MMF combination strategy effectively prevented acute and chronic GVHD after alloPBSCT from HLA-matched donors and achieved an unprecedented low NRM without losing efficacy in disease control or impaired development of the graft-versus-tumor effect. This trial is registered at clinicaltrials.gov as NCT02300571. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  13. Endoscopic and Histological Findings Are Predicted by Fecal Calprotectin in Acute Intestinal Graft-Versus-Host-Disease.

    Science.gov (United States)

    Adam, Birgit; Koldehoff, Michael; Ditschkowski, Markus; Gromke, Tanja; Hlinka, Michal; Trenschel, Rudolf; Kordeals, Lambros; Steckel, Nina K; Beelen, Dietrich W; Liebregts, Tobias

    2016-07-01

    Gastrointestinal graft-versus-host-disease (GI-GVHD) is a major cause of nonrelapse mortality after hematopoietic stem cell transplantation (HSCT) necessitating endoscopic examinations and biopsies for diagnosis. Fecal calprotectin (CPT) has been widely used in gastrointestinal inflammation, but comprehensive data in GI-GVHD are lacking. We aimed to identify an association of CPT with endoscopic findings, mucosal damage and symptoms for diagnosing and monitoring acute GI-GVHD. Symptoms were prospectively evaluated in 110 consecutive HSCT recipients by standardized questionnaires and Bristol Stool Scale (BSS). CPT was assayed by ELISA. Symptom assessment and CPT were performed weekly and with onset of first symptoms. GVHD was diagnosed according to the Glucksberg criteria and by endoscopic biopsies. Patients with GI-GVHD received standard high-dose corticosteroid therapy and follow-up CPT, and symptom evaluation was performed after 28 days. Patients not responding to steroid treatment were re-evaluated by colonoscopy. GI-GVHD was diagnosed in 40 patients. Twelve patients with GI symptoms and CMV colitis and 24 patients with isolated skin GVHD were included as control subjects. CPT was significantly higher in GI-GVHD compared to skin GVHD and CMV colitis. Endoscopic findings, histological grading, abdominal cramps, diarrhea, urgency and BSS correlated with CPT. At follow-up, CPT correlated with abdominal cramps, diarrhea, urgency and BSS. In steroid refractory patients, CPT level was still significantly associated with severity of mucosal damage. CPT predicts endoscopic and histological findings in GI-GVHD and correlates with lower GI symptoms. It enables to discriminate GVHD from CMV colitis and to monitor therapeutic success.

  14. The Role of B Cell Targeting in Chronic Graft-Versus-Host Disease

    Directory of Open Access Journals (Sweden)

    Ruben Rhoades

    2017-10-01

    Full Text Available Chronic graft-versus-host disease (cGVHD is a leading cause of late morbidity and mortality following allogeneic stem cell transplantation. Current therapies, including corticosteroids and calcineurin inhibitors, are only effective in roughly 50% of cases; therefore, new treatment strategies are under investigation. What was previously felt to be a T cell disease has more recently been shown to involve activation of both T and B cells, as well as a number of cytokines. With a better understanding of its pathophysiology have come more expansive preclinical and clinical trials, many focused on B cell signaling. This report briefly reviews our current understanding of cGVHD pathophysiology and reviews clinical and preclinical trials with B cell-targeted agents.

  15. Efficacy and Safety of Topical Corticosteroids for Management of Oral Chronic Graft versus Host Disease

    OpenAIRE

    Elsaadany, Basma Abdelaleem; Ahmed, Eman Magdy; Aghbary, Sana Maher Hasan

    2017-01-01

    Background. Oral chronic graft versus host disease (cGVHD) is a major complication in transplantation community, a problem that can be addressed with topical intervention. Topical corticosteroids are the first line of treatment although the choice remains challenging as none of the available treatments is supported by strong clinical evidence. Objective. This systematic review aims to determine the clinical efficacy and safety of topical corticosteroids for the management of the mucosal alter...

  16. Mesenchymal stromal cells in the antimicrobial host response of hematopoietic stem cell recipients with graft-versus-host disease--friends or foes?

    Science.gov (United States)

    Balan, A; Lucchini, G; Schmidt, S; Schneider, A; Tramsen, L; Kuçi, S; Meisel, R; Bader, P; Lehrnbecher, T

    2014-10-01

    Mesenchymal stromal cells (MSCs) are multipotent cells, which exhibit broad immunosuppressive activities. Moreover, they may be administered irrespectively of human leukocyte antigen (HLA) compatibility, without inducing life-threatening immunological reactions, as they express no HLA class II and limited HLA class I antigens under resting conditions. These characteristics have made MSC an appealing candidate for cell therapy after hematopoietic stem cell transplantation (HSCT), for example, for treatment of graft-versus-host disease (GvHD) or for graft rejection prevention/treatment in allogeneic HSCT recipients. Unfortunately, information regarding the effect of MSC infusion on the host response to infectious agents is scarce, and study results on infectious complications in patients receiving MSC are conflicting. The present review focuses on the available data from in vitro studies and animal models regarding the interaction of MSC with bacterial, viral and fungal pathogens. In a clinical part, we present the current information on infectious complications in allogeneic HSCT recipients who had received MSCs as prophylaxis or treatment of GvHD disease.

  17. Graft-Versus-Host Disease after Liver Transplantation Complicated by Systemic Aspergillosis with Pancarditis

    Directory of Open Access Journals (Sweden)

    Joseph Romagnuolo

    2000-01-01

    Full Text Available Acute graft-versus-host disease (GVHD is a common complication after bone marrow transplantation, with characteristic rash and diarrhea being the most common features. After liver transplantation, however, this phenomenon is very rare. Most transplant patients are on a variety of medications, including immunosuppressants; therefore, the differential diagnosis of skin rash or diarrhea is broad. A 37-year-old man who underwent liver transplantation for primary biliary cirrhosis, and developed a rash and watery diarrhea, is presented. Skin and colonic biopsies confirmed acute GVHD. A pulse of intravenous steroids was given. The skin rash improved, but he developed pancytopenia. His course was complicated by central line infection, jugular and subclavian vein thrombosis, pseudomembranous colitis, recurrent bacteremia, cholestasis on total parenteral nutrition and cytomegalovirus infection. After the onset of pleuritic chest pain and clinical sepsis, spiral computed tomography scan of his chest and abdomen revealed septic infarcts in multiple organs. Despite empirical treatment with amphotericin B, he died of multiorgan dysfunction syndrome within 72 h. Autopsy revealed systemic aspergillosis with pancarditis, endocardial vegetations, and septic pulmonary, splenic, hepatic and renal infarcts. The pathogenesis and experience with this rare, but often fatal, complication of liver transplantation are reviewed. In contrast to GVHD after bone marrow transplantation, pancytopenia is common and liver dysfunction is rare. One should have a high level of suspicion in the liver transplant recipient presenting with rash and/or diarrhea.

  18. Emerging technologies for oral diagnostics: lessons from chronic graft-versus-host disease

    Science.gov (United States)

    Mays, Jacqueline W.; Ambatipudi, Kiran S.; Bassim, Carol W.; Melvin, James E.

    2013-05-01

    Saliva is a protein-rich oral fluid that contains information about systemic and oral-specific disease pathogenesis and diagnosis. Technologies are emerging to improve detection of protein components of human saliva for use not only in biomarker discovery, but also for the illumination of pathways involved in oral disease. These include the optimization of liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) analysis of saliva in health and disease. Downstream of saliva component identification and validation comes the complex task of connecting salivary proteomic data to biological function, disease state, and other clinical patient information in a meaningful way. Augmentation of database information with biological expertise is crucial for effective analysis of potential biomarkers and disease pathways in order to improve diagnosis and identify putative therapeutic targets. This presentation will use LC-MS/MS analysis of saliva from chronic Graft-versus-Host disease (cGVHD) patients to illustrate these principles, and includes a discussion of the complex clinical and diagnostic issues related to proteomics and biomarker research in cGVHD.

  19. Skin ulcers related to chronic graft-versus-host disease: clinical findings and associated morbidity.

    Science.gov (United States)

    Jachiet, M; de Masson, A; Peffault de Latour, R; Rybojad, M; Robin, M; Bourhis, J-H; Xhaard, A; Dhedin, N; Sicre de Fontbrune, F; Suarez, F; Barete, S; Parquet, N; Nguyen, S; Ades, L; Rubio, M-T; Wittnebel, S; Bagot, M; Socié, G; Bouaziz, J-D

    2014-07-01

    According to the National Institutes of Health classification of chronic graft-versus-host disease (cGVHD), skin ulcers after allogeneic haematopoietic stem-cell transplantation (HSCT) are recorded as having the maximal severity score but published data are scarce. To describe skin ulcers related to cGVHD with an emphasis on clinical findings, associated morbidity, management and evolution. A multicentre retrospective analysis was carried out of patients with a diagnosis of cGVHD skin ulcers. All 25 patients included in the study had sclerotic skin cGVHD and 21 had lichenoid skin lesions associated with the sclerotic skin lesions. Thirteen patients had severe cGVHD without considering the skin, because of the involvement of an extracutaneous organ by cGVHD. The median time from HSCT to the onset of ulcers was 44 months. In addition to scleroderma, initial skin lesions at the site of ulcers were bullous erosive lichen in 21 patients and bullous erosive morphoea in four patients. Fifteen patients had an inaugural oedema. Ulcers were mostly bilateral with a predilection for the lower limbs. They were frequently colonized but few infections occurred. Four patients died during a median follow-up period of 55 months. Chronic graft-versus-host disease skin ulcers occur in patients with sclerodermatous skin cGVHD, are associated with severe cGVHD, often start with bullous lichenoid lesions or bullous morphoea and seem to cause more morbidity than mortality, given the low rate of mortality observed in our series of patients. © 2014 British Association of Dermatologists.

  20. Ocular manifestations of graft-versus-host disease

    Science.gov (United States)

    Nassar, Amr; Tabbara, Khalid F.; Aljurf, Mahmoud

    2013-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) has evolved over the past two decades to become the standard of care for hematologic and lymphoid malignancies. Major ocular complications after allogeneic HSCT have been increasing in number and severity. Graft-versus-host disease (GVHD) remains a major cause of ocular morbidity after allogeneic HSCT. The main objective of this review is to elucidate the ocular complications in patients developing GVHD following HSCT. Ocular complications secondary to GVHD are common and include dry eye syndrome, acquisition of ocular allergy from donors with allergic disorders. Eyelid changes may occur in GVHD leading to scleroderma-like changes. Patients may develop poliosis, madarosis, vitiligo, lagophthalmos, and entropion. The cornea may show filamentary keratitis, superficial punctate keratitis, corneal ulcers, and peripheral corneal melting which may lead to perforation in severe cases. Scleritis may also occur which can be anterior or posterior. Keratoconjunctivis sicca appears to be the most common presentation of GVHD. The lacrimal glands may be involved with mononuclear cell infiltration of both the major and accessory lacrimal glands and decrease in tear production. Severe dry eye syndrome in patients with GVHD may develop conjunctival scarring, keratinization, and cicatrization of the conjunctiva. Therapy of GVHD includes systemic immunosuppression and local therapy. Surgical treatment in refractory cases includes surgical intervention to improve the manifestation of GVHD of the eye. This may include tarsorrhapy, prose lenses, punctal occlusions and corneal transplantation. PMID:24227989

  1. SEVERE (GRADE III-IV ACUTE GRAFT VERSUS HOST DISEASE AFTER ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANTATION

    Directory of Open Access Journals (Sweden)

    Irena Preložnik-Zupan

    2002-09-01

    Full Text Available Background. Beside greater susceptibility to infections, acute graft host disease is a consequence of the activation of donor T-cells against host antigens. Most common target organs are skin, liver and intestinal mucosis.Methods. In the 6-year period between January 1995 and December 2000, 49 patients were treated with allogeneic haematopoietic stem cell transplantation (allo-HSCT in Transplant unit, Department of Hematology, Clinical Centre Ljubljana. The standard GVHD prophylaxis regimen consisted of cyclosporine and short-course methotrexate. Severe, grade III-IV aGVHD with skin and/or gastrointestinal and/or liver involvement appeared in 16 (32% of the 49 patients.Results. Among the 16 patients with severe aGVHD, 14 had liver involvement, ten gastrointestinal and eight skin involvement. One patient had skin involvement only, the rest of them had combined involvement of two or three organ systems. Routine first-line treatment for aGVHD, given to all 16 pts with severe forms of the disease, was methylprednisolone (MP 2mg/ kg. Six patients with predominant skin involvement responded to MP. Other ten patients with mainly liver and gastrointestinal involvement needed second or even third line aGVHD treatment. These were anti-thymocyte globulin (ATG and/or monoclonal antibodies (OKT3 and/or mycophenolate mofetil (MMF and/or FK506 (tacrolimus. Seven patients died of advanced aGVHD and treatment related infection.Conclusions. Based on our experiences, we conclude that in critically ill patients with severe aGVHD, neutropenia and high risk for opportunistic infection, each day of ineffective MP therapy may have fatal consequences. Simultaneous institution of a combination of corticosteroids and a second-line drug might prove more appropriate for patients with a severe form of aGVHD.

  2. Incidence and Pattern of Graft-versus-Host Disease in Patients Undergoing Allogeneic Transplantation after Nonmyeloablative Conditioning with Total Lymphoid Irradiation and Antithymocyte Globulin

    Directory of Open Access Journals (Sweden)

    Lauren Veltri

    2013-01-01

    Full Text Available Nonmyeloablative (NMA conditioning with total lymphoid irradiation and antithymocyte globulin (TLI/ATG has been shown to protect against acute graft-versus-host disease (GVHD. We report here our institutional experience with allogeneic transplantation following NMA conditioning with TLI/ATG (. GVHD prophylaxis consisted of a combination of a calcineurin inhibitor and mycophenolate mofetil. Median patient age was 59 years. The median followup of surviving patients is 545 days. One patient experienced primary graft rejection. The median time to neutrophil engraftment was 18 days and platelet engraftment was 9.5 days. The cumulative incidence (CI of grade II–IV acute GVHD at day +100 was 28.6% and 38.1% at day +180. The CI for grade III-IV acute GVHD was 28.6% at day +180. CI of chronic GVHD was 45.2% at 1 year. The CI of disease relapse was 9.5% at 1 year. The rate of nonrelapse mortality (NRM was 0% at day +100 and only 9.5% at 1 year. The overall and progression free survival at 1 year was 81% and 80.4%, respectively. Our limited, retrospective data show encouraging relapse and NRM rates with TLI/ATG-based NMA conditioning, but with higher than previously reported rates of acute and chronic GVHD, underscoring the need for novel strategies designed to effectively prevent GVHD.

  3. Prevention of graft-versus-host-disease with preserved graft-versus-leukemia-effect by ex vivo and in vivo modulation of CD4(+) T-cells.

    Science.gov (United States)

    Fricke, Stephan; Hilger, Nadja; Fricke, Christian; Schönfelder, Uta; Behre, Gerhard; Ruschpler, Peter; Boldt, Andreas; Oelkrug, Christopher; Sack, Ulrich; Emmrich, Frank

    2014-06-01

    This is the first report showing that an epitope-specific ex vivo modulation of an allogeneic hematopoietic stem cell graft by the anti-human CD4 antibody MAX.16H5 IgG1 simultaneously facilitates the anti-tumor capacity of the graft (Graft-versus-leukemia effect, GvL) and the long-term suppression of the deleterious side effect Graft-versus-host-disease (GvHD). To distinguish and consolidate GvL from GvHD, the anti-human CD4 antibody MAX16.H5 IgG1 was tested in murine GvHD and tumor models. The survival rate was significantly increased in recipients receiving a MAX.16H5 IgG1 short-term (2 h) pre-incubated graft even when tumor cells were co-transplanted or when recipient mice were treated by MAX.16H5 IgG1 before transplantation. After engraftment, regulatory T-cells are generated only supporting the GvL effect. It was also possible to transfer the immune tolerance from GvHD-free recipient chimeras into third party recipient mice without the need of reapplication of MAX.16H5 IgG1 anti-human CD4 antibodies. These findings are also benefical for patients with leukemia when no matched related or unrelated donor is available and provides a safer allogeneic HSCT, which is more effective against leukemia. It also facilitates allogeneic (stem) cell transplantations for other indications (e.g., autoimmune-disorders).

  4. A case of membranous nephropathy as a manifestation of graft-versus-host disease

    Directory of Open Access Journals (Sweden)

    Jae Hyun Han

    2013-03-01

    Full Text Available Nephrotic syndrome (NS rarely occurs after hematopoietic stem cell transplantation (HSCT as a late manifestation of graft-versus-host disease (GVHD. Herein, we report a case of HSCT-associated membranous nephropathy in a female patient with aplastic anemia. The patient received an allogeneic HSCT from her human leukocyte antigen-identical brother following myeloablative conditioning chemotherapy. NS occurred 21 months after HSCT without any concurrent features of chronic GVHD. The patient was treated with prednisolone and cyclosporine after renal biopsy confirmed membranous nephropathy, and achieved complete remission. Our report contradicts previous assumptions that concomitant chronic GVHD is responsible for the development of NS, suggesting that NS can develop as a new, independent manifestation of GVHD.

  5. Photobiomodulation Therapy Alleviates Tissue Fibroses Associated with Chronic Graft-Versus-Host Disease: Two Case Reports and Putative Anti-Fibrotic Roles of TGF-

    NARCIS (Netherlands)

    Epstein, Joel B.; Raber-Durlacher, Judith E.; Huysmans, Marie-Charlotte; Schoordijk, Maria C. E.; Cheng, Jerry E.; Bensadoun, Rene-Jean; Arany, Praveen R.

    2018-01-01

    Objective: Patients who receive allogeneic hematopoietic stem cell transplantation may experience oral complications due to chronic graft-versus-host disease (cGVHD). The manifestations may include progressive sclerosis-like changes that may involve various body sites, including the oropharynx.

  6. Pulp Obliteration in a Patient with Sclerodermatous Chronic Graft-versus-Host Disease.

    Science.gov (United States)

    Gomes, Camilla Borges Ferreira; Treister, Nathaniel Simon; Miller, Brian; Armand, Philippe; Friedland, Bernard

    2016-04-01

    Dental pulp calcification is a common finding associated with localized dental trauma, genetic disorders, and systemic inflammatory diseases. Chronic graft-versus-host disease (cGVHD) is a frequent complication after allogeneic hematopoietic cell transplantation (allo-HCT) characterized by immune-mediated injury to the skin, mouth, eyes, liver, and other tissues, resulting in significant disability and reduced quality of life. We report a patient with sclerodermatous cGVHD who presented with general pulp calcification in all teeth 5 years after allo-HCT. A review of full mouth dental radiographs obtained just before allo-HCT revealed normal-appearing pulp chambers. Based on prior reports of generalized pulp calcification associated with progressive systemic sclerosis, we hypothesized that the etiology was likely related to the presence of cGVHD with associated vascular and fibrotic tissue changes within the pulp vasculature. Clinicians should consider cGVHD in the differential diagnosis of generalized pulp calcification. Copyright © 2016 American Association of Endodontists. All rights reserved.

  7. Clinical approach in the management of oral chronic graft-versus-host disease (cGVHD) in a series of specialized medical centers

    DEFF Research Database (Denmark)

    Elad, Sharon; Jensen, Siri Beier; Raber-Durlacher, Judith E

    2015-01-01

    BACKGROUND: The oral cavity is frequently affected in chronic graft-versus-host disease (cGVHD), with variable clinical presentations. The literature on the effective management of patients suffering from oral cGVHD is limited. OBJECTIVE: The objective of this study was to assess the clinical app...

  8. Human regulatory T cells control xenogeneic graft-versus-host disease induced by autologous T cells in RAG2-/-gammac-/- immunodeficient mice.

    NARCIS (Netherlands)

    Mutis, T; Rijn, R.S. van; Simonetti, E.R.; Aarts-Riemens, T.; Emmelot, M.E.; Bloois, L. van; Martens, A.; Verdonck, L.F.; Ebeling, S.B.

    2006-01-01

    PURPOSE: Effective prevention of graft-versus-host disease (GvHD) is a major challenge to improve the safety of allogeneic stem cell transplantation for leukemia treatment. In murine transplantation models, administration of naturally occurring CD4+CD25+ regulatory T cells (Treg) can prevent GvHD.

  9. Brazilian situation of blood component irradiation practice for the prevention of transfusion associated Graft-versus-Host disease

    International Nuclear Information System (INIS)

    Goes, E.G.; Borges, J.C.; Covas, D.T.; Motta, I.

    1998-01-01

    Transfusion-associated graft-versus-host disease (TA-GVHD) is a usually complication of transfusion of blood component containing T lymphocytes what recently has also involved immunocompetent patient. Gamma irradiation of cellular blood components has been the mainstay against TA-GVHD, nevertheless there is little information in the literature about current transfusion medicine practices regarding gamma irradiation of blood products. This work presents an overview of the Brazilian reality and suggests policies to optimize TA-GVHD prevention. (Author)

  10. Brazilian situation of blood component irradiation practice for the prevention of transfusion associated Graft-versus-Host disease

    Energy Technology Data Exchange (ETDEWEB)

    Goes, E.G.; Borges, J.C. [EE/COPPE-UFRJ (Brazil); Covas, D.T. [Faculdade deMedicina-USP-RP (Brazil); Motta, I. [Instituto Nacional do Cancer- Rio deJaneiro (Brazil)

    1998-12-31

    Transfusion-associated graft-versus-host disease (TA-GVHD) is a usually complication of transfusion of blood component containing T lymphocytes what recently has also involved immunocompetent patient. Gamma irradiation of cellular blood components has been the mainstay against TA-GVHD, nevertheless there is little information in the literature about current transfusion medicine practices regarding gamma irradiation of blood products. This work presents an overview of the Brazilian reality and suggests policies to optimize TA-GVHD prevention. (Author)

  11. Photobiomodulation therapy alleviates tissue fibroses associated with chronic Graft-Versus-Host Disease : Two case reports and putative anti-fibrotic roles of TGF-β

    NARCIS (Netherlands)

    Epstein, J.B.; Raber-Durlacher, J.E.; Huysmans, M.C.; Schoordijk, M.C.E.; Cheng, J.E.; Bensadoun, R.J.; Arany, P.R.

    2018-01-01

    Objective: Patients who receive allogeneic hematopoietic stem cell transplantation may experience oral complications due to chronic graft-versus-host disease (cGVHD). The manifestations may include progressive sclerosis-like changes that may involve various body sites, including the oropharynx.

  12. Graft-versus-host disease is enhanced by selective CD73 blockade in mice.

    Directory of Open Access Journals (Sweden)

    Long Wang

    Full Text Available CD73 functions as an ecto-5'-nucleotidase to produce extracellular adenosine that has anti-inflammatory and immunosuppressive activity. We here demonstrate that CD73 helps control graft-versus-host disease (GVHD in mouse models. Survival of wild-type (WT recipients of either allogeneic donor naïve CD73 knock-out (KO or WT T cells was similar suggesting that donor naïve T cell CD73 did not contribute to GVHD. By contrast, donor CD73 KO CD4(+CD25(+ regulatory T cells (Treg had significantly impaired ability to mitigate GVHD mortality compared to WT Treg, suggesting that CD73 on Treg is critical for GVHD protection. However, compared to donor CD73, recipient CD73 is more effective in limiting GVHD. Pharmacological blockade of A2A receptor exacerbated GVHD in WT recipients, but not in CD73 KO recipients, suggesting that A2 receptor signaling is primarily implicated in CD73-mediated GVHD protection. Moreover, pharmacological blockade of CD73 enzymatic activity induced stronger alloreactive T cell activity, worsened GVHD and enhanced the graft-versus-leukemia (GVL effect. These findings suggest that both donor and recipient CD73 protects against GVHD but also limits GVL effects. Thus, either enhancing or blocking CD73 activity has great potential clinical application in allogeneic bone marrow transplants.

  13. [Mesenchymal stromal cells in the treatment of graft-versus-host disease: where do we stand?].

    Science.gov (United States)

    Schüle, Silke; Berger, André

    2015-11-01

    Medicinal products based on mesenchymal stromal cells (MSC) are expected to have a therapeutic benefit in a variety of conditions and, accordingly, are being tested in many clinical studies. The treatment and prevention of graft-versus-host disease (GVHD) is one of the world's most widely studied MSC therapy concepts. So far, one MSC medicinal product has been approved for the treatment of GvHD. This article gives an overview of the particular features related to the production of MSC-based medicinal products, the state of non-clinical research, and the clinical development status of MSCs and the associated challenges, especially in the context of GvHD.

  14. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius.

    Science.gov (United States)

    Socié, Gérard; Schmoor, Claudia; Bethge, Wolfgang A; Ottinger, Hellmut D; Stelljes, Matthias; Zander, Axel R; Volin, Liisa; Ruutu, Tapani; Heim, Dominik A; Schwerdtfeger, Rainer; Kolbe, Karin; Mayer, Jiri; Maertens, Johan A; Linkesch, Werner; Holler, Ernst; Koza, Vladimir; Bornhäuser, Martin; Einsele, Hermann; Kolb, Hans-Jochem; Bertz, Hartmut; Egger, Matthias; Grishina, Olga; Finke, Jürgen

    2011-06-09

    Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD). Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P < .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] = 1.21, P = .47, and HR = 0.68, P = .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR = 0.84, P = .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P < .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity.

  15. Cell-mediated immunity to histocompatibility antigens : controlling factors, with emphasis on Graft-versus-host reactions in mice

    NARCIS (Netherlands)

    H. Bril (Herman)

    1984-01-01

    textabstractGraft-versus-Host (GvH) disease is characterized by weight loss, diarrhea, skin lesions, hypofunction of the immune system with concomitant infections, etc. This syndrome is potentially lethal. GvH reactions, which underly this disease, may occur when immunocompetent T lymphocytes are

  16. MicroRNA-155 Modulates Acute Graft-versus-Host Disease by Impacting T Cell Expansion, Migration, and Effector Function.

    Science.gov (United States)

    Zitzer, Nina C; Snyder, Katiri; Meng, Xiamoei; Taylor, Patricia A; Efebera, Yvonne A; Devine, Steven M; Blazar, Bruce R; Garzon, Ramiro; Ranganathan, Parvathi

    2018-06-15

    MicroRNA-155 (miR-155) is a small noncoding RNA critical for the regulation of inflammation as well as innate and adaptive immune responses. MiR-155 has been shown to be dysregulated in both donor and recipient immune cells during acute graft-versus-host disease (aGVHD). We previously reported that miR-155 is upregulated in donor T cells of mice and humans with aGVHD and that mice receiving miR-155-deficient (miR155 -/- ) splenocytes had markedly reduced aGVHD. However, molecular mechanisms by which miR-155 modulates T cell function in aGVHD have not been fully investigated. We identify that miR-155 expression in both donor CD8 + T cells and conventional CD4 + CD25 - T cells is pivotal for aGVHD pathogenesis. Using murine aGVHD transplant experiments, we show that miR-155 strongly impacts alloreactive T cell expansion through multiple distinct mechanisms, modulating proliferation in CD8 + donor T cells and promoting exhaustion in donor CD4 + T cells in both the spleen and colon. Additionally, miR-155 drives a proinflammatory Th1 phenotype in donor T cells in these two sites, and miR-155 -/- donor T cells are polarized toward an IL-4-producing Th2 phenotype. We further demonstrate that miR-155 expression in donor T cells regulates CCR5 and CXCR4 chemokine-dependent migration. Notably, we show that miR-155 expression is crucial for donor T cell infiltration into multiple target organs. These findings provide further understanding of the role of miR-155 in modulating aGVHD through T cell expansion, effector cytokine production, and migration. Copyright © 2018 by The American Association of Immunologists, Inc.

  17. Dendritic cell chimerism in oral mucosa of transplanted patients affected by graft-versus-host disease.

    Science.gov (United States)

    Pérez, Claudio A; Rabanales, Ramón; Rojas-Alcayaga, Gonzalo; Larrondo, Milton; Escobar, Alejandro F; López, Mercedes N; Salazar-Onfray, Flavio; Alfaro, Jorge I; González, Fermín E

    2016-02-01

    Graft-versus-host disease (GVHD) is one of the main complications after haematopoietic stem cell transplantation. Clinical features of GVHD include either an acute (aGVHD) or a chronic (cGVHD) condition that affects locations such as the oral mucosa. While the involvement of the host's dendritic cells (DCs) has been demonstrated in aGVHD, the origin (donor/host) and mechanisms underlying oral cGVHD have not been completely elucidated. In this study, we intend to determine the origin of DCs present in mucosal tissue biopsies from the oral cavity of transplanted patients affected by cGVHD. We purified DCs, from oral biopsies of three patients with cGVHD, through immunobeads and subsequently performed DNA extraction. The origin of the obtained DCs was determined by PCR amplification of 13 informative short tandem repeat (STR) alleles. We also characterised the DCs phenotype and the inflammatory infiltrate from biopsies of two patients by immunohistochemistry. Clinical and histological features of the biopsies were concordant with oral cGVHD. We identified CD11c-, CD207- and CD1a-positive cells in the epithelium and beneath the basal layer. Purification of DCs from the mucosa of patients affected by post-transplantation cGVHD was >95%. PCR-STR data analysis of DCs DNA showed that 100% of analysed cells were of donor origin in all of the evaluated patients. Our results demonstrate that resident DCs isolated from the oral tissue of allotransplanted patients affected by cGVHD are originated from the donor. Further research will clarify the role of DCs in the development and/or severity of oral cGVHD. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Impact of Donor Epstein-Barr Virus Serostatus on the Incidence of Graft-Versus-Host Disease in Patients With Acute Leukemia After Hematopoietic Stem-Cell Transplantation: A Study From the Acute Leukemia and Infectious Diseases Working Parties of the European Society for Blood and Marrow Transplantation.

    Science.gov (United States)

    Styczynski, Jan; Tridello, Gloria; Gil, Lidia; Ljungman, Per; Hoek, Jennifer; Iacobelli, Simona; Ward, Katherine N; Cordonnier, Catherine; Einsele, Hermann; Socie, Gerard; Milpied, Noel; Veelken, Hendrik; Chevallier, Patrice; Yakoub-Agha, Ibrahim; Maertens, Johan; Blaise, Didier; Cornelissen, Jan; Michallet, Mauricette; Daguindau, Etienne; Petersen, Eefke; Passweg, Jakob; Greinix, Hildegard; Duarte, Rafael F; Kröger, Nicolaus; Dreger, Peter; Mohty, Mohamad; Nagler, Arnon; Cesaro, Simone

    2016-07-01

    We investigated the effect of Epstein-Barr virus (EBV) serostatus on the overall outcome of allogeneic hematopoietic stem-cell transplantation (allo-HSCT). The study included 11,364 patients who underwent allogeneic peripheral-blood or bone marrow transplantation for acute leukemia between 1997 and 2012. We analyzed the impact of donor and recipient EBV serologic status on overall survival, relapse-free survival, relapse incidence, nonrelapse mortality, and incidence of graft-versus-host disease (GVHD) after allo-HSCT. Patients receiving grafts from EBV-seropositive donors had the same overall survival as patients who received grafts from EBV-seronegative donors (hazard ratio [HR], 1.05; 95% CI, 0.97 to 1.12; P = .23). Seropositive donors also had no influence on relapse-free survival (HR, 1.04; 95% CI, 0.97 to 1.11; P = 0.31), relapse incidence (HR, 1.03; 95% CI, 0.94 to 1.12; P = .58), and nonrelapse mortality (HR, 1.05; 95% CI, 0.94 to 1.17; P = .37). However, in univariate analysis, recipients receiving grafts from seropositive donors had a higher risk of chronic GVHD than those with seronegative donors (40.8% v 31.0%, respectively; P donors, the HR for chronic GVHD was 1.30 (95% CI, 1.06 to 1.59; P = .039). In seropositive patients with seropositive donors, the HR was 1.24 (95% CI, 1.07 to 1.45; P = .016) for acute GVHD and 1.43 (95% CI, 1.23 to 1.67; P donors did not have an increased risk of GVHD. Our data suggest that donor EBV status significantly influences development of acute and chronic GVHD after allo-HSCT. © 2016 by American Society of Clinical Oncology.

  19. Presentations and treatment of childhood scleroderma: localized scleroderma, eosinophilic fasciitis, systemic sclerosis, and graft-versus-host disease.

    Science.gov (United States)

    Hedrich, Christian Michael; Fiebig, Barbara; Hahn, Gabriele; Suttorp, Meinolf; Gahr, Manfred

    2011-07-01

    Juvenile scleroderma is a rare connective tissue disease that involves the skin and subcutaneous tissue. Among all presentations of juvenile scleroderma, localized scleroderma (JLSc) is the most frequent, followed by systemic disease (JSSc) and eosinophilic fasciitis (EF). In posttransplantation chronic graft-versus-host disease (GvHD), scleroderma-like skin involvement can occur. Systemic forms of juvenile scleroderma and GvHD can affect the internal organs, such as the lungs, the gastrointestinal tract, the heart, and kidneys and cause disability and severe, sometimes lethal, complications. Here, the authors give an overview of different presentations of juvenile scleroderma. They report their experience with the different forms and presentations of scleroderma, diagnostic workups, treatment, and outcome of all forms of childhood scleroderma in the context of the existing literature.

  20. Use of lymphokine-activated killer cells to prevent bone marrow graft rejection and lethal graft-vs-host disease

    International Nuclear Information System (INIS)

    Azuma, E.; Yamamoto, H.; Kaplan, J.

    1989-01-01

    Prompted by our recent finding that lymphokine-activated killer (LAK) cells mediate both veto and natural suppression, we tested the ability of adoptively transferred LAK cells to block two in vivo alloreactions which complicate bone marrow transplantation: resistance to transplanted allogeneic bone marrow cells, and lethal graft-vs-host disease. Adoptive transfer of either donor type B6D2 or recipient-type B6 lymphokine-activated bone marrow cells, cells found to have strong LAK activity, abrogated or inhibited the resistance of irradiated B6 mice to both B6D2 marrow and third party-unrelated C3H marrow as measured by CFU in spleen on day 7. The ability of lymphokine-activated bone marrow cells to abrogate allogeneic resistance was eliminated by C lysis depletion of cells expressing asialo-GM1, NK1.1, and, to a variable degree, Thy-1, but not by depletion of cells expressing Lyt-2, indicating that the responsible cells had a LAK cell phenotype. Similar findings were obtained by using splenic LAK cells generated by 3 to 7 days of culture with rIL-2. Demonstration that allogeneic resistance could be blocked by a cloned LAK cell line provided direct evidence that LAK cells inhibit allogeneic resistance. In addition to inhibiting allogeneic resistance, adoptively transferred recipient-type LAK cells prevented lethal graft-vs-host disease, and permitted long term engraftment of allogeneic marrow. Irradiation prevented LAK cell inhibition of both allogeneic resistance and lethal graft-vs-host disease. These findings suggest that adoptive immunotherapy with LAK cells may prove useful in preventing graft rejection and graft-versus-host disease in human bone marrow transplant recipients

  1. Graft-Versus-Host Disease in Adolescents and Young Adults (15-24 Years Old) After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Leukemia in First Complete Remission.

    Science.gov (United States)

    Vignon, Marguerite; Andreoli, Annalisa; Dhédin, Nathalie; Lengliné, Etienne; Masson, Emeline; Robin, Marie; Granier, Clémence; Larghero, Jérôme; Schlageter, Marie-Hélène; de Latour, Régis Peffault; Socié, Gérard; Boissel, Nicolas

    2017-06-01

    Adolescents and young adults (AYAs) with cancer are a unique group of patients in terms of disease incidence and biology, outcome, and psychosocial needs. This study aims to correlate the risk of graft-versus-host disease (GvHD) and age in a population of children and young adults with acute leukemia undergoing hematopoietic stem cell transplantation (HSCT) in first complete remission (CR). We analyzed the outcome of 153 consecutive children (<15 years), AYAs (15-24 years), and adults (25-35 years) with lymphoblastic or myeloid acute leukemia in first CR who underwent HSCT with matched donors after myeloablative conditioning. GvHD prophylaxis was methotrexate and cyclosporine A (CsA) in all patients. The cumulative incidence of grade II-IV acute GvHD (aGvHD) was significantly higher in AYA patients than in children (subdistribution hazard ratio (SHR), 2.04, p = 0.005) or adults (SHR 1.59, p = 0.048). Both gut and skin aGvHD occurred more frequently in AYA patients. Increasing CsA blood levels with age could not fully account for this difference. No difference in terms of grade III-IV aGvHD was observed. Chronic GvHD was more frequent in AYAs (SHR 2.81, p = 0.007) and adults (SHR 2.31, p = 0.033) than in children. No difference in terms of nonrelated mortality and overall survival was observed among the age subgroups. Since GvHD occurrence is strongly correlated to quality of life, specific attention should be paid to AYAs undergoing HSCT. Further studies should investigate the reasons for the excess of GvHD observed in this population.

  2. Engraftment of allogeneic bone marrow without graft-versus-host disease in mongrel dogs using total lymphoid irradiation

    International Nuclear Information System (INIS)

    Gottlieb, M.; Strober, S.; Hoppe, R.T.; Grumet, F.C.; Kaplan, H.S.

    1980-01-01

    We achieved long-term engraftment of unmatched bone marrow (BM) in dogs without graft-versus-host disease (GVHD) using a regimen of total lymphoid irradiation (TLI) which could be applied clinically. Twelve normal adult mongrel dogs were given TLI in 18 fractions of 100 rad each (total dose, 1800 rad) over 4 weeks to mantle and abdominal fields in continuity. Nine of the 12 were transfused with one or two random donor whole blood transfusions during the irradiation regimen to determine the risk of sensitization after the onset of immunosuppression. A mean (+- SD) of 0.71 +- 0.54 x 10 9 BM cells/kg of recipient body weight from unrelated sex-mismatched donors was infused within 24 h of the 18th irradiation fraction. Engraftment was assessed by demonstration of donor-type sex chromosomes in spontaneous metaphase spreads of recipient marrow aspirates, and by the appearance of donor-type red blood cells antigens (DEA) in the recipients' blood. Three untransfused and nine transfused recipients were shown to be stable mixed BM chimeras during a followup period of 2 to 11 months after transplantation. Blood transfusion during TLI did not result in graft rejection. We observed no clinical signs of acute or chronic GVHD. TLI has minimal toxicity when compared with conditioning regimens currently used in BM transplantation for aplastic anemia. Potential advantages of the TLI regimen include the opportunity to use unmatched marrow donors and protection from GVHD

  3. Prediction of graft-versus-host disease in humans by donor gene-expression profiling.

    Directory of Open Access Journals (Sweden)

    Chantal Baron

    2007-01-01

    Full Text Available BACKGROUND: Graft-versus-host disease (GVHD results from recognition of host antigens by donor T cells following allogeneic hematopoietic cell transplantation (AHCT. Notably, histoincompatibility between donor and recipient is necessary but not sufficient to elicit GVHD. Therefore, we tested the hypothesis that some donors may be "stronger alloresponders" than others, and consequently more likely to elicit GVHD. METHODS AND FINDINGS: To this end, we measured the gene-expression profiles of CD4(+ and CD8(+ T cells from 50 AHCT donors with microarrays. We report that pre-AHCT gene-expression profiling segregates donors whose recipient suffered from GVHD or not. Using quantitative PCR, established statistical tests, and analysis of multiple independent training-test datasets, we found that for chronic GVHD the "dangerous donor" trait (occurrence of GVHD in the recipient is under polygenic control and is shaped by the activity of genes that regulate transforming growth factor-beta signaling and cell proliferation. CONCLUSIONS: These findings strongly suggest that the donor gene-expression profile has a dominant influence on the occurrence of GVHD in the recipient. The ability to discriminate strong and weak alloresponders using gene-expression profiling could pave the way to personalized transplantation medicine.

  4. The prevalence and prognostic value of concomitant eosinophilia in chronic graft-versus-host disease after allogeneic stem cell transplantation

    DEFF Research Database (Denmark)

    Mortensen, Katrine Brandt; Gerds, Thomas Alexander; Bjerrum, Ole Weis

    2014-01-01

    The prognostic significance of eosinophilia after myeloablative allogeneic stem cell transplantation (ASCT) remains to be established. Patients, whom developed chronic graft-versus-host disease (cGVHD) after ASCT, were included (n = 142). Eosinophil count was analyzed at cGVHD onset. We observed...... no significant association between EO and the grade of cGVHD, thrombocytopenia, nor extensive skin involvement. Importantly, we observed no significant association between cGVHD with concomitant eosinophilia and long-term clinical outcomes, and subgroup analyses revealed a considerable confounding effect...

  5. Characterization of regulatory dendritic cells that mitigate acute graft-versus-host disease in older mice following allogeneic bone marrow transplantation.

    Science.gov (United States)

    Scroggins, Sabrina M; Olivier, Alicia K; Meyerholz, David K; Schlueter, Annette J

    2013-01-01

    Despite improvements in human leukocyte antigen matching and pharmacologic prophylaxis, acute graft-versus-host disease (GVHD) is often a fatal complication following hematopoietic stem cell transplant (HSCT). Older HSCT recipients experience significantly increased morbidity and mortality compared to young recipients. Prophylaxis with syngeneic regulatory dendritic cells (DCreg) in young bone marrow transplanted (BMT) mice has been shown to decrease GVHD-associated mortality. To evaluate this approach in older BMT recipients, young (3-4 months) and older (14-18 months) DCreg were generated using GM-CSF, IL-10, and TGFβ. Analysis of young versus older DCreg following culture revealed no differences in phenotype. The efficacy of DCreg treatment in older BMT mice was evaluated in a BALB/c→C57Bl/6 model of GVHD; on day 2 post-BMT (d +2), mice received syngeneic, age-matched DCreg. Although older DCreg-treated BMT mice showed decreased morbidity and mortality compared to untreated BMT mice (all of which died), there was a small but significant decrease in the survival of older DCreg-treated BMT mice (75% survival) compared to young DCreg-treated BMT mice (90% survival). To investigate differences between dendritic cells (DC) in young and older DCreg-treated BMT mice that may play a role in DCreg function in vivo, DC phenotypes were assessed following DCreg adoptive transfer. Transferred DCreg identified in older DCreg-treated BMT mice at d +3 showed significantly lower expression of PD-L1 and PIR B compared to DCreg from young DCreg-treated BMT mice. In addition, donor DC identified in d +21 DCreg-treated BMT mice displayed increased inhibitory molecule and decreased co-stimulatory molecule expression compared to d +3, suggesting induction of a regulatory phenotype on the donor DC. In conclusion, these data indicate DCreg treatment is effective in the modulation of GVHD in older BMT recipients and provide evidence for inhibitory pathways that DCreg and donor DC may

  6. Characterization of regulatory dendritic cells that mitigate acute graft-versus-host disease in older mice following allogeneic bone marrow transplantation.

    Directory of Open Access Journals (Sweden)

    Sabrina M Scroggins

    Full Text Available Despite improvements in human leukocyte antigen matching and pharmacologic prophylaxis, acute graft-versus-host disease (GVHD is often a fatal complication following hematopoietic stem cell transplant (HSCT. Older HSCT recipients experience significantly increased morbidity and mortality compared to young recipients. Prophylaxis with syngeneic regulatory dendritic cells (DCreg in young bone marrow transplanted (BMT mice has been shown to decrease GVHD-associated mortality. To evaluate this approach in older BMT recipients, young (3-4 months and older (14-18 months DCreg were generated using GM-CSF, IL-10, and TGFβ. Analysis of young versus older DCreg following culture revealed no differences in phenotype. The efficacy of DCreg treatment in older BMT mice was evaluated in a BALB/c→C57Bl/6 model of GVHD; on day 2 post-BMT (d +2, mice received syngeneic, age-matched DCreg. Although older DCreg-treated BMT mice showed decreased morbidity and mortality compared to untreated BMT mice (all of which died, there was a small but significant decrease in the survival of older DCreg-treated BMT mice (75% survival compared to young DCreg-treated BMT mice (90% survival. To investigate differences between dendritic cells (DC in young and older DCreg-treated BMT mice that may play a role in DCreg function in vivo, DC phenotypes were assessed following DCreg adoptive transfer. Transferred DCreg identified in older DCreg-treated BMT mice at d +3 showed significantly lower expression of PD-L1 and PIR B compared to DCreg from young DCreg-treated BMT mice. In addition, donor DC identified in d +21 DCreg-treated BMT mice displayed increased inhibitory molecule and decreased co-stimulatory molecule expression compared to d +3, suggesting induction of a regulatory phenotype on the donor DC. In conclusion, these data indicate DCreg treatment is effective in the modulation of GVHD in older BMT recipients and provide evidence for inhibitory pathways that DCreg and

  7. Marked in Vivo Donor Regulatory T Cell Expansion via Interleukin-2 and TL1A-Ig Stimulation Ameliorates Graft-versus-Host Disease but Preserves Graft-versus-Leukemia in Recipients after Hematopoietic Stem Cell Transplantation.

    Science.gov (United States)

    Wolf, Dietlinde; Barreras, Henry; Bader, Cameron S; Copsel, Sabrina; Lightbourn, Casey O; Pfeiffer, Brent J; Altman, Norman H; Podack, Eckhard R; Komanduri, Krishna V; Levy, Robert B

    2017-05-01

    Regulatory T cells (Tregs) are critical for self-tolerance. Although adoptive transfer of expanded Tregs limits graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT), ex vivo generation of large numbers of functional Tregs remains difficult. Here, we demonstrate that in vivo targeting of the TNF superfamily receptor TNFRSF25 using the TL1A-Ig fusion protein, along with IL-2, resulted in transient but massive Treg expansion in donor mice, which peaked within days and was nontoxic. Tregs increased in multiple compartments, including blood, lymph nodes, spleen, and colon (GVHD target tissue). Tregs did not expand in bone marrow, a critical site for graft-versus-malignancy responses. Adoptive transfer of in vivo-expanded Tregs in the setting of MHC-mismatched or MHC-matched allogeneic HSCT significantly ameliorated GVHD. Critically, transplantation of Treg-expanded donor cells facilitated transplant tolerance without GVHD, with complete sparing of graft-versus-malignancy. This approach may prove valuable as a therapeutic strategy promoting transplantation tolerance. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  8. Efficacy of two different doses of rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease in children with haematological malignancies transplanted from an unrelated donor: a multicentre, randomised, open-label, phase 3 trial

    OpenAIRE

    Locatelli, Franco; Bernardo, Maria Ester; Bertaina, Alice; Rognoni, Carla; Comoli, Patrizia; Rovelli, Attilio; Pession, Andrea; Fagioli, Franca; Favre, Claudio; Lanino, Edoardo; Giorgiani, Giovanna; Merli, Pietro; Pagliara, Daria; Prete, Arcangelo; Zecca, Marco

    2017-01-01

    Background Although rabbit anti-T-lymphocyte globulin (ATLG) is largely used for the prevention of immunemediated complications in patients given allogeneic haemopoietic stem-cell transplantation (HSCT) from an unrelated donor, the optimum dose of this drug in children is still undefined. We aimed to test whether a higher dose of ATLG was superior to a lower dose for prevention of grade II–IV acute graft-versus-host disease (GVHD). Methods We conducted a multicentre, randomised, open-label, p...

  9. Serum Vitamin A Levels May Affect the Severity of Ocular Graft-versus-Host Disease.

    Science.gov (United States)

    Tong, Jiefeng; Hu, Renjian; Zhao, Yingying; Xu, Yang; Zhao, Xiaoying; Jin, Xiuming

    2017-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapeutic option for a range of inherited and acquired hematological disorders. However, graft-versus-host disease (GVHD) remains the leading cause of non-relapse mortality in allogeneic HSCT recipients. Ocular involvement occurs in up to 80% of chronic GVHD patients. In our cases, the diagnosis of vitamin A deficiency was suspected for GVHD patients. Serum vitamin A measurements were conducted to confirm clinical suspicions. Our study revealed significant decrease in serum levels of vitamin A in chronic liver GVHD patients. Although there have been many studies evaluating ocular manifestations in patients with GVHD, the present study is, to our knowledge, the first to study the relationship between vitamin A and ocular manifestations of GVHD in humans. Our data suggest that vitamin A deficiency affects the severity of ocular GVHD in adults.

  10. [Ocular graft-versus-host disease: An often misdiagnosed etiology of dry eye syndrome].

    Science.gov (United States)

    Moyal, L; Adam, R; Akesbi, J; Rodallec, F T; Nordmann, J-P

    2017-02-01

    To report a case of severe ocular graft-versus-host disease (GVHD) after cataract surgery. Observational case report. We describe the case of a 59-year-old man with postoperative corneal ulcer on his only functional eye. His past history reported allogenic bone marrow transplant. His visual acuity (VA) was limited to hand motions. Slit lamp examination revealed diffuse conjunctival hyperemia, severe blepharitis, Meibomian dysfunction, total corneal opacification with epithelial and stromal keratitis and neovascular invasion. Because of the severe dry eye symptoms and history of allogenic hematological stem cell transplantation, ocular GVHD was diagnosed. Functional and anatomical improvement occurred rapidly with topical cyclosporine 2%, with improved VA after treatment. With any severe dry eye syndrome in the context of allogenic bone marrow transplant, ocular GVHD must be considered. For planned ocular surgery, we recommend adding cyclosporine 0.1% treatment before and after surgery to prevent severe ocular GVHD. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  11. HY-Specific Induced Regulatory T Cells Display High Specificity and Efficacy in the Prevention of Acute Graft-versus-Host Disease.

    Science.gov (United States)

    Li, Jun; Heinrichs, Jessica; Haarberg, Kelley; Semple, Kenrick; Veerapathran, Anandharaman; Liu, Chen; Anasetti, Claudio; Yu, Xue-Zhong

    2015-07-15

    Naturally derived regulatory T cells (Tregs) may prevent graft-versus-host disease (GVHD) while preserving graft-versus-leukemia (GVL) activity. However, clinical application of naturally derived regulatory T cells has been severely hampered by their scarce availability and nonselectivity. To overcome these limitations, we took alternative approaches to generate Ag-specific induced Tregs (iTregs) and tested their efficacy and selectivity in the prevention of GVHD in preclinical models of bone marrow transplantation. We selected HY as a target Ag because it is a naturally processed, ubiquitously expressed minor histocompatibility Ag (miHAg) with a proven role in GVHD and GVL effect. We generated HY-specific iTregs (HY-iTregs) from resting CD4 T cells derived from TCR transgenic mice, in which CD4 cells specifically recognize HY peptide. We found that HY-iTregs were highly effective in preventing GVHD in male (HY(+)) but not female (HY(-)) recipients using MHC II-mismatched, parent→F1, and miHAg-mismatched murine bone marrow transplantation models. Interestingly, the expression of target Ag (HY) on the hematopoietic or nonhematopoietic compartment alone was sufficient for iTregs to prevent GVHD. Furthermore, treatment with HY-iTregs still preserved the GVL effect even against pre-established leukemia. We found that HY-iTregs were more stable in male than in female recipients. Furthermore, HY-iTregs expanded extensively in male but not female recipients, which in turn significantly reduced donor effector T cell expansion, activation, and migration into GVHD target organs, resulting in effective prevention of GVHD. This study demonstrates that iTregs specific for HY miHAgs are highly effective in controlling GVHD in an Ag-dependent manner while sparing the GVL effect. Copyright © 2015 by The American Association of Immunologists, Inc.

  12. Serum Vitamin A Levels May Affect the Severity of Ocular Graft-versus-Host Disease

    Directory of Open Access Journals (Sweden)

    Jiefeng Tong

    2017-06-01

    Full Text Available Allogeneic hematopoietic stem cell transplantation (HSCT is a well-established therapeutic option for a range of inherited and acquired hematological disorders. However, graft-versus-host disease (GVHD remains the leading cause of non-relapse mortality in allogeneic HSCT recipients. Ocular involvement occurs in up to 80% of chronic GVHD patients. In our cases, the diagnosis of vitamin A deficiency was suspected for GVHD patients. Serum vitamin A measurements were conducted to confirm clinical suspicions. Our study revealed significant decrease in serum levels of vitamin A in chronic liver GVHD patients. Although there have been many studies evaluating ocular manifestations in patients with GVHD, the present study is, to our knowledge, the first to study the relationship between vitamin A and ocular manifestations of GVHD in humans. Our data suggest that vitamin A deficiency affects the severity of ocular GVHD in adults.

  13. The Green Tea Catechin Epigallocatechin Gallate Ameliorates Graft-versus-Host Disease.

    Directory of Open Access Journals (Sweden)

    Sabine Westphal

    Full Text Available Allogeneic hematopoetic stem cell transplantation (allo-HSCT is a standard treatment for leukemia and other hematologic malignancies. The major complication of allo-HSCT is graft-versus-host-disease (GVHD, a progressive inflammatory illness characterized by donor immune cells attacking the organs of the recipient. Current GVHD prevention and treatment strategies use immune suppressive drugs and/or anti-T cell reagents these can lead to increased risk of infections and tumor relapse. Recent research demonstrated that epigallocatechin gallate (EGCG, a component found in green tea leaves at a level of 25-35% at dry weight, may be useful in the inhibition of GVHD due to its immune modulatory, anti-oxidative and anti-angiogenic capacities. In murine allo-HSCT recipients treated with EGCG, we found significantly reduced GVHD scores, reduced target organ GVHD and improved survival. EGCG treated allo-HSCT recipients had significantly higher numbers of regulatory T cells in GVHD target organs and in the blood. Furthermore, EGCG treatment resulted in diminished oxidative stress indicated by significant changes of glutathione blood levels as well as glutathione peroxidase in the colon. In summary, our study provides novel evidence demonstrating that EGCG ameliorates lethal GVHD and reduces GVHD-related target organ damage. Possible mechanisms are increased regulatory T cell numbers and reduced oxidative stress.

  14. Preventing transfusion-associated graft-versus-host disease: state of the art

    Directory of Open Access Journals (Sweden)

    Fast LD

    2015-01-01

    Full Text Available Loren D Fast Division of Hematology/Oncology, Rhode Island Hospital and Warren Alpert School of Medicine at Brown University, Providence, RI, USA Abstract: The transfer of pathogens and the induction of immune responses are deleterious consequences that can result from the transfusion of blood products. Transfusion-associated graft-versus-host disease (TA-GVHD, the most severe immune consequence, occurs when recipient immune responses are incapable of effectively eliminating donor leukocytes, permitting unabated responses of the donor T lymphocytes. Currently, prevention of TA-GVHD is routinely accomplished by exposing blood products to γ-irradiation in order to prevent donor T cell proliferation. Alternative protocols are being developed to meet the challenges associated with the use of γ-irradiation. Use of pathogen reduction protocols, which interfere with nucleic acid replication by modifying nucleic acids, are increasing. Comparison of pathogen reduction protocols with γ-irradiation have found that both protocols are equally effective in preventing T lymphocyte proliferation and GVHD responses when testing in both in vitro and in vivo models. The potential use of pathogen reduction protocols to treat whole blood prior to separation into its components could provide a cost-effective method for preventing TA-GVHD in the future. Keywords: blood transfusion, GVHD, pathogen reduction, irradiation

  15. Small hypoxia-primed mesenchymal stem cells attenuate graft-versus-host disease

    KAUST Repository

    Kim, YongHwan

    2018-05-22

    Mesenchymal stem cells (MSCs) are of particular interest for the treatment of immune-related diseases due to their immunosuppressive capacity. Here, we show that Small MSCs primed with Hypoxia and Calcium ions (SHC-MSCs) exhibit enhanced stemness and immunomodulatory functions for treating allogeneic conflicts. Compared with naïve cultured human umbilical cord blood-derived MSCs, SHC-MSCs were resistant to passage-dependent senescence mediated via the monocyte chemoattractant protein-1 and p53/p21 cascade and secreted large amounts of pro-angiogenic and immunomodulatory factors, resulting in suppression of T-cell proliferation. SHC-MSCs showed DNA demethylation in pluripotency, germline, and imprinted genes similarly to very small embryonic-like stem cells, suggesting a potential mutual relationship. Genome-wide DNA methylome and transcriptome analyses indicated that genes related to immune modulation, cell adhesion, and the cell cycle were up-regulated in SHC-MSCs. Particularly, polo-like kinase-1 (PLK1), zinc-finger protein-143, dehydrogenase/reductase-3, and friend-of-GATA2 play a key role in the beneficial effects of SHC-MSCs. Administration of SHC-MSCs or PLK1-overexpressing MSCs significantly ameliorated symptoms of graft-versus-host disease (GVHD) in a humanized mouse model, resulting in significantly improved survival, less weight loss, and reduced histopathologic injuries in GVHD target organs compared with naïve MSC-infused mice. Collectively, our findings suggest that SHC-MSCs can improve the clinical treatment of allogeneic conflicts, including GVHD.

  16. Ocular manifestations of graft-versus-host disease: 10 years’ experience

    Directory of Open Access Journals (Sweden)

    Lin X

    2015-07-01

    Full Text Available Xihui Lin, Harrison Dwight Cavanagh Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX, USA Purpose: To evaluate the ocular presentation, treatment, and clinical course of graft-versus-host disease (GVHD. Design: Retrospective case series. Participants: Two hundred and forty-nine patients with systemic GVHD were included in the study. Methods: Ocular and systemic data were collected from 2003 to 2013. Main outcome measures: Mortality, visual acuity, and response of ocular symptoms. Results: Sixty-four patients had ocular manifestations (25.7%. At presentation, the mean age was 44.5 years and mean latency was 16.4 months. The most common presentations were keratoconjunctivitis sicca, cataract, blepharitis, ocular hypertension, and filamentary keratitis. Visual acuity at presentation was 20/49; at the worst point in the disease was 20/115; and at most recent visit was 20/63. When topical anti-inflammatory drops were used in addition to tears, 54.3% of patients’ ocular symptoms stabilized. When autologous serum was used in addition, 80% stabilized. The overall 10-year mortality of GVHD was 29.7%. For those with ocular involvement, it was 21.9%. Conclusion: Systemic GVHD has a high mortality rate, but ocular involvement does not suggest a worse prognosis. The main ocular presentations were keratoconjunctivitis sicca, cataracts, and ocular hypertension. Dry eyes in this population were very severe with overall worsening in visual acuity. However, with a step-wise approach involving topical anti-inflammatory medications and autologous serum tears, ocular symptoms do improve. It is important to monitor these patients closely, as they are prone to serious ocular complications such as corneal perforation and endophthalmitis. Keywords: dry eye, keratitis, corneal ulceration

  17. MR findings in patients with disabling musculocutaneous chronic graft-versus-host disease

    Energy Technology Data Exchange (ETDEWEB)

    Horger, M.; Boss, A.; Claussen, C.D. [Eberhard-Karls-University, Department of Diagnostic Radiology, Tuebingen (Germany); Bethge, W.; Faul, C.; Vogel, W. [Eberhard-Karls-University, Department of Internal Medicine-Oncology, Tuebingen (Germany); Fierlbeck, G. [Eberhard-Karls-University, Department of Dermatology, Tuebingen (Germany); Bornemann, A. [Eberhard-Karls-University, Insitute for Brain Research, Tuebingen (Germany)

    2008-10-15

    To describe musculocutaneous MR-findings responsible for disability in chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT). Between June 2005 and February 2008, we performed whole-body musculoskeletal magnetic resonance imaging (MRI; n = 12) or regional MRI (n = 4) in 16 consecutive patients presenting with disabling sclerodermatous cGVHD (e.g., skin edema, fixed deep dermal sclerosis, joint contractures, painful muscular contractures, or myalgia). In all patients, MRI showed musculocutaneous abnormalities reflecting different degrees of inflammation and collagen tissue involvement of the skin (n = 10), subcutaneous fat tissue (n = 13), muscle fasciae (n = 16), subfascial muscular septae (n = 6), or findings compatible with myositis (n = 3). The most frequently involved muscle fasciae comprised those of the vastus lateralis muscle (n = 12), biceps femoris muscle (n = 11), gastrocnemius medialis muscle (n = 8), serratus anterior muscle, and latissimus dorsi muscle (each, n = 5). Increased signal of involved tissues on STIR-images and fat-saturated postgadolinium T1-weighted images represented the most frequent MR-signal abnormalities. MR imaging of musculocutaneous cGVHD allows accurate evaluation including assessment of deep tissue infiltration and assists in the differential diagnosis. (orig.)

  18. MR findings in patients with disabling musculocutaneous chronic graft-versus-host disease

    International Nuclear Information System (INIS)

    Horger, M.; Boss, A.; Claussen, C.D.; Bethge, W.; Faul, C.; Vogel, W.; Fierlbeck, G.; Bornemann, A.

    2008-01-01

    To describe musculocutaneous MR-findings responsible for disability in chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT). Between June 2005 and February 2008, we performed whole-body musculoskeletal magnetic resonance imaging (MRI; n = 12) or regional MRI (n = 4) in 16 consecutive patients presenting with disabling sclerodermatous cGVHD (e.g., skin edema, fixed deep dermal sclerosis, joint contractures, painful muscular contractures, or myalgia). In all patients, MRI showed musculocutaneous abnormalities reflecting different degrees of inflammation and collagen tissue involvement of the skin (n = 10), subcutaneous fat tissue (n 13), muscle fasciae (n = 16), subfascial muscular septae (n = 6), or findings compatible with myositis (n = 3). The most frequently involved muscle fasciae comprised those of the vastus lateralis muscle (n = 12), biceps femoris muscle (n = 11), gastrocnemius medialis muscle (n = 8), serratus anterior muscle, and latissimus dorsi muscle (each, n = 5). Increased signal of involved tissues on STIR-images and fat-saturated postgadolinium T1-weighted images represented the most frequent MR-signal abnormalities. MR imaging of musculocutaneous cGVHD allows accurate evaluation including assessment of deep tissue infiltration and assists in the differential diagnosis. (orig.)

  19. IL-17 Genetic and Immunophenotypic Evaluation in Chronic Graft-versus-Host Disease

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    Renata Gonçalves Resende

    2014-01-01

    Full Text Available Although interleukin-17 (IL-17 is a recently discovered cytokine associated with several autoimmune diseases, its role in the pathogenesis of chronic graft-versus-host disease (cGVHD was not established yet. The objective of this study was to investigate the association of IL17A and IL17F genes polymorphisms and IL-17A and IL-17F levels with cGVHD. IL-17A expression was also investigated in CD4+ T cells of patients with systemic cGVHD. For Part I of the study, fifty-eight allo-HSCT recipients and donors were prospectively studied. Blood samples were obtained to determine IL17A and IL17F genes polymorphisms. Cytokines levels in blood and saliva were assessed by ELISA at days +35 and +100 after HSCT. In Part II, for the immunophenotypic evaluation, eight patients with systemic cGVHD were selected and the expression of IL-17A was evaluated. We found association between recipient AA genotype with systemic cGVHD. No association was observed between IL-17A levels and cGVHD. Lower IL-17A levels in the blood were associated with AA genotype. In flow cytometry analysis, decreased expression of IL-17A was observed in patients with cGVHD after stimulation. In conclusion, IL-17A may have an important role in the development of systemic cGVHD.

  20. Graft-versus-host reaction in small bowel transplantation and possibilities for its circumvention

    International Nuclear Information System (INIS)

    Deltz, E.; Ulrichs, K.; Schack, T.; Friedrichs, B.; Mueller-Ruchholtz, W.M.; Mueller-Hermelink, H.K.T.; Thiede, A.

    1986-01-01

    To describe GVHR in small bowel transplantation and its underlying mechanisms and to find methods for circumventing that response, accessory small bowel transplantation was carried out in the rat model. Animals not treated with cyclosporine, irradiation, or removal of the mesenteric lymph nodes of the graft died within 22 days postoperatively due to graft versus host disease. Mesenteric lymph nodes of the graft and recipient spleen and peripheral lymph nodes showed strong immunologic stimulation histologically and high antihost T-cell-mediated cytotoxic antihost reactivity. Seventy-one percent of the animals that had received 15 mg of cyclosporine per kilogram body weight orally survived 150 days after transplantation. After donor irradiation with 50 rads, 77 percent of the recipients survived 120 days. After microsurgical removal of the mesenteric lymph nodes of the graft, 89 percent survived 120 days. We conclude that GVHR plays an important role in small bowel transplantation and that the experimental regimens of donor, graft, and recipient treatment described herein have proved their efficacy for circumventing GVHR

  1. Ultraviolet irradiation modulates MHC-alloreactive cytotoxic T-cell precursors involved in the onset of graft-versus-host disease

    International Nuclear Information System (INIS)

    Prooijen, H.C. Van; Aarts-Riemens, M.I.; Weelden, H. Van; Grijzenhout, M.A.

    1992-01-01

    Ultraviolet B (UVB) irradiation of cellular blood components has been proposed as a new technology to prevent HLA sensitization in recipients. Earlier studies have shown that a dose of 2 J/cm 2 abrogates the ability of lymphocytes to serve as stimulators in mixed lymphocyte cultures (MLC). In this study the authors evaluate the effect of UV energy on T-lymphocytes for the prevention of transfusion-associated graft-versus-host disease (TA-GvHD). The response of cytotoxic T-lymphocyte precursors against host alloantigens was almost undetectable at a dose of 0.5 J/cm 2 . T-cell proliferation in MLC or in response to phytohaemagglutinin was inhibited by more than 95% at doses of 1 J/cm 2 or higher. The data suggest that UV irradiation can be used to prevent both HLA sensitization and TA-GvHD in recipients. (Author)

  2. Lethal graft-versus-host disease: modification with allogeneic cultured donor cells

    International Nuclear Information System (INIS)

    Mauch, P.; Lipton, J.M.; Hamilton, B.; Obbagy, J.; Kudisch, M.; Nathan, D.; Hellman, S.

    1984-01-01

    The use of the bone marrow culture technique was studied as a means to prepare donor marrow for bone marrow transplantation to avoid lethal graft-versus-host disease (GVHD). Preliminary experiments demonstrated the rapid loss of theta-positive cells in such cultures, so that theta-positive cells were not detected after 6 days. Initial experiments in C3H/HeJ (H-2k, Hbbd) recipients prepared with 900 rad demonstrated improved survival when 3-day cultured C57BL/6 (H-2b, Hbbs) donor cells were used in place of hind limb marrow for transplantation. However, hemoglobin typing of recipient animals revealed only short-term donor engraftment, with competitive repopulation of recipient marrow occurring. Subsequent experiments were done in 1,200-rad prepared recipients, with long-term donor engraftment demonstrated. The majority of 1,200-rad prepared animals receiving cultured allogeneic cells died of GVHD, but animals receiving 28-day cultured cells had an improved 90-day survival and a delay in GVHD development over animals receiving hind limb marrow or marrow from shorter times in culture. In addition, animals receiving anti-theta-treated, 3-day nonadherent cells had an improved survival (44%) over animals receiving anti-theta-treated hind limb marrow (20%). These experiments demonstrate modest benefit for the use of cultured cells in bone marrow transplantation across major H-2 histocompatibility complex differences

  3. Reversal of CD8 T-Cell–Mediated Mucocutaneous Graft-Versus-Host-Like Disease by the JAK Inhibitor Tofacitinib

    Science.gov (United States)

    Okiyama, Naoko; Furumoto, Yasuko; Villarroel, Vadim A; Linton, Jay T; Tsai, Wanxia L; Gutermuth, Jan; Ghoreschi, Kamran; Gadina, Massimo; O'Shea, John J; Katz, Stephen I

    2014-01-01

    The utility of allogeneic hematopoietic stem cell transplantation is limited by graft-versus-host disease (GVHD), a significant cause of morbidity and mortality. Patients with GVHD exhibit cutaneous manifestations with histological features of interface dermatitis followed by scleroderma-like changes. JAK inhibitors represent a class of immunomodulatory drugs that inhibit signaling by multiple cytokines. Herein we report the effects of tofacitinib in a murine model of GVHD. Oral administration of tofacitinib prevented GVHD-like disease manifested by weight loss and mucocutaneous lesions. More importantly, tofacitinib was also effective in reversing established disease. Tofacitinib diminished the expansion and activation of murine CD8 T cells in this model, and had similar effects on IL-2-stimulated human CD8 T cells. Tofacitinib also inhibited the expression of IFN-γ-inducible chemoattractants by keratinocytes, and IFN-γ-inducible cell death of keratinocytes. Tofacitinib may be an effective drug for treatment against CD8 T-cell–mediated mucocutaneous diseases in patients with GVHD. PMID:24213371

  4. Vision-Related Quality of Life in Patients with Ocular Graft-versus-Host Disease.

    Science.gov (United States)

    Saboo, Ujwala S; Amparo, Francisco; Abud, Tulio B; Schaumberg, Debra A; Dana, Reza

    2015-08-01

    To assess the vision-related quality of life (QOL) in a cohort of patients with ocular graft-versus-host disease (GVHD). Prospective study. Eighty-four patients diagnosed with chronic ocular GVHD. We assessed the vision-related QOL with the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). The symptoms of ocular GVHD were assessed using the Ocular Surface Disease Index (OSDI) and Symptom Assessment in Dry Eye (SANDE) questionnaires. We assessed vision-related QOL with the NEI-VFQ-25 and compared the scores obtained from patients with ocular GVHD with those from a healthy population. In the ocular GVHD population, we also evaluated the associations between the NEI-VFQ-25 and the dry eye symptoms measured by the OSDI and SANDE questionnaires, age, duration of disease, best-corrected visual acuity (BCVA), corneal fluorescein staining (CFS), tear break-up time, and Schirmer test. The mean composite NEI-VFQ-25 score in patients with ocular GVHD was 76.5±17. Compared with healthy subjects, patients with ocular GVHD reported reduced scores on all NEI-VFQ-25 subscales (each P vision (P = 0.11). The NEI-VFQ-25 composite scores significantly correlated with OSDI (R = -0.81, P vision-related QOL. This study highlights the impact of ocular GVHD on the vision-related QOL, and thus the importance of comprehensive diagnosis and treatment of this condition. Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

  5. RANTES polymorphisms and the risk of graft-versus-host disease in human leukocyte antigen-matched sibling allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Shin, Dong-Yeop; Kim, Inho; Kim, Jin Hee; Lee, Yun-Gyoo; Kang, Eun Joo; Cho, Hyeon Jin; Lee, Kyung-Hun; Kim, Hye Jin; Park, Eun-Hee; Lee, Jong-Eun; Bae, Ji-Yeon; See, Cha Ja; Yoon, Sung-Soo; Park, Sung Sup; Han, Kyou-Sup; Park, Myoung Hee; Hong, Yun-Chul; Park, Seonyang; Kim, Byoung Kook

    2013-01-01

    We investigated the association between RANTES (regulated upon activation, normal T cell expressed and secreted) polymorphisms and clinical outcomes in patients treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Three RANTES gene polymorphisms, i.e., -403G/A (rs2107538), -28C/G (rs2280788) and In1.1T/C (rs2280789), were genotyped, and the effects of the genotypes and haplotypes of RANTES on clinical outcomes were analyzed. The competing risk regression analysis was used to investigate the relationship between the polymorphisms and the cumulative risk of graft-versus-host disease (GVHD). An AGC haplotype in a recessive model showed significant harmful effects on the cumulative risk of acute GVHD and relapse-free survival (adjusted hazard ratios 2.42 and 2.71, 95% confidence intervals 1.29-4.55 and 1.30-5.64; p = 0.018 and 0.024, respectively), whereas a GCT haplotype did not. RANTES polymorphisms were not significantly associated with overall survival and the risk of chronic GVHD. This study suggests that RANTES polymorphisms might be associated with the occurrence of acute GVHD rather than of chronic GVHD and also of relapse-free survival in the patients treated with allo-HSCT. Further larger prospective investigations are needed to establish the role of RANTES polymorphisms in patients treated with allo-HSCT. Copyright © 2012 S. Karger AG, Basel.

  6. Vulvar and vaginal graft versus host disease: A healthcare clinic initiative

    Directory of Open Access Journals (Sweden)

    Naomi Van Dam

    2017-01-01

    Full Text Available Objective: In patients receiving bone marrow transplantation (BMT, their mucosa becomes altered and sclerotic changes in the female external genital organs occur. Although a few studies have specifically addressed vulvar and vaginal graft versus host disease (VVGvHD and its repercussions on the sexual health and quality of life of patients, VVGvHD can be overlooked by health practitioners. The objective of the study is to describe the initiation of a health care clinic specializing in VVGvHD in a general tertiary hospital. Methods: A VVGvHD clinic was founded as a part of BMT daycare in a joint initiative of the nursing staff and the medical director of the department and a gynecologist specializing in vulva and vaginal disease. Patients were assessed for vulvovaginal symptoms, such as dryness, burning, itching, pain to touch, pain during intercourse, and dysuria. These patients might be subsequently referred to the VVGvHD clinic according to their needs assessed by daycare nurses. Treatment guidelines were developed by the specialist gynecologist. Results: A total of 81 women aged 2–66 years (median age = 38 years visited the clinic from 2009 to 2015. Of these women, 70 received an allogeneic transplant and 11 underwent autologous transplantation before consultation in our clinic. VVGvHD was detected in 54% of the patients. Conclusions: The VVGvHD clinic was developed to fulfill the specific needs of female patients who underwent BMT. The pioneer clinic was founded as a joint effort of the multidisciplinary team. Evidence supporting the optimum treatment for this condition is insufficient. This was the main reason for performing this study to explore the clinic that was newly based in Israel. VVGvHD may be a fluctuating condition with frequent deterioration and improvement. Therefore, regular clinical examinations are necessary.

  7. Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice

    Science.gov (United States)

    Nguyen, Hung; Bastian, David; Heinrichs, Jessica; Wu, Yongxia; Liu, Chen; McDonald, Daniel G.; Pidala, Joseph; Yu, Xue-Zhong

    2015-01-01

    Bruton’s Tyrosine Kinase (BTK) and IL-2 Inducible T-cell Kinase (ITK) are enzymes responsible for the phosphorylation and activation of downstream effectors in the B-cell receptor (BCR) signaling and T cell receptor (TCR) signaling pathways, respectively. Ibrutinib is an FDA-approved potent inhibitor of both BTK and ITK that impairs B-cell and T-cell function. CD4 T cells and B cells are essential for the induction of chronic graft-versus-host disease (cGVHD). We evaluated these targets by testing the ability of Ibrutinib to prevent or ameliorate cGVHD, which is one of the major complications for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that Ibrutinib significantly alleviated cGVHD across four different mouse models, accompanied by increased long-term survival and reduced clinical score. The clinical improvements in Ibrutinib-treated recipients were associated with decreased serum-autoantibodies, costimulatory molecule activation, B-cell proliferation, and glomerulonephritis compared to vehicle controls. Ibrutinib was also able to alleviate the clinical manifestations in acute GVHD (aGVHD), where the recipients were given grafts with or without B cells, suggesting that an inhibitory effect of Ibrutinib on T cells contributes to a reduction in both aGVHD and cGVHD pathogenesis. An effective prophylactic regimen is still lacking to both reduce the incidence and severity of human cGVHD following allo-HSCT. Our study shows that Ibrutinib is an effective prophylaxis against several mouse models of cGVHD with minimal toxicity and could be a promising strategy to combat human cGVHD clinically. PMID:26348529

  8. Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice.

    Directory of Open Access Journals (Sweden)

    Steven D Schutt

    Full Text Available Bruton's Tyrosine Kinase (BTK and IL-2 Inducible T-cell Kinase (ITK are enzymes responsible for the phosphorylation and activation of downstream effectors in the B-cell receptor (BCR signaling and T cell receptor (TCR signaling pathways, respectively. Ibrutinib is an FDA-approved potent inhibitor of both BTK and ITK that impairs B-cell and T-cell function. CD4 T cells and B cells are essential for the induction of chronic graft-versus-host disease (cGVHD. We evaluated these targets by testing the ability of Ibrutinib to prevent or ameliorate cGVHD, which is one of the major complications for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT. We found that Ibrutinib significantly alleviated cGVHD across four different mouse models, accompanied by increased long-term survival and reduced clinical score. The clinical improvements in Ibrutinib-treated recipients were associated with decreased serum-autoantibodies, costimulatory molecule activation, B-cell proliferation, and glomerulonephritis compared to vehicle controls. Ibrutinib was also able to alleviate the clinical manifestations in acute GVHD (aGVHD, where the recipients were given grafts with or without B cells, suggesting that an inhibitory effect of Ibrutinib on T cells contributes to a reduction in both aGVHD and cGVHD pathogenesis. An effective prophylactic regimen is still lacking to both reduce the incidence and severity of human cGVHD following allo-HSCT. Our study shows that Ibrutinib is an effective prophylaxis against several mouse models of cGVHD with minimal toxicity and could be a promising strategy to combat human cGVHD clinically.

  9. Reduction of fatal graft-versus-host disease by 3H--thymidine suicide of donor cells cultured with host cells

    International Nuclear Information System (INIS)

    Cheever, M.A.; Einstein, A.B. Jr.; Kempf, R.A.; Fefer, A.

    1977-01-01

    The effect of the tritiated thymidine ( 3 H-TdR) suicide technique on the ability of donor cells to induce fatal graft-versus-host disease (GVHD) was studied. C57BL/6 (H-2/sup b/) spleen cells were stimulated in vitro with irradiated BALB/c (H-2/sup d/) Moloney lymphoma cells in mixed culture and 3 H-TdR of high-specific activity added to eliminate proliferating cells. The ability of such cells to induce fatal GVHD was assayed by injecting them i.v. into adult BALB/c mice immunosuppressed with cyclophosphamide (180 mg/kg). These cells induced fatal GVHD in fewer mice (52 percent) than did C57BL/6 cells cultured with BALB/c lymphoma cells but without 3 H-TdR (87 percent) and C57BL/6 cells cultured with irradiated C57BL/6 cells with (95 percent) or without 3 H-TdR (86 percent). Thus, the 3 H-TdR suicide technique greatly diminished the ability of cells to induce lethal GVHD

  10. Autologous Graft versus Host Disease: An Emerging Complication in Patients with Multiple Myeloma

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    Anu Batra

    2014-01-01

    Full Text Available Autologous graft versus host disease (autoGVHD is a rare transplant complication with significant morbidity and mortality. It has been hypothesized that patients with multiple myeloma might be predisposed to autoGVHD through dysregulation of the immune response resulting from either their disease, the immunomodulatory agents (IMiDs used to treat it, or transplant conditioning regimen. Hematopoietic progenitor cell (HPC products were available from 8 multiple myeloma patients with biopsy-proven autoGVHD, 16 matched multiple myeloma patients who did not develop autoGVHD, and 7 healthy research donors. The data on number of transplants prior to developing autoGVHD, mobilization regimens, exposure to proteasome inhibitors, use of IMiDs, and class I human leukocyte antigen types (HLA A and B were collected. The HPC products were analyzed by flow cytometry for expression of CD3, CD4, CD8, CD25, CD56, and FoxP3. CD3+ cell number was significantly lower in autoGVHD patients compared to unaffected controls (P=0.047. On subset analysis of CD3+ cells, CD8+ cells (but not CD4+ cells were found to be significantly lower in patients with autoGVHD (P=0.038. HLA-B55 expression was significantly associated with development of autoGVHD (P=0.032. Lower percentages of CD3+ and CD8+ T-cells and HLA-B55 expression may be predisposing factors for developing autoGVHD in myeloma.

  11. Avoidance of graft versus host reactions in cured W-anemic mice

    International Nuclear Information System (INIS)

    Harrison, D.E.

    1976-01-01

    Graft-versus-host reactions of parental cells in F 1 hybrids were studied with two unrelated inbred strains of mice that differed at the mouse major histocompatibility locus. W-anemic F 1 recipients were compared with lethally irradiated normal F 1 recipients. Both sets of recipients were populated by marrow and spleen cell grafts from parental and F 1 donors. Most W-anemic F 1 recipients were cured by parental and F 1 cell grafts (except B6 spleen). Even after 13 to 18 months, they showed little or no effect from GVH reactions. Lethally irradiated normal F 1 recipients tolerated parental marrow grafts almost as well, but gave dramatically different results with parental spleen grafts. Seventy-nine of 80 irradiated F 1 recipients of parental spleen grafts died within 1 month. Unlike lethally irradiated recipients, W-anemic recipients have substantial numbers of their own cells along with the donor cells in their lymphoid tissues. These F 1 lymphocytes may interact with parental lymphocytes in vivo to restrain reactions against F 1 allogeneic antigens

  12. Beneficial Role of Low-Dose Antithymocyte Globulin in Unrelated Stem Cell Transplantation for Adult Patients with Acquired Severe Aplastic Anemia: Reduction of Graft-versus-Host Disease and Improvement of Graft-versus-Host Disease-Free, Failure-Free Survival Rate.

    Science.gov (United States)

    Park, Sung-Soo; Kwak, Dae Hun; Jeon, Young-Woo; Yoon, Jae-Ho; Lee, Sung-Eun; Cho, Byung-Sik; Eom, Ki-Seong; Kim, Yoo-Jin; Kim, Hee-Je; Lee, Seok; Min, Chang-Ki; Cho, Seok-Goo; Kim, Dong-Wook; Min, Woo-Sung; Lee, Jong Wook

    2017-09-01

    Stem cell transplantation (SCT) from an unrelated donor (URD) is often considered in patients with severe aplastic anemia (SAA) whom immunosuppressive therapy failed and matched sibling donor is not available. To reduce the incidence of graft-versus-host disease (GVHD) in URD SCT, introducting antithymocyte globulin (ATG) into the conditioning regimen has been proposed. Although ATG was shown to play a role in reducing GVHD in a cohort with diverse hematologic diseases, its role in SAA remains uncertain. The aim of this study was to determine the efficacy and toxicity of ATG in URD SCT for adult patients with SAA. We investigated 83 adult patients with SAA who underwent URD SCT between 2003 and 2014. The transplantation strategy consisted of total body irradiation (total 800 cGy) and cyclophosphamide (total 100 mg/kg to 120 mg/kg), followed by tacrolimus and a short-term methotrexate. We divided patients into 2 groups: group 1 (n = 25), which received HLA-matched (8/8) bone marrow (BM) without ATG, and group 2 (n = 58), which received SCT from either an HLA-mismatched donor or peripheral blood (PB). Thereafter, group 2 was subdivided according to ATG use into group 2A (without ATG, n = 26), which served as a historical cohort, and group 2B (with ATG, n = 32). Rabbit ATG (Thymoglobulin; Genzyme-Sanofi, Lyon, France) was used in group 2B at a dose of 2.5 mg/kg. The median age of all patients was 30 years (range, 17 to 59 years). The incidence of GVHD was significantly lower in group 2B than group 2A, as demonstrated by the rate of grade II to IV acute GVHD at day 100 (31.2% versus 61.5%, P = .003) and the rate of chronic GVHD at 3 years (21.9% versus 65.4%, P = .002). The overall survival rates of the 3 groups were similar. However, GVHD-free, failure-free survival (GFFS) was significantly higher in group 2B than group 2A (P = .034). A multivariable model identified use of ATG as an independent factor affecting grades II to IV acute

  13. CD4+CD25highCD127low Regulatory T Cells in Peripheral Blood Are Not an Independent Factor for Chronic Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Jolanta B. Perz

    2012-01-01

    Full Text Available Background. The therapeutic efficacy of allogeneic hemopoietic stem cell transplantation (HSCT largely relies on the graft-versus-leukemia (GVL effect. Uncontrolled graft-versus-host disease (GVHD is a feared complication of HSCT. Regulatory T cells (Treg are a subset of CD4+ T-helper cells believed to maintain tolerance after HSCT. It remains unclear whether low peripheral blood Treg have an impact on the risk for acute (aGVHD and chronic GVHD (cGVHD. Methods. In this paper we enumerated the CD4+CD25highCD127low Treg in the peripheral blood of 84 patients after at least 150 days from HSCT and in 20 healthy age-matched controls. Results. Although similar mean lymphocyte counts were found in patients and controls, CD3+CD4+ T-cell counts were significantly lower in patients. Patients also had significantly lower Treg percentages among lymphocytes as compared to controls. Patients with cGVHD had even higher percentages of Treg if compared to patients without cGVHD. In multivariate analysis, Treg percentages were not an independent factor for cGVHD. Conclusions. This paper did not show a relation between deficient peripheral blood Treg and cGVHD, therefore cGVHD does not seem to occur as a result of peripheral Treg paucity.

  14. Ocular graft versus host disease in allogenic haematopoetic stem cell transplantation in a tertiary care centre in India

    Directory of Open Access Journals (Sweden)

    Rehan Khan

    2015-01-01

    Full Text Available Background & objectives: This study was aimed to report the occurrence of ocular graft versus host disease (oGVHD in allogeneic haematopoietic stem cell transplantation (allo-HSCT patients in a tertiary care hospital setting. Methods: A cross-sectional study of ocular surface of allo-HSCT patients was done. Slit lamp biomicroscopy, symptom score, tear meniscus height, fluorescein tear break-up time, Schirmer′s test I, ocular surface staining, dry eye severity, ocular surface disease index score were done. Indications for allo-HSCT, human leukocyte antigen (HLA matching, GVHD risk factor, systemic manifestation and treatment were also noted. Results: GVHD occurred in 44.4 per cent of 54 allo-HSCT patients (mean age 26.7 ± 12 yr included in the study. GVHD risk factors identified included female gender, relapse, older age of donor, cytomagelo virus (CMV reactivation, and multiparous female donors. oGVHD was noted in 31.5 per cent with mean time to occurrence being 17.8 ± 21.9 months after the allo-HSCT and was observed in 89.5 per cent of chronic GVHD cases. Acute GVHD (oral and dermatological involvement showed a significant association with GVHD in our patients (P< 0.001, 0R 23.0, CI 6.4-82.1. Chronic GVHD was observed to be associated with the occurrence of oGVHD (dry eye (P<0.001, OR = 24.0, CI 0.02 - 0.29. Of the 34 eyes with oGHVD, dry eye of level 3 severity was seen in 16, level 2 in six, level 1 in 12 eyes. Interpretation & conclusions: GVHD occurred in 44.4 per cent of the patients studied in the present study. Acute and chronic GVHD showed a strong association with oGVHD. Dry eye disease due to chronic oGVHD was observed in 17 (31.5% of 54 allo-HSCT patient with chronic oGVHD occurring in 17 (89.4% of chronic GVHD cases in allo-HSCT patients. Our study on oGVHD in post allo-HSCT patients in tertiary care centre points towards the fact that ocular morbidity due to dry eye disease as a result of oGVHD is a cause for concern in these

  15. Human mesenchymal stem cells suppress donor CD4(+) T cell proliferation and reduce pathology in a humanized mouse model of acute graft-versus-host disease.

    Science.gov (United States)

    Tobin, L M; Healy, M E; English, K; Mahon, B P

    2013-05-01

    Acute graft-versus-host disease (aGVHD) is a life-threatening complication following allogeneic haematopoietic stem cell transplantation (HSCT), occurring in up to 30-50% of patients who receive human leucocyte antigen (HLA)-matched sibling transplants. Current therapies for steroid refractory aGVHD are limited, with the prognosis of patients suboptimal. Mesenchymal stem or stromal cells (MSC), a heterogeneous cell population present in many tissues, display potent immunomodulatory abilities. Autologous and allogeneic ex-vivo expanded human MSC have been utilized to treat aGVHD with promising results, but the mechanisms of therapeutic action remain unclear. Here a robust humanized mouse model of aGVHD based on delivery of human peripheral blood mononuclear cells (PBMC) to non-obese diabetic (NOD)-severe combined immunodeficient (SCID) interleukin (IL)-2rγ(null) (NSG) mice was developed that allowed the exploration of the role of MSC in cell therapy. MSC therapy resulted in the reduction of liver and gut pathology and significantly increased survival. Protection was dependent upon the timing of MSC therapy, with conventional MSC proving effective only after delayed administration. In contrast, interferon (IFN)-γ-stimulated MSC were effective when delivered with PBMC. The beneficial effect of MSC therapy in this model was not due to the inhibition of donor PBMC chimerism, as CD45(+) and T cells engrafted successfully in this model. MSC therapy did not induce donor T cell anergy, FoxP3(+) T regulatory cells or cause PBMC apoptosis in this model; however, it was associated with the direct inhibition of donor CD4(+) T cell proliferation and reduction of human tumour necrosis factor-α in serum. © 2012 British Society for Immunology.

  16. Donor genotype in the Interleukin-7 receptor α-chain predicts risk of graft-versus-host disease and cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Kielsen, Katrine; Enevold, Christian; Heilmann, Carsten

    2018-01-01

    The efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) is challenged by acute and chronic graft-versus-host disease (aGVHD and cGVHD) and viral infections due to long-lasting immunodeficiency. Interleukin-7 (IL-7) is a cytokine essential for de novo T cell generation in thymus.......1-3.8, P = 0.034) and with significantly increased risk of extensive cGVHD (HR = 2.0, 95% CI = 1.1-3.6, P = 0.025) after adjustment for potential risk factors. In addition, the TT genotype was associated with a higher risk of cytomegalovirus (CMV) infection post-transplant (HR = 2.4, 95% CI = 1.2-4.3, P.......7, 95% CI = 1.2-2.3, P = 0.0027) and increased treatment-related mortality (HR = 2.3, 95% CI = 1.3-4.0, P = 0.0047), but was not associated with the risk of relapse (P = 0.35). In conclusion, the IL-7Rα rs6897932 genotype of the donor is predictive of aGVHD and cGVHD, CMV infection, and mortality...

  17. Granzyme A Is Required for Regulatory T-Cell Mediated Prevention of Gastrointestinal Graft-versus-Host Disease.

    Directory of Open Access Journals (Sweden)

    Sarvari Velaga

    Full Text Available In our previous work we could identify defects in human regulatory T cells (Tregs likely favoring the development of graft-versus-host disease (GvHD following allogeneic stem cell transplantation (SCT. Treg transcriptome analyses comparing GvHD and immune tolerant patients uncovered regulated gene transcripts highly relevant for Treg cell function. Moreover, granzyme A (GZMA also showed a significant lower expression at the protein level in Tregs of GvHD patients. GZMA induces cytolysis in a perforin-dependent, FAS-FASL independent manner and represents a cell-contact dependent mechanism for Tregs to control immune responses. We therefore analyzed the functional role of GZMA in a murine standard model for GvHD. For this purpose, adoptively transferred CD4+CD25+ Tregs from gzmA-/- mice were analyzed in comparison to their wild type counterparts for their capability to prevent murine GvHD. GzmA-/- Tregs home efficiently to secondary lymphoid organs and do not show phenotypic alterations with respect to activation and migration properties to inflammatory sites. Whereas gzmA-/- Tregs are highly suppressive in vitro, Tregs require GZMA to rescue hosts from murine GvHD, especially regarding gastrointestinal target organ damage. We herewith identify GZMA as critical effector molecule of human Treg function for gastrointestinal immune response in an experimental GvHD model.

  18. Usefulness of blood irradiation before transfusion to avoid transfusion associated graft versus host disease (TA-GVHD)

    International Nuclear Information System (INIS)

    Takahashi, Koki

    1997-01-01

    We summarize the pathology of the transfusion associated graft versus host disease (TA-GVHD) and examine the usefulness of the blood irradiation before transfusion as more widely used prophylaxis. The symptom of TA-GVHD was as follows: after (asymptomatic phase) for 1 to 2 weeks after blood transfusion, pyrexia and erythema appeared. Furthermore, hepatic disorder, diarrhea and bloody stool occurred. In no longer time, pancytopenia by aplastic crisis of the bone marrow appeard, and severe granulocytopenia occurred. Finally, by the complication with severe infectious disease such as septicemia, almost all the patients died with in 3 to 4 weeks after blood transfusion. TA-GVHD was found in some patients without immune deficiency syndrome. The cause of the frequent occurrence of the disease in Japan was shown by the probability of the one-way matching analysis. As the countermeasure of TA-GVHD, we examined the effectiveness of the blood irradiation before transfusion under the consideration of the safety and the emergency. After the responder cells were beforehand irradiated with various doses of radiation (X-ray or g-ray), the proliferative response was investigated through the uptake of 3 H-thymidine, and we obtained 15-50 Gy as the optimum dose of the radiation. We discuss the establishment of the countermeasure for the TA-GVHD and the formation of the nationwide support system for TV-GVHD (K.H.). 33 refs

  19. The effect of total body irradiation dose and chronic graft-versus-host disease on leukaemic relapse after allogeneic bone marrow transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Frassoni, F; Bacigalupo, A [Ospedale San Martino (Italy). Centro Trapianti Midollo Osseo; Scarpati, D [Univ. di Genova (Italy). Ist. di Radiologia; and others

    1989-10-01

    One-hundred and five patients undergoing allo-geneic bone marrow transplantation (BMT) for acute myeloid leukaemia (AML) (n=61) and chronic myeloid leukaemia (n=44) were analysed for risk factors associated with relapse. All patients received marrow from an HLA identical sibling after preparation with cyclophosphamide 120 mg/kg and total body irradiation (TBI) 330 cGy on each of the three days prior to transplantation. A multivariate Cox analysis indicated that a lower TBI dose (less than 990 cGy) was the most significant factor associated with relapse and the second most important factor associated with recurrence of leukaemia was the absence of chronic graft-versus-host-disease (cGvHD). Actuarial relapse incidence was 62%, 28% and 18% for patients with no, limited or extensive chronic GvHD respectively. However, chronic GvHD had no significant impact on survival. Combined stratification for TBI dose and cGvHD showed that the dose effect of TBI on relapse was evident both in patients with and without cGvHD. Chronic GvHD influenced the risk of relapse only in patients receiving less than 990 cGy. These results suggest that a higher dose of TBI, within this schedule, produced long-term disease-free survival in the majority of AMLs and CMLs. Minor radiobiological side effects were experienced, but a small reduction of the dose may significantly increase the risk of relapse. (author).

  20. The effect of total body irradiation dose and chronic graft-versus-host disease on leukaemic relapse after allogeneic bone marrow transplantation

    International Nuclear Information System (INIS)

    Frassoni, F.; Bacigalupo, A.; Scarpati, D.

    1989-01-01

    One-hundred and five patients undergoing allo-geneic bone marrow transplantation (BMT) for acute myeloid leukaemia (AML) (n=61) and chronic myeloid leukaemia (n=44) were analysed for risk factors associated with relapse. All patients received marrow from an HLA identical sibling after preparation with cyclophosphamide 120 mg/kg and total body irradiation (TBI) 330 cGy on each of the three days prior to transplantation. A multivariate Cox analysis indicated that a lower TBI dose (less than 990 cGy) was the most significant factor associated with relapse and the second most important factor associated with recurrence of leukaemia was the absence of chronic graft-versus-host-disease (cGvHD). Actuarial relapse incidence was 62%, 28% and 18% for patients with no, limited or extensive chronic GvHD respectively. However, chronic GvHD had no significant impact on survival. Combined stratification for TBI dose and cGvHD showed that the dose effect of TBI on relapse was evident both in patients with and without cGvHD. Chronic GvHD influenced the risk of relapse only in patients receiving less than 990 cGy. These results suggest that a higher dose of TBI, within this schedule, produced long-term disease-free survival in the majority of AMLs and CMLs. Minor radiobiological side effects were experienced, but a small reduction of the dose may significantly increase the risk of relapse. (author)

  1. Clinical laboratory markers of inflammation as determinants of chronic graft-versus-host disease activity and NIH global severity.

    Science.gov (United States)

    Grkovic, L; Baird, K; Steinberg, S M; Williams, K M; Pulanic, D; Cowen, E W; Mitchell, S A; Hakim, F T; Martires, K J; Avila, D N; Taylor, T N; Salit, R B; Rowley, S D; Zhang, D; Fowler, D H; Bishop, M R; Gress, R E; Pavletic, S Z

    2012-04-01

    Chronic graft-versus-host disease (cGVHD) remains a major cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Currently there are no accepted measures of cGVHD activity to aid in clinical management and disease staging. We analyzed clinical markers of inflammation in the sera of patients with established cGVHD and correlated those with definitions of disease activity. In all, 189 adults with cGVHD (33% moderate and 66% severe according to National Institutes of Health (NIH) global scoring) were consecutively enrolled onto a cross-sectional prospective cGVHD natural history study. At the time of evaluation, 80% were receiving systemic immunosuppression and failed a median of four prior systemic therapies (PST) for their cGVHD. Lower albumin (P<0.0001), higher C-reactive protein (P = 0.043), higher platelets (P = 0.030) and higher number of PST (P<0.0001) were associated with active disease defined as clinician's intention to intensify or alter systemic therapy due to the lack of response. Higher platelet count (P = 0.021) and higher number of PST (P<0.0001) were associated with more severe diseased defined by NIH global score. This study identified common laboratory indicators of inflammation that can serve as markers of cGVHD activity and severity.

  2. A colitogenic memory CD4+ T cell population mediates gastrointestinal graft-versus-host disease

    Science.gov (United States)

    Zhou, Vivian; Agle, Kimberle; Chen, Xiao; Beres, Amy; Komorowski, Richard; Belle, Ludovic; Taylor, Carolyn; Zhu, Fenlu; Haribhai, Dipica; Williams, Calvin B.; Verbsky, James; Blumenschein, Wendy; Sadekova, Svetlana; Bowman, Eddie; Ballantyne, Christie; Weaver, Casey; Serody, David A.; Vincent, Benjamin; Serody, Jonathan; Cua, Daniel J.; Drobyski, William R.

    2016-01-01

    Damage to the gastrointestinal tract is a major cause of morbidity and mortality in graft-versus-host disease (GVHD) and is attributable to T cell–mediated inflammation. In this work, we identified a unique CD4+ T cell population that constitutively expresses the β2 integrin CD11c and displays a biased central memory phenotype and memory T cell transcriptional profile, innate-like properties, and increased expression of the gut-homing molecules α4β7 and CCR9. Using several complementary murine GVHD models, we determined that adoptive transfer and early accumulation of β2 integrin–expressing CD4+ T cells in the gastrointestinal tract initiated Th1-mediated proinflammatory cytokine production, augmented pathological damage in the colon, and increased mortality. The pathogenic effect of this CD4+ T cell population critically depended on coexpression of the IL-23 receptor, which was required for maximal inflammatory effects. Non–Foxp3-expressing CD4+ T cells produced IL-10, which regulated colonic inflammation and attenuated lethality in the absence of functional CD4+Foxp3+ T cells. Thus, the coordinate expression of CD11c and the IL-23 receptor defines an IL-10–regulated, colitogenic memory CD4+ T cell subset that is poised to initiate inflammation when there is loss of tolerance and breakdown of mucosal barriers. PMID:27500496

  3. Female genital tract graft-versus-host disease: incidence, risk factors and recommendations for management.

    Science.gov (United States)

    Zantomio, D; Grigg, A P; MacGregor, L; Panek-Hudson, Y; Szer, J; Ayton, R

    2006-10-01

    Female genital tract graft-versus-host disease (GVHD) is an under-recognized complication of allogeneic stem cell transplantation impacting on quality of life. We describe a prospective surveillance programme for female genital GVHD to better characterize incidence, risk factors and clinical features and the impact of a structured intervention policy. A retrospective audit was conducted on the medical records of all female transplant recipients surviving at least 6 months at a single centre over a 5-year period. Patients commenced topical vaginal oestrogen early post transplant with hormone replacement as appropriate for age, prior menopausal status and co-morbidities. A genital tract management programme included regular gynaecological review and self-maintenance of vaginal capacity by dilator or intercourse. The incidence of genital GVHD was 35% (95% confidence interval (CI) (25, 50%)) at 1 year and 49% (95% CI (36, 63%)) at 2 years. Topical therapy was effective in most cases; no patient required surgical intervention to divide vaginal adhesions. The main risk factor was stem cell source with peripheral blood progenitor cells posing a higher risk than marrow (hazard ratio=3.07 (1.22, 7.73), P=0.017). Extensive GVHD in other organs was a common association. We conclude that female genital GVHD is common, and early detection and commencement of topical immunosuppression with dilator use appears to be highly effective at preventing progression.

  4. In vitro regulation of immunoglobulin synthesis after marrow transplantation. I. T-cell and B-cell deficiencies in patients with and without chronic graft-versus-host disease

    International Nuclear Information System (INIS)

    Lum, L.G.; Seigneuret, M.C.; Storb, R.F.; Witherspoon, R.P.; Thomas, E.D.

    1981-01-01

    Twenty-four patients with aplastic anemia or acute leukemia were treated by marrow grafts from HLA-identical donors after conditioning with high doses of cyclophosphamide and/or today body irradiation. They were studied between 4 and 63 mo (median 14.2) after transplantation. Seventeen patients had chronic graft-versus-host disease (C-GVHD) and 7 were healthy. They were studied for defects in their T- and B-cell function using and indirect hemolytic plaque assay for Ig production after 6 days of culture in the presence of pokeweek mitogen. T or B cells from the patients with or without C-GVHD were cocultured with T or B cells from their HLA-identical marrow donors or unrelated normal controls. Intrinsic B-cell defects, lack of helper T-cell activity, and suppressor T-cell activity were more frequently found in patients with C-GVHD than in healthy patients. Fifteen of the 17 patients with C-GVHD showed on or more defects in their T-and B-cell function compared to only 3 of the 7 patients without C-GVHD. None of the healthy controls, including the marrow donors, showed defects in their T- and B-cell functions. These in vitro findings may be helpful in assessing the process of immune reconstitution and the immunologic aberration found after human marrow transplantation

  5. Use of telecobalt-therapy in transfusion-associated graft-versus-host disease

    International Nuclear Information System (INIS)

    Goes, Evamberto Garcia de

    1999-08-01

    The transfusion-associated Graft-Versus-Host Disease (TA-GVHD) is prevented through the irradiation of blood components before transfusion. This work started with a diagnostic about blood irradiation practices in Brazil, through the application of a questionnaire to 56 regional blood centers, and showed that the majority of the regional blood centers have no means to irradiate their own blood components. This survey have also shown that 62,5% of the regional blood centers have local facilities to irradiate their own blood components, through the use of telecobalt-therapy services. Assuming the use of telecobalt-therapy equipment as an alternative solution to the Brazilian blood irradiation problem, the development of an appropriate technique allowed a good quality for irradiated blood. A prototype of a thermic box was made in acrylic and foam, and an automated system of data acquisition, kept the temperature of blood components bellow 6 deg C, during irradiation. Phantoms built using polystyrene plastic represented blood volume routinely irradiated by the regional blood centers. The distribution of doses on the phantoms volumes determined with LiF-100 thermoluminescent dosimeters, were represented in terms of isodoses curves. The doses distributions on the phantom with higher dimensions, 30 x 30 x 20 cm, changed from a minimum relative dose of 80% up to a maximum of 106%. An investigation concerning effects of Cobalt-60 gamma radiation on red blood cells, irradiated and stored, showed increase in potassium levels, up to the tenth day, in blood units irradiated at 3,00 cGy. Surveillance of the reduction in the capacity of T-Cells proliferation as a function of dose, using Limiting Dilution Analysis, showed that a minimum of 2,500 cGy is necessary to prevent TA-GVHD. Methodology developed in this work guarantee good quality for blood irradiated with telecobalt-therapy equipment, a valid alternative for Brazilian institutions which have available only this technique

  6. An early-biomarker algorithm predicts lethal graft-versus-host disease and survival.

    Science.gov (United States)

    Hartwell, Matthew J; Özbek, Umut; Holler, Ernst; Renteria, Anne S; Major-Monfried, Hannah; Reddy, Pavan; Aziz, Mina; Hogan, William J; Ayuk, Francis; Efebera, Yvonne A; Hexner, Elizabeth O; Bunworasate, Udomsak; Qayed, Muna; Ordemann, Rainer; Wölfl, Matthias; Mielke, Stephan; Pawarode, Attaphol; Chen, Yi-Bin; Devine, Steven; Harris, Andrew C; Jagasia, Madan; Kitko, Carrie L; Litzow, Mark R; Kröger, Nicolaus; Locatelli, Franco; Morales, George; Nakamura, Ryotaro; Reshef, Ran; Rösler, Wolf; Weber, Daniela; Wudhikarn, Kitsada; Yanik, Gregory A; Levine, John E; Ferrara, James L M

    2017-02-09

    BACKGROUND. No laboratory test can predict the risk of nonrelapse mortality (NRM) or severe graft-versus-host disease (GVHD) after hematopoietic cellular transplantation (HCT) prior to the onset of GVHD symptoms. METHODS. Patient blood samples on day 7 after HCT were obtained from a multicenter set of 1,287 patients, and 620 samples were assigned to a training set. We measured the concentrations of 4 GVHD biomarkers (ST2, REG3α, TNFR1, and IL-2Rα) and used them to model 6-month NRM using rigorous cross-validation strategies to identify the best algorithm that defined 2 distinct risk groups. We then applied the final algorithm in an independent test set ( n = 309) and validation set ( n = 358). RESULTS. A 2-biomarker model using ST2 and REG3α concentrations identified patients with a cumulative incidence of 6-month NRM of 28% in the high-risk group and 7% in the low-risk group ( P < 0.001). The algorithm performed equally well in the test set (33% vs. 7%, P < 0.001) and the multicenter validation set (26% vs. 10%, P < 0.001). Sixteen percent, 17%, and 20% of patients were at high risk in the training, test, and validation sets, respectively. GVHD-related mortality was greater in high-risk patients (18% vs. 4%, P < 0.001), as was severe gastrointestinal GVHD (17% vs. 8%, P < 0.001). The same algorithm can be successfully adapted to define 3 distinct risk groups at GVHD onset. CONCLUSION. A biomarker algorithm based on a blood sample taken 7 days after HCT can consistently identify a group of patients at high risk for lethal GVHD and NRM. FUNDING. The National Cancer Institute, American Cancer Society, and the Doris Duke Charitable Foundation.

  7. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy.

    Science.gov (United States)

    Miklos, David; Cutler, Corey S; Arora, Mukta; Waller, Edmund K; Jagasia, Madan; Pusic, Iskra; Flowers, Mary E; Logan, Aaron C; Nakamura, Ryotaro; Blazar, Bruce R; Li, Yunfeng; Chang, Stephen; Lal, Indu; Dubovsky, Jason; James, Danelle F; Styles, Lori; Jaglowski, Samantha

    2017-11-23

    Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2-inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ≥20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ≥1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869. © 2017 by The American Society of Hematology.

  8. Steroid-sparing effect of extracorporeal photopheresis in the therapy of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Ussowicz, M; Musiał, J; Mielcarek, M; Tomaszewska, A; Nasiłowska-Adamska, B; Kałwak, K; Gorczyńska, E; Mariańska, B; Chybicka, A

    2013-11-01

    Steroid-refractory graft-versus-host disease (GVHD) remains a challenging therapeutic problem after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate the clinical effect of extracorporeal photopheresis (ECP), and its impact on intensivity of immunosuppresive therapy in allogeneic HSCT patients. In this study 443 Therakos ECP procedures were performed in 21 patients after allogeneic HSCT with acute (aGVHD, 8 patients) or chronic (cGVHD, 13 patients) therapy-refractory GVHD. The median age at ECP onset was 20.5 years (range, 10-55). Venous access was provided by a nontunelized central venous catheter (12 patients) or 9.6-French portacath (9 patients). In the cGVHD group 9/13 patients were improved with a 4-year overall survival rate of 67.7%. ECP led to steroid discontinuation in 6 and substantial dose reduction in 5 patients. The prednisone dose equivalent per kilogram body weight decreased from 0.32 mg to 0.07 mg after therapy. Therapy of aGVHD led to complete or partial symptom remission in 3/9 subjects. The change in steroid dose in the aGVHD group was not significant, there were no long-term survivors. Portacath access was well tolerated and provided adequate blood flow rates. The ECP therapy significantly reduced the rates of remissions with steroid discontinuation among cGVHD but not aGVHD patients. Rare ECP-related complications were either catheter related or anticoagulation induced during ECP procedures. Photopheresis was a safe, effective method to treat steroid-resistant cGVHD. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Reacción de ingerto versus huésped: de la comprensión a la utilización de un fenómeno biológico Graft versus host reation: from comprehension to utilization of a biological phenomenon

    Directory of Open Access Journals (Sweden)

    Jorge Eliécer Ossa Londoño

    1999-01-01

    Full Text Available La enfermedad de injerto versus huésped es una de las complicaciones con mayor mortalidad que se presentan después de un trasplante, usualmente de médula ósea, o después de una transfusión sanguínea.- Los principales órganos blanco son la piel. el hígado, el tracto gastrointestinal y el sistema inmune. Sin embargo. la apreciación de esta enfermedad ha venido cambiando a medida que avanza la comprensión de la inmunología de trasplantes. pues se ha visto que puede tener resultados benéficos como son un efecto antireucémico y un aumento de la tolerancia a los trasplantes. Graft versus host disease is one of the complications with greater lethality after transplantation, usually of bone marrow, or after blood transfusion. Organs involved include skin, liver, gastrointestinal tract and the immune system. However, the conception of graft versus host disease has been changing as comprehension of transplant immunology has advanced, since it has been demonstrated that it can have beneficial results as an antileucemic response and because of an increased tolerance to grafts.

  10. Extracorporeal photopheresis for graft-versus-host disease: the role of patient, transplant, and classification criteria and hematologic values on outcome-results from a large single-center study.

    Science.gov (United States)

    Berger, Massimo; Albiani, Roberto; Sini, Bruno; Fagioli, Franca

    2015-04-01

    Extracorporeal photopheresis (ECP) has been shown as active therapy for graft-versus-host disease (GVHD). The aim was to ascertain the role of ECP in 71 patients with steroid-refractory or -dependent acute and chronic GVHD (aGVHD and cGVHD) with special focus on hematologic variables and GVHD staging classification. A total of 34 patients were treated for aGVHD and 37 for cGVHD. The overall response rate (ORR) for aGVHD was 65% and the complete aGVHD-free survival was 50% (95% confidence interval [CI], 36%-70%). The ORR for cGVHD response was 81% while the complete cGVHD-free survival was 50% (95% CI, 34%-73%). The aGVHD-free survival was associated with aGVHD grading (Grade II 81%, Grade III 33%, and Grade IV 0%, p ≤ 0.00) and the absence of visceral involvement (77% vs. 33%, p = 0.03). The cGVHD-free survival was associated with the female sex (67% vs. 25%, p = 0.01) and with the limited form according to the Seattle classification (67% vs. 20%, p = 0.003). No role for hematologic values or apheresis cell count was found, except for the cGVHD ORR (p = 0.037). Transplant-related mortality and overall survival were associated with ECP response 0% versus 54% (p = 0.0001) and 77% versus 45% (p = 0.03) for aGVHD patients and 7% versus 14% (p = 0.02) and 73% versus 20% (p = 0.0003) for cGVHD patients, respectively. While confirming a higher probability of GVHD responses for early GVHD, our study shows no role of hematologic values or apheresis cell count on GVHD response. © 2014 The Authors. Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.

  11. Autologous Stem Cell Transplantation in Patients with Acute Myeloid Leukemia: a Single-Centre Experience

    Directory of Open Access Journals (Sweden)

    Kakucs Enikő

    2013-04-01

    Full Text Available Introduction: Autologous haemopoietic stem cell transplantation (SCT is an important treatment modality for patients with acute myeloid leukemia with low and intermediate risk disease. It has served advantages over allogenic transplantation, because it does not need a matched donor, there is no graft versus host disease, there are less complications and a faster immune reconstitution than in the allo-setting. The disadvantage is the lack of the graft versus leukaemia effect.

  12. Performance of a new clinical grading system for chronic graft-versus-host disease: a multicenter study.

    Science.gov (United States)

    Akpek, Gorgun; Lee, Stephanie J; Flowers, Mary E; Pavletic, Steven Z; Arora, Mukta; Lee, Shing; Piantadosi, Steven; Guthrie, Katherine A; Lynch, James C; Takatu, Alessandra; Horowitz, Mary M; Antin, Joseph H; Weisdorf, Daniel J; Martin, Paul J; Vogelsang, Georgia B

    2003-08-01

    We recently reported 3 risk factors (RFs) at diagnosis of chronic graft-versus-host disease (cGVHD) that were significantly associated with increased nonrelapse mortality. These included extensive skin involvement (ESI), thrombocytopenia (TP), and progressive type of onset (PTO). The hazard ratio (HR) for mortality of the patients with prognostic score (PS) between 0 and 2 (intermediate-risk; 1 RF) compared to those with PS 0 (favorable-risk; 0 RF) was 3.7 (95% CI, 1.4, 9.3); the HR for patients with PS equal to or more than 2 (high-risk; > 1 RF) compared with intermediate-risk group was 6.9 (3.8, 12.4). A rare presentation of TP and PTO without ESI yielded a PS of 1.8 (intermediate-risk). This paper reports the performance of the prognostic model and the individual RFs using data from an additional 1105 patients from University of Nebraska (n = 60), International Bone Marrow Transplantation Registry (n = 708), Fred Hutchinson Cancer Research Center (n = 188), and University of Minnesota (n = 149). The extent of skin involvement was quantified in 3 cohorts using the available data collected in different formats before the analysis. Although the HR for mortality of the patients in the intermediate-risk group versus those in the favorable-risk group ranged from 2.3 to 8.9 across the centers, it was between 1.6 to 6.9 for patients in the high-risk group versus those in the intermediate-risk group. Although TP itself was uniformly associated with increased risk of mortality across all test samples, ESI and PTO showed statistically significant associations with mortality in 1 and 2 cohorts, respectively. In conclusion, the model was predictive of cGVHD-specific survival, but the mortality hazard associated with ESI was lower in each of these test samples compared with the learning sample. Although the new clinical grading based on the model is promising because of its utility across multiple independent data sets, prospective validation is needed.

  13. Donor T cells primed on leukemia lysate-pulsed recipient APCs mediate strong graft-versus-leukemia effects across MHC barriers in full chimeras

    OpenAIRE

    Ghosh, Arnab; Koestner, Wolfgang; Hapke, Martin; Schlaphoff, Verena; Länger, Florian; Baumann, Rolf; Koenecke, Christian; Cornberg, Markus; Welte, Karl; Blazar, Bruce R.; Sauer, Martin G.

    2009-01-01

    Antigen-presenting cells (APCs) of host origin drive graft-versus-leukemia (GVL) effects but can also trigger life-threatening graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) across major histocompatibility complex (MHC) barriers. We show that in vitro priming of donor lymphocytes can circumvent the need of recipient-derived APCs in vivo for mediating robust GVL effects and significantly diminishes the risk of severe GVHD. In vitro, generated and expanded T cel...

  14. Segmentation of skin lesions in chronic graft versus host disease photographs with fully convolutional networks

    Science.gov (United States)

    Wang, Jianing; Chen, Fuyao; Dellalana, Laura E.; Jagasia, Madan H.; Tkaczyk, Eric R.; Dawant, Benoit M.

    2018-02-01

    Chronic graft-versus-host disease (cGVHD) is a frequent and potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HCT) and commonly affects the skin, resulting in distressing patient morbidity. The percentage of involved body surface area (BSA) is commonly used for diagnosing and scoring the severity of cGVHD. However, the segmentation of the involved BSA from patient whole body serial photography is challenging because (1) it is difficult to design traditional segmentation method that rely on hand crafted features as the appearance of cGVHD lesions can be drastically different from patient to patient; (2) to the best of our knowledge, currently there is no publicavailable labelled image set of cGVHD skin for training deep networks to segment the involved BSA. In this preliminary study we create a small labelled image set of skin cGVHD, and we explore the possibility to use a fully convolutional neural network (FCN) to segment the skin lesion in the images. We use a commercial stereoscopic Vectra H1 camera (Canfield Scientific) to acquire 400 3D photographs of 17 cGVHD patients aged between 22 and 72. A rotational data augmentation process is then applied, which rotates the 3D photos through 10 predefined angles, producing one 2D projection image at each position. This results in 4000 2D images that constitute our cGVHD image set. A FCN model is trained and tested using our images. We show that our method achieves encouraging results for segmenting cGVHD skin lesion in photographic images.

  15. Prevention of transfusion-associated graft-versus-host disease by irradiation: technical aspect of a new ferrous sulphate dosimetric system.

    Directory of Open Access Journals (Sweden)

    Lucas Sacchini Del Lama

    Full Text Available Irradiation of whole blood and blood components before transfusion is currently the only accepted method to prevent Transfusion-Associated Graft-Versus-Host-Disease (TA-GVHD. However, choosing the appropriate technique to determine the dosimetric parameters associated with blood irradiation remains an issue. We propose a dosimetric system based on the standard Fricke Xylenol Gel (FXG dosimeter and an appropriate phantom. The modified dosimeter was previously calibrated using a (60Co teletherapy unit and its validation was accomplished with a (137Cs blood irradiator. An ionization chamber, standard FXG, radiochromic film and thermoluminescent dosimeters (TLDs were used as reference dosimeters to determine the dose response and dose rate of the (60Co unit. The dose distributions in a blood irradiator were determined with the modified FXG, the radiochromic film, and measurements by TLD dosimeters. A linear response for absorbed doses up to 54 Gy was obtained with our system. Additionally, the dose rate uncertainties carried out with gel dosimetry were lower than 5% and differences lower than 4% were noted when the absorbed dose responses were compared with ionization chamber, film and TLDs.

  16. Prevention of Transfusion-Associated Graft-versus-Host Disease by Irradiation: Technical Aspect of a New Ferrous Sulphate Dosimetric System

    Science.gov (United States)

    Del Lama, Lucas Sacchini; de Góes, Evamberto Garcia; Petchevist, Paulo César Dias; Moretto, Edson Lara; Borges, José Carlos; Covas, Dimas Tadeu; de Almeida, Adelaide

    2013-01-01

    Irradiation of whole blood and blood components before transfusion is currently the only accepted method to prevent Transfusion-Associated Graft-Versus-Host-Disease (TA-GVHD). However, choosing the appropriate technique to determine the dosimetric parameters associated with blood irradiation remains an issue. We propose a dosimetric system based on the standard Fricke Xylenol Gel (FXG) dosimeter and an appropriate phantom. The modified dosimeter was previously calibrated using a 60Co teletherapy unit and its validation was accomplished with a 137Cs blood irradiator. An ionization chamber, standard FXG, radiochromic film and thermoluminescent dosimeters (TLDs) were used as reference dosimeters to determine the dose response and dose rate of the 60Co unit. The dose distributions in a blood irradiator were determined with the modified FXG, the radiochromic film, and measurements by TLD dosimeters. A linear response for absorbed doses up to 54 Gy was obtained with our system. Additionally, the dose rate uncertainties carried out with gel dosimetry were lower than 5% and differences lower than 4% were noted when the absorbed dose responses were compared with ionization chamber, film and TLDs. PMID:23762345

  17. Quantitative computed tomography assessment of graft-versus-host disease-related bronchiolitis obliterans in children: A pilot feasibility study

    International Nuclear Information System (INIS)

    Kim, Hyun Gi; Shin, Hyun Joo; Kim, Myung-Joon; Lee, Mi-Jung; Kim, Yoon Hee; Sohn, Myung Hyun; Kim, Kyung Won; Lyu, Chuhl Joo

    2015-01-01

    To suggest a simple method that can quantify air trapping from chest CT in children with graft-versus-host disease (GVHD)-related bronchiolitis obliterans (BO). This institutional review board-approved retrospective study included eight GVHD-related BO patients (age, 6 - 17 years) who underwent both 31 CTs of variable settings and pulmonary function tests (PFT). The attenuation values of lung parenchyma in normal (An) and air trapping (Aa) areas were obtained. Individualized threshold [(An + Aa)/2] and fixed threshold of -950 HU were set for air trapping quantification. Spearman correlation analysis and generalized linear mixed models were used for statistical analysis. The mean value of individualized threshold was -830.2 ± 48.3 HU. The mean air trapping lung volume percentage with individualized threshold and -950 HU were 45.4 ± 18.9 % and 1.4 ± 1.9 %, respectively. The air trapping lung volume percentage with individualized threshold showed a significant negative correlation with the PFT of FEV1/FVC% in all data (γ = -0.795, P <.001) and in the correction of repetition (γ = -0.837, P =.010). We suggest a simple and individualized threshold attenuation setting method for air trapping quantification insusceptible to CT imaging protocols or respiratory phase control in children with GVHD-related BO. (orig.)

  18. Quantitative computed tomography assessment of graft-versus-host disease-related bronchiolitis obliterans in children: A pilot feasibility study

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hyun Gi [Yonsei University College of Medicine, Department of Radiology and Research Institute of Radiological Science, Severance Children' s Hospital, Seoul (Korea, Republic of); Ajou University Medical Center, Department of Radiology, Ajou University School of Medicine, Suwon (Korea, Republic of); Shin, Hyun Joo; Kim, Myung-Joon; Lee, Mi-Jung [Yonsei University College of Medicine, Department of Radiology and Research Institute of Radiological Science, Severance Children' s Hospital, Seoul (Korea, Republic of); Kim, Yoon Hee; Sohn, Myung Hyun; Kim, Kyung Won [Yonsei University College of Medicine, Department of Pediatrics and Institute of Allergy, Severance Children' s Hospital, Seoul (Korea, Republic of); Lyu, Chuhl Joo [Yonsei University College of Medicine, Department of Pediatric Hematology and Oncology, Severance Children' s Hospital, Seoul (Korea, Republic of)

    2015-10-15

    To suggest a simple method that can quantify air trapping from chest CT in children with graft-versus-host disease (GVHD)-related bronchiolitis obliterans (BO). This institutional review board-approved retrospective study included eight GVHD-related BO patients (age, 6 - 17 years) who underwent both 31 CTs of variable settings and pulmonary function tests (PFT). The attenuation values of lung parenchyma in normal (An) and air trapping (Aa) areas were obtained. Individualized threshold [(An + Aa)/2] and fixed threshold of -950 HU were set for air trapping quantification. Spearman correlation analysis and generalized linear mixed models were used for statistical analysis. The mean value of individualized threshold was -830.2 ± 48.3 HU. The mean air trapping lung volume percentage with individualized threshold and -950 HU were 45.4 ± 18.9 % and 1.4 ± 1.9 %, respectively. The air trapping lung volume percentage with individualized threshold showed a significant negative correlation with the PFT of FEV1/FVC% in all data (γ = -0.795, P <.001) and in the correction of repetition (γ = -0.837, P =.010). We suggest a simple and individualized threshold attenuation setting method for air trapping quantification insusceptible to CT imaging protocols or respiratory phase control in children with GVHD-related BO. (orig.)

  19. Refractory Graft-Versus-Host Disease-Free, Relapse-Free Survival as an Accurate and Easy-to-Calculate Endpoint to Assess the Long-Term Transplant Success.

    Science.gov (United States)

    Kawamura, Koji; Nakasone, Hideki; Kurosawa, Saiko; Yoshimura, Kazuki; Misaki, Yukiko; Gomyo, Ayumi; Hayakawa, Jin; Tamaki, Masaharu; Akahoshi, Yu; Kusuda, Machiko; Kameda, Kazuaki; Wada, Hidenori; Ishihara, Yuko; Sato, Miki; Terasako-Saito, Kiriko; Kikuchi, Misato; Kimura, Shun-Ichi; Tanihara, Aki; Kako, Shinichi; Kanamori, Heiwa; Mori, Takehiko; Takahashi, Satoshi; Taniguchi, Shuichi; Atsuta, Yoshiko; Kanda, Yoshinobu

    2018-02-21

    The aim of this study was to develop a new composite endpoint that accurately reflects the long-term success of allogeneic hematopoietic stem cell transplantation (allo-HSCT), as the conventional graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) overestimates the impact of GVHD. First, we validated current GRFS (cGRFS), which recently was proposed as a more accurate endpoint of long-term transplant success. cGRFS was defined as survival without disease relapse/progression or active chronic GVHD at a given time after allo-HSCT, calculated using 2 distinct methods: a linear combination of a Kaplan-Meier estimates approach and a multistate modelling approach. Next, we developed a new composite endpoint, refractory GRFS (rGRFS). rGRFS was calculated similarly to conventional GRFS treating grade III to IV acute GVHD, chronic GVHD requiring systemic treatment, and disease relapse/progression as events, except that GVHD that resolved and did not require systemic treatment at the last evaluation was excluded as an event in rGRFS. The 2 cGRFS curves obtained using 2 different approaches were superimposed and both were superior to that of conventional GRFS, reflecting the proportion of patients with resolved chronic GVHD. Finally, the curves of cGRFS and rGRFS overlapped after the first 2 years of post-transplant follow-up. These results suggest that cGRFS and rGRFS more accurately reflect transplant success than conventional GRFS. Especially, rGRFS can be more easily calculated than cGRFS and analyzed with widely used statistical approaches, whereas cGRFS more accurately represents the burden of GVHD-related morbidity in the first 2 years after transplantation. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  20. Radiation-induced mouse chimeras: a cellular analysis of the major lymphoid compartments, factors affecting lethal graft versus host disease and host-tumor interactions

    International Nuclear Information System (INIS)

    Almaraz, R.

    1981-01-01

    The major lymphoid compartments of allogeneic bone marrow chimeras were evaluated for the extent of cell chimerism and distribution of Thy 1 and la bearing cells. These chimeras contained lymphoid cell primarily of donor origin. The bone marrow compartment was a mixture of host and donor origin cells. The distribution of Thy 1 and la bearing cells was similar as in normal mice. The effect of adult thymectomy alone or followed by whole-body irradiation and bone marrow reconstitution on the distribution of the Thy 1 positive cells was also investigated. Thymectomy with or without WBI and bone marrow reconstitution significantly lowered the number of Thy 1 bearing cells in the blood and spleen. The number of la bearing cells did not appear to be affected by thymectomy. The role of circulating lymphoid cells in the incidence of lethal graft versus host disease (GVHD) in radiation induced fully allogeneic mouse chimeras was studied. Mice reconstituted with allogeneic bone marrow from bled donors had a statistically lower incidence of GVHD than those reconstituted with bone marrow from unbled donors. Addition of mature peripheral lymphocytes from blood to the reconstituting bone marrow cells from bled donors reduplicated the high incidence of lethal GVHD. It was demonstrated that the bone marrow of mice not exsanguinated prior to harvesting of bone marrow contained significant numbers of peripheral contaminating cells in the harvested bone marrow. The role of suppressor cell elimination in resisting tumor growth was investigated using radiation induced mouse chimeras. Local effects of irradiation alone at the site of tumor inoculation could account for this lack of growth

  1. Current outcome of HLA identical sibling versus unrelated donor transplants in severe aplastic anemia

    DEFF Research Database (Denmark)

    Bacigalupo, Andrea; Socié, Gerard; Hamladji, Rose Marie

    2015-01-01

    We have analyzed 1448 patients with acquired aplastic anemia grafted between 2005 and 2009, and compared outcome of identical sibling (n=940) versus unrelated donor (n=508) transplants. When compared to the latter, sibling transplants were less likely to be performed beyond 180 days from diagnosis.......04). In conclusion, in multivariate analysis, the outcome of unrelated donor transplants for acquired aplastic anemia, is currently not statistically inferior when compared to sibling transplants, although patients are at greater risk of acute and chronic graft-versus-host disease. The use of peripheral blood grafts...

  2. Characteristics and risk of chronic graft-versus-host disease of liver in allogeneic hematopoietic stem cell transplant recipients.

    Directory of Open Access Journals (Sweden)

    Chien-Ting Chen

    Full Text Available Chronic graft-versus-host-disease (cGvHD is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT. Among various organ-specific cGvHD, the cGvHD of liver is less well-characterized. In this study, we applied the National Institutes of Health 2014 scoring criteria of cGvHD to analyze a retrospective cohort of 362 allo-HSCT recipients focusing on cGvHD of liver. The overall incidence of liver cGvHD with a score of 3 by 1.5 years post-transplant was 5.8% (21/362. Poor outcome, in terms of overall survival (OS, were observed in patients with scores of 3 liver cGvHD, comparing to those with scores less than 3 (hazard ratio [HR] 2.037, 95% confidence interval [CI] 1.123-3.696, P = 0.019. In multivariate analysis, male gender (HR 4.004, P = 0.042 and chronic hepatitis C virus (HCV infection status (HR 19.087, P < 0.001 were statistically significant risk factors for scores of 3 liver cGvHD. Our results indicate that liver cGvHD with scores of 3 has a grave prognosis following allo-HSCT, and that HCV carrier status and male are risk factors. Early recognition of this devastating complication might help in prompt immunosuppressive therapy and reducing late poor outcome.

  3. Platelet lysate mucohadesive formulation to treat oral mucositis in graft versus host disease patients: a new therapeutic approach.

    Science.gov (United States)

    Del Fante, Claudia; Perotti, Cesare; Bonferoni, Maria Cristina; Rossi, Silvia; Sandri, Giuseppina; Ferrari, Franca; Scudeller, Luigia; Caramella, Carla Marcella

    2011-09-01

    Optimal treatment of oral mucositis (OM) due to graft versus host disease (GvHD) is currently not available. Platelet-derived growth factors (PDGFs) have high capability for tissue healing and may play a role in repairing the mucosal barrier. The aim of the present work was to develop a mucoadhesive formulation to administer platelet lysate to oral cavity prolonging contact time of platelet lysate with oral mucosa. The mucoadhesive formulation was characterized for in vitro properties (PDGF-AB concentration, mucoadhesive properties, cytotoxicity, fibroblast proliferation, wound healing). Moreover, a preliminary clinical study on seven GvHD patients with OM refractory to other therapies was conducted, to evaluate feasibility, safety, and efficacy. GVPL (mucoadhesive gel vehicle mixed with platelet lysate)showed good mucoadhesive properties; additionally, it was characterized by good biocompatibility in vitro on fibroblasts and it was able to enhance fibroblast proliferation and wound healing, maintaining the efficacy for up to 14 days following storage at 2-8°C. In vivo, clinical response was good-to-complete in five, fair in one, none in the remaining one. The in vitro results indicate that GVPL has optimal mucoadhesive and healing enhancer properties, maintained over time (up to 14 days); preliminary clinical results suggest that oral application of platelet lysate-loaded mucoadhesive formulation is feasible, safe, well tolerated, and effective. A larger controlled randomized study is needed.

  4. Freeze and Thaw of CD4+CD25+Foxp3+ Regulatory T Cells Results in Loss of CD62L Expression and a Reduced Capacity to Protect against Graft-versus-Host Disease.

    Directory of Open Access Journals (Sweden)

    Mareike Florek

    Full Text Available The adoptive transfer of CD4+CD25+Foxp3+ regulatory T cells (Tregs in murine models of allogeneic hematopoietic cell transplantation (HCT has been shown to protect recipient mice from lethal acute graft-versus-host disease (GVHD and this approach is being actively investigated in human clinical trials. Here, we examined the effects of cryopreservation on Tregs. We found that freeze and thaw of murine and human Tregs is associated with reduced expression of L-selectin (CD62L, which was previously established to be an important factor that contributes to the in vivo protective effects of Tregs. Frozen and thawed murine Tregs showed a reduced capacity to bind to the CD62L binding partner MADCAM1 in vitro as well as an impaired homing to secondary lymphoid organs in vivo. Upon adoptive transfer frozen and thawed Tregs failed to protect against lethal GVHD compared with fresh Tregs in a murine model of allogeneic HCT across major histocompatibility barriers. In summary, the direct administration of adoptively transferred frozen and thawed Tregs adversely affects their immunosuppressive potential which is an important factor to consider in the clinical implementation of Treg immunotherapies.

  5. Increased incidence of murine graft-versus-host disease after allogeneic bone marrow transplantation by previous infusion of syngeneic bone marrow cells

    International Nuclear Information System (INIS)

    Waer, M.; Ang, K.K.; van der Schueren, E.; Vandeputte, M.

    1984-01-01

    Different groups of BALB/c mice received supralethal total-body irradiation (TBI; 8.5 Gy, day 0). When 30 x 10(6) allogeneic (C57B1) bone marrow (BM) cells were infused with or without 10 x 10(6) syngeneic (BALB/c) bM cells on day 1, many animals (60%) died from graft-versus-host disease (GVHD). Typing of peripheral blood leukocytes for donor antigens showed that, respectively, 22/22 and 17/21 of the mice in both groups became chimeric. When syngeneic bone marrow was given on day 1 and allogeneic bone marrow on day 2 after TBI, a similar number of animals (21/23) became chimeric, but GVHD occurred more frequently in this group (25/26 mice, P less than 0.01). When the syngeneic bone marrow cells were replaced by spleen cells, or when the transplantation of allogeneic bone marrow was delayed till days 3 or 6 after TBI, almost all mice rejected the allogeneic BM graft and became long-term survivors. BALB/c mice receiving 30 x 10(6) C57B1 BM cells after 17 daily fractions of 0.2 Gy of total lymphoid irradiation (TLI), showed a high incidence of chimerism (15/17) and in none of the latter animals was GVHD observed. Despite the high incidence of GVHD in the mice receiving allogeneic BM after TBI and syngeneic BM transplantation, as compared with mice prepared with TLI which do not develop GVHD, suppressor cells were as easily induced after TBI and syngeneic BM transplantation as after TLI

  6. Graft-versus-host disease and sialodacryoadenitis viral infection in bone marrow transplanted rats

    International Nuclear Information System (INIS)

    Rossie, K.M.; Sheridan, J.F.; Barthold, S.W.; Tutschka, P.J.

    1988-01-01

    The effect of a localized viral infection on the occurrence of graft-vs.-host disease (GVHD) was examined in allogeneic rat bone marrow chimeras (ACI/LEW). Animals without clinical evidence of GVHD, 62 days after bone marrow transplant, were infected in salivary and lacrimal glands with sialodacryoadenitis virus (SDAV), and sacrificed 8-25 days postinfection. Using established histologic criteria, GVHD was found more frequently in salivary and lacrimal glands of SDAV-infected chimeras than uninfected chimeras. Skin and oral mucosa, tissues not infected by the virus, showed no differences in occurrence of GVHD, suggesting that the viral infection induced only local and not systemic GVHD. GVHD and SDAV infection, which are histologically similar, were differentiated by examining tissues for SDAV antigen using immunoperoxidase technique. Histologic changes were present for at least 1 week longer than viral antigen, suggesting they represented GVHD rather than viral infection. GVHD and SDAV infection were also differentiated by looking for a histologic feature characteristic of GVHD and not found in SDAV infection (periductal lymphocytic infiltrate). This was found in SDAV-infected chimeras more frequently than uninfected chimeras, suggesting that the viral infection somehow induced GVHD. Results showed a localized increase in the occurrence of GVHD subsequent to localized viral infection

  7. Effect of peripheral lymphoid cells on the incidence of lethal graft versus host disease following allogeneic mouse bone marrow transplantation

    International Nuclear Information System (INIS)

    Almaraz, R.; Ballinger, W.; Sachs, D.H.; Rosenberg, S.A.

    1983-01-01

    Experiments were performed to study the role of circulating lymphoid cells in the incidence of lethal graft versus host disease (GVHD) in radiation-induced fully allogeneic mouse chimeras. The incidence of GVHD was reduced significantly in BALB/c leads to C57BL/6 radiation chimeras if bone marrow donors were exsanguinated immediately prior to marrow harvest. Chimeras resulting from the injection of bone marrow from bled donors exhibited only donor cells in spleen, bone marrow and peripheral blood and normal levels of Thy 1+ and Ia+ cells were found in each of these lymphoid compartments. The addition of as few as 3 X 10(4) peripheral mononuclear cells to the marrow from exsanguinated donors uniformly led to lethal GVHD. 51 Cr-labeled cell traffic studies revealed that prior exsanguination of marrow donors led to about a 70% reduction in the number of circulating mononuclear cells contaminating the bone marrow at the time of marrow harvest. This decrease in contaminating peripheral cells was calculated to be in the appropriate range to account for the decreased GVHD seen when marrow from exsanguinated donors was used. It thus appears that peripheral cells contaminating marrow can be an important factor in causing lethal GVHD in allogeneic radiation chimeras

  8. Reduced intensity haplo plus single cord transplant compared to double cord transplant: improved engraftment and graft-versus-host disease-free, relapse-free survival

    Science.gov (United States)

    van Besien, Koen; Hari, Parameswaran; Zhang, Mei-Jie; Liu, Hong-Tao; Stock, Wendy; Godley, Lucy; Odenike, Olatoyosi; Larson, Richard; Bishop, Michael; Wickrema, Amittha; Gergis, Usama; Mayer, Sebastian; Shore, Tsiporah; Tsai, Stephanie; Rhodes, Joanna; Cushing, Melissa M.; Korman, Sandra; Artz, Andrew

    2016-01-01

    Umbilical cord blood stem cell transplants are commonly used in adults lacking HLA-identical donors. Delays in hematopoietic recovery contribute to mortality and morbidity. To hasten recovery, we used co-infusion of progenitor cells from a partially matched related donor and from an umbilical cord blood graft (haplo-cord transplant). Here we compared the outcomes of haplo-cord and double-cord transplants. A total of 97 adults underwent reduced intensity conditioning followed by haplo-cord transplant and 193 patients received reduced intensity conditioning followed by double umbilical cord blood transplantation. Patients in the haplo-cord group were more often from minority groups and had more advanced malignancy. Haplo-cord recipients received fludarabine-melphalan-anti-thymocyte globulin. Double umbilical cord blood recipients received fludarabine-cyclophosphamide and low-dose total body irradiation. In a multivariate analysis, haplo-cord had faster neutrophil (HR=1.42, P=0.007) and platelet (HR=2.54, Pdisease (HR=0.26, Pdisease (HR=0.06, Pdisease-free, relapse-free survival was superior with haplo-cord (HR 0.63, P=0.002) but not overall survival (HR=0.97, P=0.85). Haplo-cord transplantation using fludarabine-melphalan-thymoglobulin conditioning hastens hematopoietic recovery with a lower risk of relapse relative to double umbilical cord blood transplantation using the commonly used fludarabine-cyclophosphamide-low-dose total body irradiation conditioning. Graft-versus-host disease-free and relapse-free survival is significantly improved. Haplo-cord is a readily available graft source that improves outcomes and access to transplant for those lacking HLA-matched donors. Trials registered at clinicaltrials.gov identifiers 00943800 and 01810588. PMID:26869630

  9. Safety and efficacy of autologous serum eye drop for treatment of dry eyes in graft-versus-host disease.

    Science.gov (United States)

    Azari, Amir A; Karadag, Remzi; Kanavi, Mozhgan Rezaei; Nehls, Sarah; Barney, Neal; Kim, Kyungmann; Longo, Walter; Hematti, Peiman; Juckett, Mark

    2017-06-01

    To evaluate the treatment of autologous serum eye drops (ASED) on dry eyes in patients with graft-versus-host disease (GVHD). A retrospective chart review of 35 patients with a history of ocular GVHD following hematopoietic stem cell transplantation that used ASED to alleviate dry eye symptoms was performed. Patients were categorized into three different groups. If patients had available ophthalmic data before and after starting treatment was group 1 (n = 14), had available ophthalmic data after starting treatment in group 2 (n = 10) and had available ophthalmic data before treatment or did not have any data after starting treatment in group 3 (n = 11). Data were collected on patient's age, gender, primary diagnosis, visual acuity and fluorescein corneal staining were collected on individual eyes in order to evaluate the efficacy of the ASED on alleviating dry eye-related signs and symptoms. No adverse ocular effect from the ASED was found in our series (except one fungal keratitis). All patients reported either improvement (55%) or stability (45%) in their ocular symptoms upon the use of ASED. In patients with available data before and after starting treatment, the corneal staining score improved by a median of 1 (p = 0.003) and the LogMAR visual acuity had a non-significant improvement. In our study, ASED used by patients with ocular GVHD were both safe and effective. ASED should be considered in patients with GVHD who suffer from dry eyes.

  10. Radiographic features of esophageal involvement in chronic graft-vs.-host disease

    International Nuclear Information System (INIS)

    McDonald, G.B.; Sullivan, K.M.; Plumley, T.F.

    1984-01-01

    Chronic graft-vs.-host disease (GVHD) is an important late complication of allogeneic bone-marrow transplantation. It resembles several naturally occurring autoimmune diseases and involves the skin, mouth, eyes, liver, and esophagus. The radiographic findings of 14 symptomatic patients with chronic GVHD involving the esophagus were reviewed and found to include webs, ringlike narrowings, and tapering strictures in the mid and upper esophagus. Esophagoscopy revealed characteristic desquamation in the 13 patients studied, but barium studies detected this lesion in only one patient. Knowledge of the site and characteristics of esophageal involvement with chronic GVHD assists the radiologic evaluation of this disorder

  11. Single nucleotide polymorphism of CC chemokine ligand 5 promoter gene in recipients may predict the risk of chronic graft-versus-host disease and its severity after allogeneic transplantation.

    Science.gov (United States)

    Kim, Dong Hwan; Jung, Hee Du; Lee, Nan Young; Sohn, Sang Kyun

    2007-10-15

    Leukocyte trafficking, regulated by chemokine ligands and their receptors, involves in the pathogenesis of graft-versus-host disease (GVHD) including CC ligand 5 (CCL5) or CC receptor 5 (CCR5). The current study analyzed the association of acute or chronic GVHD (cGVHD) with the CCR5/CCL5 gene single nucleotide polymorphisms (SNPs) of recipients and donors. We evaluated the SNPs of CCL5 promoter gene at position -28 (rs1800825)/-403 (rs2107538) and CCR5 gene at 59029 (rs1799987) in 72 recipients and donors using polymerase chain reaction/RFLP (Restriction Fragment Length Polymorphism) methods. With a median follow up of 924 days for survivors (range 48-2,360 days), the CG genotype of CCL5 gene at position -28 in recipients was significantly associated with a higher incidence of cGVHD (P=0.004), extensive cGVHD (P=0.038 by Seattle's criteria), and severe grade of cGVHD at presentation (P=0.017 by prognostic grading by Apkek et al.) compared to CC genotype. In terms of haplotype analysis, the recipients with AG haplotype of CCL5 gene also showed a higher incidence of cGVHD (P=0.003), extensive cGVHD (P=0.023), and more severe grade of cGVHD (P=0.020). However, there was no association of CCL5/CCR5 SNPs with acute GVHD. The donors' genotype of CCL5/CCR5 was not associated with the risk of cGVHD. The CCL5 promoter gene polymorphism of recipients was associated with the risk of cGVHD and its severity. The current study suggested an involvement of CCL5 in leukocyte trafficking for the development of cGVHD.

  12. Xenogeneic graft-versus-host-disease in NOD-scid IL-2Rγnull mice display a T-effector memory phenotype.

    Science.gov (United States)

    Ali, Niwa; Flutter, Barry; Sanchez Rodriguez, Robert; Sharif-Paghaleh, Ehsan; Barber, Linda D; Lombardi, Giovanna; Nestle, Frank O

    2012-01-01

    The occurrence of Graft-versus-Host Disease (GvHD) is a prevalent and potentially lethal complication that develops following hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic-GvHD based upon immunodeficient strains injected with human peripheral blood mononuclear cells (PBMC; "Hu-PBMC mice") are important tools to study human immune function in vivo. The recent introduction of targeted deletions at the interleukin-2 common gamma chain (IL-2Rγ(null)), notably the NOD-scid IL-2Rγ(null) (NSG) and BALB/c-Rag2(null) IL-2Rγ(null) (BRG) mice, has led to improved human cell engraftment. Despite their widespread use, a comprehensive characterisation of engraftment and GvHD development in the Hu-PBMC NSG and BRG models has never been performed in parallel. We compared engrafted human lymphocyte populations in the peripheral blood, spleens, lymph nodes and bone marrow of these mice. Kinetics of engraftment differed between the two strains, in particular a significantly faster expansion of the human CD45(+) compartment and higher engraftment levels of CD3(+) T-cells were observed in NSG mice, which may explain the faster rate of GvHD development in this model. The pathogenesis of human GvHD involves anti-host effector cell reactivity and cutaneous tissue infiltration. Despite this, the presence of T-cell subsets and tissue homing markers has only recently been characterised in the peripheral blood of patients and has never been properly defined in Hu-PBMC models of GvHD. Engrafted human cells in NSG mice shows a prevalence of tissue homing cells with a T-effector memory (T(EM)) phenotype and high levels of cutaneous lymphocyte antigen (CLA) expression. Characterization of Hu-PBMC mice provides a strong preclinical platform for the application of novel immunotherapies targeting T(EM)-cell driven GvHD.

  13. Xenogeneic graft-versus-host-disease in NOD-scid IL-2Rγnull mice display a T-effector memory phenotype.

    Directory of Open Access Journals (Sweden)

    Niwa Ali

    Full Text Available The occurrence of Graft-versus-Host Disease (GvHD is a prevalent and potentially lethal complication that develops following hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic-GvHD based upon immunodeficient strains injected with human peripheral blood mononuclear cells (PBMC; "Hu-PBMC mice" are important tools to study human immune function in vivo. The recent introduction of targeted deletions at the interleukin-2 common gamma chain (IL-2Rγ(null, notably the NOD-scid IL-2Rγ(null (NSG and BALB/c-Rag2(null IL-2Rγ(null (BRG mice, has led to improved human cell engraftment. Despite their widespread use, a comprehensive characterisation of engraftment and GvHD development in the Hu-PBMC NSG and BRG models has never been performed in parallel. We compared engrafted human lymphocyte populations in the peripheral blood, spleens, lymph nodes and bone marrow of these mice. Kinetics of engraftment differed between the two strains, in particular a significantly faster expansion of the human CD45(+ compartment and higher engraftment levels of CD3(+ T-cells were observed in NSG mice, which may explain the faster rate of GvHD development in this model. The pathogenesis of human GvHD involves anti-host effector cell reactivity and cutaneous tissue infiltration. Despite this, the presence of T-cell subsets and tissue homing markers has only recently been characterised in the peripheral blood of patients and has never been properly defined in Hu-PBMC models of GvHD. Engrafted human cells in NSG mice shows a prevalence of tissue homing cells with a T-effector memory (T(EM phenotype and high levels of cutaneous lymphocyte antigen (CLA expression. Characterization of Hu-PBMC mice provides a strong preclinical platform for the application of novel immunotherapies targeting T(EM-cell driven GvHD.

  14. National Institutes of Health classification for chronic graft-versus-host disease predicts outcome of allo-hematopoietic stem cell transplant after fludarabine-busulfan-antithymocyte globulin conditioning regimen.

    Science.gov (United States)

    Saillard, Colombe; Crocchiolo, Roberto; Furst, Sabine; El-Cheikh, Jean; Castagna, Luca; Signori, Alessio; Oudin, Claire; Faucher, Catherine; Lemarie, Claude; Chabannon, Christian; Granata, Angela; Blaise, Didier

    2014-05-01

    Abstract In 2005, the National Institutes of Health (NIH) proposed standard criteria for diagnosis, organ scoring and global assessment of chronic graft-versus-host disease (cGvHD) severity. We retrospectively reclassified cGvHD with NIH criteria in a monocentric cohort of 130 consecutive adult patients with hematological malignancies presenting cGvHD after receiving allo-hematopoietic stem cell transplant (HSCT) with a fludarabine-busulfan-antithymocyte globulin (ATG) conditioning regimen, among 313 consecutive HSCT recipients. We compared NIH and Seattle classifications to correlate severity and outcome. The follow up range was effectively 2-120 months. Forty-four percent developed Seattle-defined cGvHD (22% limited, 78% extensive forms). Using NIH criteria, there were 23%, 40% and 37% mild, moderate and severe forms, respectively, and 58%, 32% and 8% classic cGvHD, late acute GvHD and overlap syndrome. Five-year overall survival was 55% (49-61), and cumulative incidences of non-relapse mortality (NRM) and relapse/progression at 2 years were 19% (14-23) and 19% (14-24). NIH mild and moderate forms were associated with better survival compared to severe cGvHD (hazard ratio [HR] = 3.28, 95% confidence interval [CI]: 1.38-7.82, p = 0.007), due to higher NRM among patients with severe cGvHD (HR = 3.04, 95% CI: 1.05-8.78, p = 0.04) but comparable relapse risk (p = NS). In conclusion, the NIH classification appears to be more accurate in predicting outcome mostly by the reclassification of old-defined extensive forms into NIH-defined moderate or severe.

  15. Are the Polyomaviruses BK and JC Associated with Opportunistic Infections, Graft-versus-Host Disease, or Worse Outcomes in Adult Patients Receiving Their First Allogeneic Stem Cell Transplantation with Low-Dose Alemtuzumab?

    Science.gov (United States)

    Schneidewind, Laila; Neumann, Thomas; Knoll, Florian; Zimmermann, Kathrin; Smola, Sigrun; Schmidt, Christian Andreas; Krüger, William

    2017-01-01

    The association of polyomaviruses BK and JC with other opportunistic infections and graft-versus-host disease (GvHD) in allogeneic stem cell transplantation is controversially discussed. We conducted a retrospective study of 64 adult patients who received their first allogeneic stem cell transplantation between March 2010 and December 2014; the follow-up time was 2 years. Acute leukemia was the most frequent underlying disease (45.3%), and conditioning included myeloablative (67.2%) and nonmyeloablative protocols (32.8%). All patients received 10 mg of alemtuzumab on day -2 (20 mg in case of mismatch) as GvHD prophylaxis. Twenty-seven patients (41.5%) developed cytomegalovirus (CMV) reactivation. BKPyV-associated hemorrhagic cystitis was diagnosed in 10 patients (15.6%). Other opportunistic infections caused by viruses or protozoa occurred rarely (reactivation, Epstein-Barr virus reactivation, human herpes virus 6, or parvovirus B19 infection requiring treatment. There was a significant correlation of BKPyV-associated hemorrhagic cystitis with toxoplasmosis (p = 0.013). Additionally, there was a significant link of simultaneous BKPyV and JCPyV viruria with toxoplasmosis (p = 0.047). BKPyV and JCPyV were not associated with GvHD, relapse, or death. We found no association of BKPyV or JCPyV with viral infections or GvHD. Only the correlation of both polyomaviruses with toxoplasmosis was significant. This is a novel and interesting finding. © 2017 S. Karger AG, Basel.

  16. Thiotepa-based versus total body irradiation-based myeloablative conditioning prior to allogeneic stem cell transplantation for acute myeloid leukaemia in first complete remission: a retrospective analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

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    Eder, Sandra; Labopin, Myriam; Arcese, William; Or, Reuven; Majolino, Ignazio; Bacigalupo, Andrea; de Rosa, Gennaro; Volin, Liisa; Beelen, Dietrich; Veelken, Hendrik; Schaap, Nicolaas P M; Kuball, Jurgen; Cornelissen, Jan; Nagler, Arnon; Mohty, Mohamad

    2016-01-01

    Thiotepa is an alkylating compound with an antineoplastic and myeloablative activity and can mimic the effect of radiation. However, it is unknown whether this new regimen could safely replace the long-established ones. This retrospective matched-pair analysis evaluated the outcome of adults with acute myeloid leukaemia in first complete remission who received myeloablative conditioning either with a thiotepa-based (n = 121) or a cyclophosphamide/total body irradiation-based (TBI; n = 358) regimen for allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling or an unrelated donor. With a median follow-up of 44 months, the outcome was similar in both groups. Acute graft-versus-host disease grade II-IV was observed in 25% after thiotepa-containing regimen versus 35% after TBI (P = 0.06). The 2-yr cumulative incidence of chronic graft-versus-host disease was 40.5% for thiotepa and 41% for TBI (P = 0.98). At 2 yrs, the cumulative incidences of non-relapse mortality and relapse incidence were 23.9% (thiotepa) vs. 22.4% (TBI; P = 0.66) and 17.2% (thiotepa) vs. 23.3% (TBI; P = 0.77), respectively. The probabilities of leukaemia-free and overall survival at 2 yrs were not significantly different between the thiotepa and TBI groups, at 58.9% vs. 54.2% (P = 0.95) and 61.4% vs. 58% (P = 0.72), respectively. Myeloablative regimens using combinations including thiotepa can provide satisfactory outcomes, but the optimal conditioning remains unclear for the individual patient in this setting. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Modulation and Apoptosis of Neutrophil Granulocytes by Extracorporeal Photopheresis in the Treatment of Chronic Graft-Versus-Host Disease.

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    Cindy Franklin

    Full Text Available Chronic graft-versus-host disease (cGVHD is a common side effect of allogeneic stem cell transplantation and a major cause of morbidity and mortality in affected patients. Especially skin, eyes and oral mucosa are affected. This can lead to pain and functional impairment. Extracorporeal photopheresis (ECP is an effective immunomodulatory therapy with minimal side effects but its mode of action is still largely unknown. The objective of the present study was to examine the effects of ECP on neutrophil granulocytes in patients with cGVHD. Analysis of leukocytes from cGVHD patients obtained from the ECP device during treatment showed that neutrophil granulocytes account for the majority of cells treated during ECP. Neutrophils from healthy donors treated in vitro with 8-methoxypsoralen and UVA light as well as neutrophils from buffy coats of patients with cGVHD treated by ECP showed increased apoptosis and decreased half-life. In remaining non-apoptotic cells chemoirradiation resulted in loss of activation markers and reduced effector functions. This was accompanied by an increase in extracellular arginase-1 activity. Additional comparison of neutrophils isolated from blood of cGVHD patients before and 24h after ECP revealed a decreased half-life and reduction of effector functions of post-ECP neutrophils ex vivo. These observations strongly suggest that ECP induces both apoptosis and physiological changes in neutrophils and that these changes also take place in vivo. This study is the first to show that ECP modulates apoptosis and inflammatory activity in neutrophil granulocytes, indicating that neutrophils may significantly contribute to the overall immunomodulatory effects attributed to this treatment.

  18. Advanced sclerosis of the chest wall skin secondary to chronic graft-versus-host disease: a case with severe restrictive lung defect.

    Science.gov (United States)

    Ödek, Çağlar; Kendirli, Tanil; İleri, Talia; Yaman, Ayhan; Fatih Çakmakli, Hasan; Ince, Elif; İnce, Erdal; Ertem, Mehmet

    2014-10-01

    Pulmonary chronic graft-versus-host disease (cGvHD) is one of the most common causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (aHSCT). Herein, we describe a patient with severe restrictive lung defect secondary to cGvHD. A 21-year-old male patient was admitted to our pediatric intensive care unit (PICU) with pneumonia and respiratory distress. He had a history of aHSCT for chronic myelogeneous leukemia at the age of 17 years. Six months after undergoing aHSCT, he had developed cGvHD involving skin, mouth, eye, lung, liver, and gastrointestinal tract. At the time of PICU admission he had respiratory distress and required ventilation support. Thorax high-resolution computed tomography was consistent with bronchiolitis obliterans. Although bronchiolitis obliterans is an obstructive lung defect, a restrictive pattern became prominent in the clinical course because of the sclerotic chest wall skin. The activity of cGvHD kept increasing despite the therapy and we lost the patient because of severe respiratory distress and massive hemoptysis secondary to bronchiectasis. In conclusion, pulmonary cGvHD can present with restrictive changes related with the advanced sclerosis of the chest wall skin. Performing a fasciotomy or a scar revision for the rigid chest wall in selected patients may improve the patients ventilation.

  19. CD24(hi)CD27⁺ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease.

    Science.gov (United States)

    de Masson, Adèle; Bouaziz, Jean-David; Le Buanec, Hélène; Robin, Marie; O'Meara, Alix; Parquet, Nathalie; Rybojad, Michel; Hau, Estelle; Monfort, Jean-Benoît; Branchtein, Mylène; Michonneau, David; Dessirier, Valérie; Sicre de Fontbrune, Flore; Bergeron, Anne; Itzykson, Raphaël; Dhédin, Nathalie; Bengoufa, Djaouida; Peffault de Latour, Régis; Xhaard, Aliénor; Bagot, Martine; Bensussan, Armand; Socié, Gérard

    2015-03-12

    Interleukin 10 (IL-10)-producing B cells (regulatory B cells [Bregs]) regulate autoimmunity in mice and humans, and a regulatory role of IL-10-producing plasma cells has been described in mice. Dysfunction of B cells that maintain homeostasis may play a role in the pathogenesis of chronic graft-versus-host disease (cGVHD) after allogeneic stem cell transplantation. Here, we found a relation between decreased Breg frequencies and cGVHD severity. An impaired ability of B cells to produce IL-10, possibly linked to poor signal transducer and activator of transcription 3 and extracellular signal-regulated kinase phosphorylation, was found in patients with active cGVHD. IL-10 production was not confined to a single B-cell subset, but enriched in both the CD24(hi)CD27(+) and CD27(hi)CD38(hi) plasmablast B-cell compartments. In vitro plasmablast differentiation increased the frequency of IL-10-producing B cells. We confirmed that allogeneic transplant recipients had an impaired reconstitution of the memory B-cell pool. cGVHD patients had less CD24(hi)CD27(+) B cells and IL-10-producing CD24(hi)CD27(+) B cells. Patients with cGVHD had increased plasmablast frequencies but decreased IL-10-producing plasmablasts. These results suggest a role of CD24(hi)CD27(+) B-cell and plasmablast-derived IL-10 in the regulation of human cGVHD. © 2015 by The American Society of Hematology.

  20. Dry Eye Disease Incidence Associated with Chronic Graft-Host Disease: Nonconcurrent Cohort Study (An American Ophthalmological Society Thesis)

    Science.gov (United States)

    Mian, Shahzad I.; De la Parra-Colín, Paola; De Melo-Franco, Rafael; Johnson, Christopher; Barrientos-Gutierrez, Tonatiuh

    2015-01-01

    Purpose: To determine if chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) is associated with stable or progressive dry eye disease and to determine the true incidence in patients with no prior history of dry eye disease. Methods: A nonconcurrent cohort study at a single institution with 136 patients who had no previous history of dry eye disease before HSCT. Survival analysis was used to estimate dry eye disease incidence. The incidence rate was calculated using life tables as the number of observed dry eye disease cases divided by the person-time at risk accumulated by the cohort. Transition probabilities were calculated from time of transplant to time of diagnosis, and then to last recorded visit. Results: Incidence rate was 0.8 cases of dry eye disease per person-year, and half of the population at risk developed dry eye disease during the first 10 months post transplant. Time to develop dry eye disease was 2.5 months for mild dry eye disease, 9.6 months for moderate dry eye disease, and 13.2 months for severe dry eye disease. In terms of cumulative incidence, 73% of subjects developed dry eye disease (50% mild, 16% moderate, and 7% severe) at the time of diagnosis. Conclusions: Our findings suggest that dry eye disease associated with cGVHD is an extremely frequent event and shows a wide spectrum of severity, with a mild form presenting early and a moderate to severe form presenting later after HSCT. These findings need to be studied further to elucidate if these are two different pathophysiological entities or just different expressions of the same pathology. PMID:27507907

  1. Graft-versus-host reaction and immune function. III. Functional pre-T cells in the bone marrow of graft-versus-host-reactive mice displaying T cell immunodeficiency

    International Nuclear Information System (INIS)

    Seddik, M.; Seemayer, T.A.; Lapp, W.S.

    1986-01-01

    Studies were performed to determine whether pre-T cells develop normally in the bone marrow of mice displaying thymic dysplasia and T cell immunodeficiency as a consequence of a graft-versus-host (GVH) reaction. GVH reactions were induced in CBAxAF1 mice by the injection of A strain lymphoid cells. To test for the presence of pre-T cells in GVH-reactive mice, bone marrow from GVH-reactive mice (GVHBM) was injected into irradiated syngeneic F1 mice and 30-40 days later thymic morphology and function were studied. Morphology studies showed nearly normal thymic architectural restoration; moreover, such glands contained normal numbers of Thy-1-positive cells. Functional pre-T cells were evaluated by transferring thymocytes from the irradiated GVHBM-reconstituted mice into T-cell-deprived mice. These thymocytes reconstituted allograft reactivity, T helper cell function and Con A and PHA mitogen responses of T-cell-deprived mice. These results suggest that the pre-T cell population in the bone marrow is not affected by the GVH reaction. Therefore, the T cell immunodeficiency associated with the GVH reaction is not due to a deficiency of pre-T cells in the bone marrow but is more likely associated with GVH-induced thymic dysplasia

  2. Ruxolitinib in steroid refractory graft-vs.-host disease: a case report

    Directory of Open Access Journals (Sweden)

    Enrico Maffini

    2016-08-01

    Full Text Available Abstract Background Allogeneic hematopoietic stem cell transplantation (HSCT is potentially curative in a variety of hematological malignancies. Graft-vs.-host disease (GvHD remains a life-threatening complication. Standard treatment is high-dose (HD corticosteroids. Steroid-refractory (SR GvHD is associated with poor prognosis. At present, second-line treatment is ill-defined and includes a number of agents. Novel insights into the pathophysiology of acute GvHD (aGvHD highlight the relevant role of the host inflammatory response governed by several kinase families, including Janus kinases (JAK1/2. Ruxolitinib, a JAK1/2 inhibitor approved for intermediate-2/high-risk myelofibrosis, was recently employed in SR-GvHD with encouraging overall response rates. Clinical experience however remains limited. Case presentation A 51-year-old male with refractory anemia with excess blast type-2 underwent a myeloablative allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with busulfan and cyclophosphamide. GvHD prophylaxis consisted of cyclosporine, methotrexate, and thymoglobulin. CD34+ cells/kg infused were 8.69 × 106 kg. On day 29, the patient developed overall grade IV aGvHD with biopsy proven stage IV gastrointestinal (GI GvHD refractory to HD corticosteroids. Patient conditions rapidly deteriorated and became critical despite the addition of mycophenolate mofetil and budesonide. On day 33, Ruxolitinib was started, and on day 39 the patient clinical conditions gradually improved. Complete resolution of aGvHD was also confirmed by histology on day 54. Conclusions At 5 months from HSCT, the patient is well and in continuous hematological complete remission without flare of GvHD. Ruxolitinib was discontinued on day 156. Ruxolitinib is feasible and effective in SR-aGvHD though large prospective clinical trials are warranted.

  3. Allogeneic stem cell transplantation in acute myeloid leukemia

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    Natasha Ali

    2012-11-01

    Full Text Available We report a case series of 12 patients with acute myeloid leukemia who underwent allogeneic stem cell transplant with a matched related donor. Male to female ratio was 1:1. The main complication post-transplant was graft-versus-host disease (n=7 patients. Transplant-related mortality involved one patient; cause of death was multi-organ failure. After a median follow up of 36.0±11.3 months, overall survival was 16%.

  4. Novel Concept of CD4-Mediated Activation of Regulatory T Cells for the Treatment of Graft-Versus-Host Disease

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    Janine Schlöder

    2017-11-01

    Full Text Available Allogeneic hematopoietic stem cell transplantation is the only curative treatment option for several hematological malignancies and immune deficiency syndromes. Nevertheless, the development of a graft-versus-host disease (GvHD after transplantation is a high risk and a severe complication with high morbidity and mortality causing therapeutic challenges. Current pharmacological therapies of GvHD lead to generalized immunosuppression followed by severe adverse side effects including infections and relapse of leukemia. Several novel cell-based immunomodulatory strategies for treatment or prevention of GvHD have been developed. Herein, thymus-derived regulatory T cells (tTreg, essential for the maintenance of peripheral immunologic tolerance, are in the focus of investigation. However, due to the limited number of tTreg in the peripheral blood, a complex, time- and cost-intensive in vitro expansion protocol is necessary for the production of an efficient cellular therapeutic. We demonstrated that activation of tTreg using the CD4-binding human immunodeficiency virus-1 protein gp120 leads to a substantially increased suppressor activity of tTreg without the need for additional expansion. Gp120-activated tTreg prevent GvHD development in a preclinical humanized mouse model. In addition, gp120 is not only effective in prevention but also in therapy of GvHD by suppressing all clinical symptoms and improving survival of treated mice. These data indicate that tTreg activation by gp120 is a feasible and potent strategy for significant functional improvement of tTreg as cellular therapeutic for GvHD treatment without the need of complicated, time-intensive, and expensive in vitro expansion of isolated tTreg.

  5. Vitamin A-coupled liposomes containing siRNA against HSP47 ameliorate skin fibrosis in chronic graft-versus-host disease.

    Science.gov (United States)

    Yamakawa, Tomohiro; Ohigashi, Hiroyuki; Hashimoto, Daigo; Hayase, Eiko; Takahashi, Shuichiro; Miyazaki, Miyono; Minomi, Kenjiro; Onozawa, Masahiro; Niitsu, Yoshiro; Teshima, Takanori

    2018-03-29

    Chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (SCT) is characterized by multiorgan fibrosis and profoundly affects the quality of life of transplant survivors. Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, plays a critical role in collagen synthesis in myofibroblasts. We explored the role of HSP47 in the fibrotic process of cutaneous chronic GVHD in mice. Immunohistochemical analysis showed massive fibrosis with elevated amounts of collagen deposits and accumulation of F4/80 + macrophages, as well as myofibroblasts expressing HSP47 and retinol-binding protein 1 in the skin after allogeneic SCT. Repeated injection of anti-colony-stimulating factor (CSF-1) receptor-blocking antibodies significantly reduced HSP47 + myofibroblasts in the skin, indicating a macrophage-dependent accumulation of myofibroblasts. Vitamin A-coupled liposomes carrying HSP47 small interfering RNA (siRNA) (VA-lip HSP47) delivered HSP47 siRNA to cells expressing vitamin A receptors and knocked down their HSP47 in vitro. Intravenously injected VA-lip HSP47 were specifically distributed to skin fibrotic lesions and did not affect collagen synthesis in healthy skin. VA-lip HSP47 knocked down HSP47 expression in myofibroblasts and significantly reduced collagen deposition without inducing systemic immunosuppression. It also abrogated fibrosis in the salivary glands. These results highlight a cascade of fibrosis in chronic GVHD; macrophage production of transforming growth factor β mediates fibroblast differentiation to HSP47 + myofibroblasts that produce collagen. VA-lip HSP47 represent a novel strategy to modulate fibrosis in chronic GVHD by targeting HSP47 + myofibroblasts without inducing immunosuppression. © 2018 by The American Society of Hematology.

  6. The effect of peripheral lymphoid cells on the incidence of lethal graft versus host disease following allogeneic mouse bone marrow transplantation

    International Nuclear Information System (INIS)

    Almaraz, R.; Ballinger, W.; Sachs, D.H.; Rosenberg, S.A.

    1983-01-01

    Experiments were performed to study the role of circulating lymphoid cells in the incidence of lethal graft versus host disease (GVHD) in radiation-induced fully allogeneic mouse chimeras. The incidence of GVHD was reduced significantly in BALB/c leads to C57BL/6 radiation chimeras if bone marrow donors were exsanguinated immediately prior to marrow harvest. Chimeras resulting from the injection of bone marrow from bled donors exhibited only donor cells in spleen, bone marrow and peripheral blood and normal levels of Thy 1+ and Ia+ cells were found in each of these lymphoid compartments. The addition of as few as 3 X 10(4) peripheral mononuclear cells to the marrow from exsanguinated donors uniformly led to lethal GVHD. 51 Cr-labeled cell traffic studies revealed that prior exsanguination of marrow donors led to about a 70% reduction in the number of circulating mononuclear cells contaminating the bone marrow at the time of marrow harvest. This decrease in contaminating peripheral cells was calculated to be in the appropriate range to account for the decreased GVHD seen when marrow from exsanguinated donors was used. It thus appears that peripheral cells contaminating marrow can be an important factor in causing lethal GVHD in allogeneic radiation chimeras. These results raise the possibility that the fulminant GVHD seen in human marrow transplantation is in part due to the major contamination of bone marrow with peripheral blood that results from the techniques currently used for human bone marrow harvest

  7. Anti-CD3 Antibody Ameliorates Transfusion-Associated Graft-Versus-Host Disease in a Chemotherapy-Based Mouse Model With Busulfan and Fludarabine

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    Xiaofan Li

    2017-05-01

    Full Text Available ABSTRACT To establish a transfusion-associated graft-versus-host disease (TA-GVHD mouse model with busulfan and fludarabine for effective treatment evaluation. BALB/c (H-2d mice were injected with busulfan (15 mg/kg and fludarabine (30 mg/kg twice a day for 4 days. The mice were transfused with 106 T cell-depleted bone marrow (TCD-BM and cells in different groups 3 days after chemotherapy: syngeneic BALB/c, MHC minor mismatch DBA/2 (H-2d, or MHC major mismatch C57BL/6(H2-b. Recipient BALB/c mice were injected with either blood only or blood+splenocyte. TA-GVHD was monitored in terms of body weight loss, clinical scores, and survival. Dexamethasone (50 mg/kg, cyclophosphamide (50 mg/kg, cyclosporine A (30 mg/kg, and anti-CD3 (1 mg/kg were injected to each group to examine the treatments. Blood transfusion alone is insufficient to induce TA-GVHD in a chemotherapy-based mouse model. A MHC-mismatched TA-GVHD model can be induced by splenocyte and blood transfusion. This MHC-mismatched TA-GVHD model was resistant to dexamethasone treatment. Treatment based on anti-CD3 monoclonal antibody slightly ameliorated TA-GVHD. Treatment effectiveness was associated with T-cell depletion following activation by anti-CD3. Busulfan and fludarabine chemotherapy regimen can be used to establish a TA-GVHD mouse model. Anti-CD3 monoclonal antibody is a potential alternative to treat TA-GVHD.

  8. Sequential studies of cell inhibition of host fibroblasts in 51 patients given HLA-identical marrow grafts

    International Nuclear Information System (INIS)

    Tsoi, M.-S.; Storb, R.; Weiden, P.; Santos, E.; Kopecky, K.J.; Thomas, E.D.

    1982-01-01

    Thirty-four patients with leukemia, two with lymphoma and 15 with aplastic anemia, were studied sequentially between 33 and 666 days after treatment with high-dose cyclophosphamide and/or total body irradiation and marrow transplantation from HLA-identical siblings. Peripheral blood mononuclear cells from patients and normals were tested for cell inhibition (CI) of cultured skin fibroblasts from patients and donors or unrelated individuals using the microcytotoxicity assay. In addition, blocking of Cl by factors in patient serum was studied. Twenty patients were tested three or more times during the first year, 15 patients were studied twice and 16 patients once. Results showed that during the first 2 mo postgrafting, mononuclear cells from 45% of the patients had neither Cl nor blocking activities, 50% had Cl and serum blocking, and 5% had Cl without blocking. As time after transplatation elapsed, the percentage of patients without Cl gradually increased, whereas the percentage of patients with Cl with or without blocking decreased. At the end of 1 yr, 89% of the patients showed neither Cl nor blocking compared with 11% who showed Cl and blocking. This trend was significant (p < 0.005). The results were in agreement with our previus conclusion that serum-blocking factors were not important in the maintenance of the stable chimeric state. Early after grafting, there was a suggestive correlation (p < 0.08) between the in vitro finding of Cl of host fibroblasts by chimeric cells and the in vivo finding of acute graft-vs-host disease. However, there was no evidence that presence or absence of serum-blocking factors early after grafting was correlated with presence or absence of graft-vs-host disease

  9. Acute Lymphoblastic Leukemia in a Man Treated With Fingolimod for Relapsing Multiple Sclerosis

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    Stanley Cohan MD, PhD

    2015-03-01

    Full Text Available A man with relapsing multiple sclerosis, treated with fingolimod 0.5 mg/d for 15 months, developed acute lymphoblastic leukemia and died 4 months after immune ablation and bone marrow allograft, from graft versus host disease. To our knowledge, this is the first case of acute lymphoblastic leukemia reported in a patient treated with fingolimod. Although no causal relationship can be established between fingolimod use and acute lymphoblastic leukemia risk in this single case, future surveillance for lymphatic cell malignancies in patients treated with fingolimod appears justified.

  10. Separate effects of irradiation and of graft-versus-host reaction on rat mucosal mast cells

    International Nuclear Information System (INIS)

    Cummins, A.G.; Munro, G.H.; Huntley, J.F.; Miller, H.R.P.; Ferguson, A.

    1989-01-01

    T cell mediated immune responses in the gut can produce enteropathy and malabsorption. The authors investigated the relevance of mucosal mast cells (MMC) to the mechanisms of this enteropathy by using graft-versus-host reaction (GvHR) in the rat as a model of mucosal delayed type hypersensitivity. x-irradiation, with or without GvHR, led to the virtual disappearance of jejunal MMC, undetectable jejunal rat mast cell protease (RMCPII) and very low levels of RMCPII in serum (all p<0.01 when compared with unirradiated controls). These experiments show that there is a modest expansion in jejunal MMC in unirradiated rats with semiallogeneic GvHR, whereas irradiation, alone or associated with GvHR, profoundly depletes MMC for at least two weeks. The enteropathy of GvHR can evolve in the virtual absence of MMC. (author)

  11. Arresting rampant dental caries with silver diamine fluoride in a young teenager suffering from chronic oral graft versus host disease post-bone marrow transplantation: a case report.

    Science.gov (United States)

    Chu, Chun-Hung; Lee, Angeline Hui-Cheng; Zheng, Liwu; Mei, May Lei; Chan, Godfrey Chi-Fung

    2014-01-03

    Rampant caries is an advanced and severe dental disease that affects multiple teeth. This case describes the management of rampant caries in a young teenager suffering from chronic oral graft versus host disease after allogeneic bone marrow transplantation. A 14-year-old Chinese boy suffering from β-thalassemia major was referred to the dental clinic for the management of rampant dental caries. An oral examination revealed pale conjunctiva, bruising of lips, and depapillation of tongue indicating an underlying condition of anemia. The poor oral condition due to topical and systemic immunosuppressants was seriously aggravated, and rampant caries developed rapidly, affecting all newly erupted, permanent teeth. The teeth were hypersensitive and halitosis was apparent. Strategies for oral health education and diet modification were given to the patient. Xylitol chewing gum was used to stimulate saliva flow to promote remineralization of teeth. Silver diamine fluoride was topically applied to arrest rampant caries and to relieve pain from hypersensitivity. Carious teeth with pulpal involvement were endodontically treated. Stainless steel crowns were provided on molars to restore chewing function, and polycarbonate crowns were placed on premolars, upper canines and incisors. This case report demonstrates success in treating a young teenager with severe rampant dental decay by contemporary caries control and preventive strategy.

  12. Preclinical Testing of Antihuman CD28 Fab' Antibody in a Novel Nonhuman Primate Small Animal Rodent Model of Xenogenic Graft-Versus-Host Disease.

    Science.gov (United States)

    Hippen, Keli L; Watkins, Benjamin; Tkachev, Victor; Lemire, Amanda M; Lehnen, Charles; Riddle, Megan J; Singh, Karnail; Panoskaltsis-Mortari, Angela; Vanhove, Bernard; Tolar, Jakub; Kean, Leslie S; Blazar, Bruce R

    2016-12-01

    Graft-versus-host disease (GVHD) is a severe complication of hematopoietic stem cell transplantation. Current therapies to prevent alloreactive T cell activation largely cause generalized immunosuppression and may result in adverse drug, antileukemia and antipathogen responses. Recently, several immunomodulatory therapeutics have been developed that show efficacy in maintaining antileukemia responses while inhibiting GVHD in murine models. To analyze efficacy and better understand immunological tolerance, escape mechanisms, and side effects of clinical reagents, testing of species cross-reactive human agents in large animal GVHD models is critical. We have previously developed and refined a nonhuman primate (NHP) large animal GVHD model. However, this model is not readily amenable to semi-high throughput screening of candidate clinical reagents. Here, we report a novel, optimized NHP xenogeneic GVHD (xeno-GVHD) small animal model that recapitulates many aspects of NHP and human GVHD. This model was validated using a clinically available blocking, monovalent anti-CD28 antibody (FR104) whose effects in a human xeno-GVHD rodent model are known. Because human-reactive reagents may not be fully cross-reactive or effective in vivo on NHP immune cells, this NHP xeno-GVHD model provides immunological insights and direct testing on NHP-induced GVHD before committing to the intensive NHP studies that are being increasingly used for detailed evaluation of new immune therapeutic strategies before human trials.

  13. Antibiotic-Induced Depletion of Anti-inflammatory Clostridia Is Associated with the Development of Graft-versus-Host Disease in Pediatric Stem Cell Transplantation Patients.

    Science.gov (United States)

    Simms-Waldrip, Tiffany R; Sunkersett, Gauri; Coughlin, Laura A; Savani, Milan R; Arana, Carlos; Kim, Jiwoong; Kim, Minsoo; Zhan, Xiaowei; Greenberg, David E; Xie, Yang; Davies, Stella M; Koh, Andrew Y

    2017-05-01

    Adult stem cell transplantation (SCT) patients with graft-versus-host-disease (GVHD) exhibit significant disruptions in gut microbial communities. These changes are associated with higher overall mortality and appear to be driven by specific antibiotic therapies. It is unclear whether pediatric SCT patients who develop GVHD exhibit similar antibiotic-induced gut microbiota community changes. Here, we show that pediatric SCT patients (from Children's Medical Center Dallas, n = 8, and Cincinnati Children's Hospital, n = 7) who developed GVHD showed a significant decline, up to 10-log fold, in gut anti-inflammatory Clostridia (AIC) compared with those without GVHD. In fact, the development of GVHD is significantly associated with this AIC decline and with cumulative antibiotic exposure, particularly antibiotics effective against anaerobic bacteria (P = .003, Firth logistic regression analysis). Using metagenomic shotgun sequencing analysis, we were able to identify specific commensal bacterial species, including AIC, that were significantly depleted in GVHD patients. We then used a preclinical GVHD model to verify our clinical observations. Clindamycin depleted AIC and exacerbated GVHD in mice, whereas oral AIC supplementation increased gut AIC levels and mitigated GVHD in mice. Together, these data suggest that an antibiotic-induced AIC depletion in the gut microbiota is associated with the development of GVHD in pediatric SCT patients. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  14. Donor characteristics and hematopoietic stem cell transplantation outcome: experience of a single center in Southern Brazil

    Directory of Open Access Journals (Sweden)

    Alessandra Paz

    2018-04-01

    Full Text Available Background: Hematopoietic stem cell transplantation is a curative treatment for many patients with hematological disorders. Donor–recipient genetic disparity, especially involving the human leukocyte antigen system is a critical factor for transplant outcome. Objective: To evaluate retrospectively donor characteristics and correlations with the occurrence of acute and chronic graft-versus-host disease, disease-free survival and overall survival in a Brazilian population submitted to allogeneic hematopoietic stem cell transplantation between 1994 and 2012 in a single center. Results: Three hundred and forty-seven consecutive transplantations were included. Related transplants (81.2% were significantly more common than unrelated transplants (18.7%; donor and recipient median ages were 34 (range: 1–61 and 33 (range: 3–65 years respectively with donor HLAs being matched for 333 (95.9% patients. Donor gender, cytomegalovirus status and ABO incompatibility did not influence the five-year overall survival. In univariate analyses, overall survival was negatively influenced by the presence of acute graft-versus-host disease (33% vs. 47%, respectively; p-value = 0.04, unrelated transplant (41.5% vs. 50.9%, respectively; p-value = 0.045 and donors aged over 40 years (41% vs. 52%, respectively; p-value = 0.03. Older donors were associated with a higher rate of acute (52% vs. 65.8%; p-value = 0.03 and chronic graft-versus-host disease (60% vs. 43%, respectively; p-value = 0.015. In multivariate analyses, acute graft-versus-host disease [relative risk (RR: 1.8; 95% confidence interval (CI: 1.1–29; p-value = 0.008] and older donors (RR: 1.6; 95% CI 1.11–2.24; p-value = 0.013 were associated with higher transplant-related mortality. Conclusions: In transplant patients, to have a donor older than 40 years of age seems to significantly increase the incidence of acute and chronic graft-versus-host disease and transplant-related mortality

  15. Chronic graft-versus-host disease in the rat radiation chimera: I. clinical features, hematology, histology, and immunopathology in long-term chimeras

    Energy Technology Data Exchange (ETDEWEB)

    Beschorner, W.E.; Tutschka, P.J.; Santos, G.W.

    1982-04-01

    The clinical features, pathology, and immunopathology of chronic graft-versus-host disease (GVHD) developing in the long-term rat radiation chimera are described. At 6 to 12 months post-transplant, the previously stable ACI/LEW chimeras developed patchy to diffuse severe hair loss and thickened skin folds, and had microscopic features resembling scleroderma, Sjogren's syndrome, and chronic hepatitis. Skin histology showed dermal inflammation and acanthosis with atrophy of the appendages, with progression to dermal sclerosis. The liver revealed chronic hepatitis with bile duct injury and proliferation and periportal piecemeal necrosis. The tongue had considerable submucosal inflammation, muscular necrosis, and atrophy and arteritis. The serous salivary glands, lacrimal glands, and bronchi had lymphocytic inflammation and injury to duct, acinar, and mucosal columnar epithelium. The thymus had lymphocyte depletion of the medulla with prominent epithelium. The spleen and lymph nodes had poorly developed germinal centers but increased numbers of plasma cells. IgM was observed along the basement membrane and around the basal cells of the skin and tongue and along the basement membrane of the bile ducts. IgM was present also in the arteries of the tongue. Immunoglobulins eluted from the skin, cross-reacted with the bile duct epithelium and usually with both ACI and Lewis skin. Increased titers of speckled antinuclear antibodies were present in the serum of rats with chronic (GVHD). Chronic GVHD in the long-term rat radiation chimera is very similar to human chronic GVHD and is a potentially excellent model for autoimmune disorders including scleroderma, Sjorgren's syndrome, and chronic hepatitis.

  16. Chronic graft-versus-host disease in the rat radiation chimera: I. clinical features, hematology, histology, and immunopathology in long-term chimeras

    International Nuclear Information System (INIS)

    Beschorner, W.E.; Tutschka, P.J.; Santos, G.W.

    1982-01-01

    The clinical features, pathology, and immunopathology of chronic graft-versus-host disease (GVHD) developing in the long-term rat radiation chimera are described. At 6 to 12 months post-transplant, the previously stable ACI/LEW chimeras developed patchy to diffuse severe hair loss and thickened skin folds, and had microscopic features resembling scleroderma, Sjogren's syndrome, and chronic hepatitis. Skin histology showed dermal inflammation and acanthosis with atrophy of the appendages, with progression to dermal sclerosis. The liver revealed chronic hepatitis with bile duct injury and proliferation and periportal piecemeal necrosis. The tongue had considerable submucosal inflammation, muscular necrosis, and atrophy and arteritis. The serous salivary glands, lacrimal glands, and bronchi had lymphocytic inflammation and injury to duct, acinar, and mucosal columnar epithelium. The thymus had lymphocyte depletion of the medulla with prominent epithelium. The spleen and lymph nodes had poorly developed germinal centers but increased numbers of plasma cells. IgM was observed along the basement membrane and around the basal cells of the skin and tongue and along the basement membrane of the bile ducts. IgM was present also in the arteries of the tongue. Immunoglobulins eluted from the skin, cross-reacted with the bile duct epithelium and usually with both ACI and Lewis skin. Increased titers of speckled antinuclear antibodies were present in the serum of rats with chronic (GVHD). Chronic GVHD in the long-term rat radiation chimera is very similar to human chronic GVHD and is a potentially excellent model for autoimmune disorders including scleroderma, Sjorgren's syndrome, and chronic hepatitis

  17. Allogeneic marrow grafting for acute leukemia: A follow-up of long-term survivors

    International Nuclear Information System (INIS)

    Stewart, P.S.; Buckner, C.D.; Clift, R.A.; Sanders, J.E.; Storb, R.; Leonard, J.M.; Thomas, E.D.

    1979-01-01

    We have reported 100 consecutive patients with refractory acute leukemia treated with chemotherapy, total body irradiation (TBI) and marrow from an HLA identical sibling. At the time of the report 17 patients were alive after 11-53 months. All patients have now been followed more than 3 years. At the time of the last report 4 of the 17 patients had relapsed: two in the narrow, one in the central nervous system and one in the testicle. Three of these four patients have died of their disease 27, 34 and 50 months following tranplant. The patient with a solitary testicular relapse remains in complete remission 49 months after local irradiation without concomitant systemic therapy. One other patient died 26 months following transplantation from cardiopulmonary complications following multiple respiratory infections. Of the 13 surviving patients, three suffer from chronic graft-versus-host disease. Summaries of the problems encountered in these patients after the first 100 days are presented. Ten of the original 100 patients are living productive lives 36-80 months after transplantation. The data clearly demonstrate that long-term unmaintained remissions are possible in a small fraction of patients with terminal leukemia treated with various chemotherapy regimens and TBO followed by marrow transplantation. (author)

  18. Allogeneic marrow grafting for acute leukemia: A follow-up of long-term survivors

    Energy Technology Data Exchange (ETDEWEB)

    Stewart, P S; Buckner, C D; Clift, R A; Sanders, J E; Storb, R; Leonard, J M; Thomas, E D [Fred Hutchinson Cancer Research Center, Division of Oncology, Department of Medicine, University of Washington School of Medicine, and U.S. Public Health Service Hospital, Seattle, Washington, USA

    1979-01-01

    We have reported 100 consecutive patients with refractory acute leukemia treated with chemotherapy, total body irradiation (TBI) and marrow from an HLA identical sibling. At the time of the report 17 patients were alive after 11-53 months. All patients have now been followed more than 3 years. At the time of the last report 4 of the 17 patients had relapsed: two in the narrow, one in the central nervous system and one in the testicle. Three of these four patients have died of their disease 27, 34 and 50 months following tranplant. The patient with a solitary testicular relapse remains in complete remission 49 months after local irradiation without concomitant systemic therapy. One other patient died 26 months following transplantation from cardiopulmonary complications following multiple respiratory infections. Of the 13 surviving patients, three suffer from chronic graft-versus-host disease. Summaries of the problems encountered in these patients after the first 100 days are presented. Ten of the original 100 patients are living productive lives 36-80 months after transplantation. The data clearly demonstrate that long-term unmaintained remissions are possible in a small fraction of patients with terminal leukemia treated with various chemotherapy regimens and TBO followed by marrow transplantation.

  19. Comprehensive Analysis of the Activation and Proliferation Kinetics and Effector Functions of Human Lymphocytes, and Antigen Presentation Capacity of Antigen-Presenting Cells in Xenogeneic Graft-Versus-Host Disease.

    Science.gov (United States)

    Kawasaki, Yasufumi; Sato, Kazuya; Hayakawa, Hiroko; Takayama, Norihito; Nakano, Hirofumi; Ito, Ryoji; Mashima, Kiyomi; Oh, Iekuni; Minakata, Daisuke; Yamasaki, Ryoko; Morita, Kaoru; Ashizawa, Masahiro; Yamamoto, Chihiro; Hatano, Kaoru; Fujiwara, Shin-Ichiro; Ohmine, Ken; Muroi, Kazuo; Kanda, Yoshinobu

    2018-04-17

    Xenogeneic graft-versus-host disease (GVHD) models in highly immunodeficient mice are currently being used worldwide to investigate human immune responses against foreign antigens in vivo. However, the individual roles of CD4 + and CD8 + T cells, and donor/host hematopoietic and nonhematopoietic antigen-presenting cells (APCs) in the induction and development of GVHD have not been fully investigated. In the present study, we comprehensively investigated the immune responses of human T cells and the antigen presentation capacity of donor/host hematopoietic and nonhematopoietic APCs in xenogeneic GVHD models using nonobese diabetic/Shi-scid-IL2rg null mice. CD4 + T cells and, to a lesser extent, CD8 + T cells individually mediated potentially lethal GVHD. In addition to inflammatory cytokine production, CD4 + T cells also supported the activation and proliferation of CD8 + T cells. Using bone marrow chimeras, we demonstrated that host hematopoietic, but not nonhematopoietic, APCs play a critical role in the development of CD4 + T cell-mediated GVHD. During early GVHD, we detected 2 distinct populations in memory CD4 + T cells. One population was highly activated and proliferated in major histocompatibility complex antigen (MHC) +/+ mice but not in MHC -/- mice, indicating alloreactive T cells. The other population showed a less activated and slowly proliferative status regardless of host MHC expression, and was associated with higher susceptibility to apoptosis, indicating nonalloreactive T cells in homeostasis-driven proliferation. These observations are clinically relevant to donor T cell response after allogeneic hematopoietic stem cell transplantation. Our findings provide a better understanding of the immunobiology of humanized mice and support the development of novel options for the prevention and treatment for GVHD. Copyright © 2018. Published by Elsevier Inc.

  20. Distinct Biomarker Profiles in Ex Vivo T Cell Depletion Graft Manipulation Strategies: CD34+ Selection versus CD3+/19+ Depletion in Matched Sibling Allogeneic Peripheral Blood Stem Cell Transplantation.

    Science.gov (United States)

    Cantilena, Caroline R; Ito, Sawa; Tian, Xin; Jain, Prachi; Chinian, Fariba; Anandi, Prathima; Keyvanfar, Keyvan; Draper, Debbie; Koklanaris, Eleftheria; Hauffe, Sara; Superata, Jeanine; Stroncek, David; Muranski, Pawel; Barrett, A John; Battiwalla, Minoo

    2018-03-01

    Various approaches have been developed for ex vivo T cell depletion in allogeneic stem cell transplantation to prevent graft-versus-host disease (GVHD). Direct comparisons of T cell depletion strategies have not been well studied, however. We evaluated cellular and plasma biomarkers in 2 different graft manipulation strategies, CD3 + CD19 + cell depletion (CD3/19D) versus CD34 + selection (CD34S), and their associations with clinical outcomes. Identical conditions, including the myeloablative preparative regimen, HLA-identical sibling donor, GVHD prophylaxis, and graft source, were used in the 2 cohorts. Major clinical outcomes were similar in the 2 groups in terms of overall survival, nonrelapse mortality, and cumulative incidence of relapse; however, the cumulative incidence of acute GVHD trended to be higher in the CD3/19D cohort compared with the CD34S cohort. A distinct biomarker profile was noted in the CD3/19D cohort: higher levels of ST2, impaired Helios - FoxP3 + Treg reconstitution, and rapid reconstitution of naïve, Th2, and Th17 CD4 cells in the early post-transplantation period. In vitro graft replication studies confirmed that CD3/19D disproportionately depleted Tregs and other CD4 subset repertoires in the graft. This study confirms the utility of biomarker monitoring, which can be directly correlated with biological consequences and possible future therapeutic indications. Published by Elsevier Inc.

  1. Allosuppressor- and allohelper-T cells in acute and chronic graft-vs.-host (GVH) disease. III. Different Lyt subsets of donor T cells induce different pathological syndromes

    International Nuclear Information System (INIS)

    Rolink, A.G.; Gleichmann, E.

    1983-01-01

    Previous work from this laboratory has led to the hypothesis that the stimulatory pathological symptoms of chronic graft-vs.-host disease (GVHD) are caused by alloreactive donor T helper (TH) cells, whereas the suppressive pathological symptoms of acute GVHD are caused by alloreactive T suppressor (TS) cells of the donor. We analyzed the Lyt phenotypes of B10 donor T cells required for the induction of either acute or chronic GVHD in H-2-different (B10 X DBA/2)F1 recipients. When nonirradiated F1 mice were used as the recipients, we found unseparated B10 T cells induced only a moderate formation of systemic lupus erythematosus (SLE)-like autoantibodies, but a high percentage of lethal GVHD (LGVHD). In contrast, Lyt-1+2- donor T cells were unable to induce LGVHD in these recipients but were capable of inducing a vigorous formation of SLE-like autoantibodies and severe immune-complex glomerulonephritis. Lyt-1-2+ T cells were incapable of inducing either acute or chronic GVHD. The sensitivity and accuracy of the GVH system were increased by using irradiated F1 mice as recipients and then comparing donor-cell inocula that contained similar numbers of T lymphocytes. Donor-cell inocula were used that had been tested for their allohelper and allosuppressor effects on F1 B cells in vitro. In the irradiated F1 recipients unseparated donor T cells were superior to T cell subsets in inducing LGVHD. In contrast Lyt-1+2- T cells, but neither unseparated T cells nor Lyt-1-2+ T cells, were capable of inducing a vigorous formation of SLE-like auto-antibodies. We conclude that the stimulatory pathological symptoms of chronic GVHD are caused by Lyt-1+2- allohelper T cells. In contrast, the development of the suppressive pathological symptoms of acute GVHD appears to involve alloreactive Lyt-1+2+ T suppressor cells

  2. The occurrence of graft-versus-host disease is the major predictive factor for response to donor lymphocyte infusions in multiple myeloma

    NARCIS (Netherlands)

    Lokhorst, Henk M.; Wu, Kalung; Verdonck, Leo F.; Laterveer, Laurens L.; van de Donk, Niels W. C. J.; van Oers, Marinus H. J.; Cornelissen, Jan J.; Schattenberg, Anton V.

    2004-01-01

    The graft-versus-myeloma (GVM) effect of donor lymphocyte infusions (DLIs) is well established. We now report the outcome of DLI in 54 patients with relapsed myeloma following allogeneic transplantation. Twenty-eight patients (52%) responded, 19 patients (35%) with a partial response and 9 patients

  3. Morbidity associated to the transfusion support in pediatric patients with acute leukemia in the National Cancer Institute

    International Nuclear Information System (INIS)

    Vizcaino Valderrama, Martha; Suarez Mattos, Amaranto; Hernandez Kunzel, Jorge Alberto; Restrepo, Alexandra

    2002-01-01

    Acute leukemia represents the most common cancer in pediatrics. The current treatments made necessary a hematological support which increases the risks of complications, like fever, immunologic reaction, infections and, graft versus host disease. The objective of the present study was to determine the morbidity associated with transfusion support in pediatric patients with acute leukemia. In the pediatric population with diagnosis of acute leukemia in the INC during one and half year, the morbidity associated with transfusions was low and couldn't be related to the treatment given to the transfused products

  4. Modeling human gastrointestinal inflammatory diseases using microphysiological culture systems.

    Science.gov (United States)

    Hartman, Kira G; Bortner, James D; Falk, Gary W; Ginsberg, Gregory G; Jhala, Nirag; Yu, Jian; Martín, Martín G; Rustgi, Anil K; Lynch, John P

    2014-09-01

    Gastrointestinal illnesses are a significant health burden for the US population, with 40 million office visits each year for gastrointestinal complaints and nearly 250,000 deaths. Acute and chronic inflammations are a common element of many gastrointestinal diseases. Inflammatory processes may be initiated by a chemical injury (acid reflux in the esophagus), an infectious agent (Helicobacter pylori infection in the stomach), autoimmune processes (graft versus host disease after bone marrow transplantation), or idiopathic (as in the case of inflammatory bowel diseases). Inflammation in these settings can contribute to acute complaints (pain, bleeding, obstruction, and diarrhea) as well as chronic sequelae including strictures and cancer. Research into the pathophysiology of these conditions has been limited by the availability of primary human tissues or appropriate animal models that attempt to physiologically model the human disease. With the many recent advances in tissue engineering and primary human cell culture systems, it is conceivable that these approaches can be adapted to develop novel human ex vivo systems that incorporate many human cell types to recapitulate in vivo growth and differentiation in inflammatory microphysiological environments. Such an advance in technology would improve our understanding of human disease progression and enhance our ability to test for disease prevention strategies and novel therapeutics. We will review current models for the inflammatory and immunological aspects of Barrett's esophagus, acute graft versus host disease, and inflammatory bowel disease and explore recent advances in culture methodologies that make these novel microphysiological research systems possible. © 2014 by the Society for Experimental Biology and Medicine.

  5. Reversal of acute (''malignant'') myelosclerosis by allogeneic bone marrow transplantation

    International Nuclear Information System (INIS)

    Wolf, J.L.; Spruce, W.E.; Bearman, R.M.; Forman, S.J.; Scott, E.P.; Fahey, J. L.; Farbstein, M.J.; Rappaport, H.; Blume, K.G.

    1982-01-01

    A 28-yr-old woman with acute malignant myelosclerosis received, as primary treatment, ablative chemotherapy and total body radiation therapy followed by bone marrow transplantation from her histocompatible brother. The patient is now well more than 15 mo after bone marrow transplantation, with normal peripheral blood counts, a normal bone marrow, no evidence of graft-versus-host disease, and is on no therapy. In light of the poor results obtained with conventional chemotherapy in this disease, bone marrow transplantation may represent the treatment of choice for patients who have an appropriate donor

  6. HLA-DP and bone marrow transplantation: DP-incompatibility and severe acute graft versus host disease

    DEFF Research Database (Denmark)

    Ødum, Niels; Platz, P; Jakobsen, B K

    1987-01-01

    Thirteen recipients of HLA-haploidentical, DR compatible bone marrow (BM) and the corresponding BM donors were HLA-DP typed using primed lymphocyte typing (PLT). Severe acute GVHD (greater than or equal to grade 2) developed within 3 months after BM-transplantation in all of eight recipients of DP...... a role as transplantation antigens....

  7. Antibodies against human cytomegalovirus late protein UL94 in the pathogenesis of scleroderma-like skin lesions in chronic graft-versus-host disease.

    Science.gov (United States)

    Pastano, Rocco; Dell'Agnola, Chiara; Bason, Caterina; Gigli, Federica; Rabascio, Cristina; Puccetti, Antonio; Tinazzi, Elisa; Cetto, Gianluigi; Peccatori, Fedro; Martinelli, Giovanni; Lunardi, Claudio

    2012-09-01

    Human cytomegalovirus (hCMV) infection and its reactivation correlate both with the increased risk and with the worsening of graft-versus-host disease (GVHD). Because scleroderma-like skin lesions can occur in chronic GVHD (cGVHD) in allogeneic stem-cell transplant (HCT) patients and hCMV is relevant in the pathogenesis of systemic sclerosis (SSc), we evaluated the possible pathogenetic link between hCMV and skin cGVHD. Plasma from 18 HCT patients was tested for anti-UL94 and/or anti-NAG-2 antibodies, identified in SSc patients, by direct ELISA assays. Both donors and recipients were anti-hCMV IgG positive, without autoimmune diseases. Patients' purified anti-UL94 and anti-NAG-2 IgG binding to human umbilical endothelial cells (HUVECs) and fibroblasts was performed by FACS analysis and ELISA test. HUVECs apoptosis and fibroblasts proliferation induced by patients' anti-NAG-2 antibodies were measured by DNA fragmentation and cell viability, respectively. About 11/18 patients developed cGVHD and all of them showed skin involvement, ranging from diffuse SSc-like lesions to limited erythema. Eight of eleven cGVHD patients were positive for anti-UL94 and/or anti-NAG-2 antibodies. Remarkably, 4/5 patients who developed diffuse or limited SSc-like lesions had antibodies directed against both UL94 and NAG-2; their anti-NAG-2 IgG-bound HUVECs and fibroblasts induce both endothelial cell apoptosis and fibroblasts proliferation, similar to that induced by purified anti-UL94 and anti-NAG-2 antibodies obtained from SSc patients. In conclusion, our data suggest a pathogenetic link between hCMV infection and scleroderma-like skin cGVHD in HCT patients through a mechanism of molecular mimicry between UL94 viral protein and NAG-2 molecule, as observed in patients with SSc.

  8. Cutaneous chronic graft-versus-host disease does not have the abnormal endothelial phenotype or vascular rarefaction characteristic of systemic sclerosis.

    Directory of Open Access Journals (Sweden)

    Jo Nadine Fleming

    2009-07-01

    Full Text Available The clinical and histologic appearance of fibrosis in cutaneous lesions in chronic graft-versus -host disease (c-GVHD resembles the appearance of fibrosis in scleroderma (SSc. Recent studies identified distinctive structural changes in the superficial dermal microvasculature and matrix of SSc skin. We compared the dermal microvasculature in human c-GVHD to SSc to determine if c-GVHD is a suitable model for SSc.We analyzed skin biopsies of normal controls (n = 24, patients with SSc (n = 30 and c-GVHD with dermal fibrosis (n = 133. Immunostaining was employed to identify vessels, vascular smooth muscle, dermal matrix, and cell proliferation. C-GVHD and SSc had similar dermal matrix composition and vascular smooth muscle pathology, including intimal hyperplasia. SSc, however, differed significantly from c-GVHD in three ways. First, there were significantly fewer (p = 0.00001 average vessels in SSc biopsies (9.8 when compared with c-GVHD (16.5. Second, in SSc, endothelial markers were decreased significantly (19/19 and 12/14 for VE cadherin and vWF (p = <0.0001 and <0.05, respectively. In contrast, 0/13 c-GVHD biopsies showed loss of staining with canonical endothelial markers. Third, c-GVHD contained areas of microvascular endothelial proliferation not present in the SSc biopsies.The sclerosis associated with c-GVHD appears to resemble wound healing. Focal capillary proliferation occurs in early c-GVHD. In contrast, loss of canonical endothelial markers and dermal capillaries is seen in SSc, but not in c-GVHD. The loss of VE cadherin in SSc, in particular, may be related to microvascular rarefaction because VE cadherin is necessary for angiogenesis. C-GVHD is a suitable model for studying dermal fibrosis but may not be applicable for studying the microvascular alterations characteristic of SSc.

  9. Graft versus host disease in a rat small bowel transplant model after T-cell depleted donor specific bone marrow infusion

    Directory of Open Access Journals (Sweden)

    Bakonyi Neto Alexandre

    2003-01-01

    Full Text Available Low cytoreductive regimen of irradiation associated to unmodified bone marrow infusion (UBM does not prevent the occurrence of graft versus host disease (GVHD after transplant. PURPOSE: In this study we evaluated the potential advantages of a long-term immunossupression and T-cell depleted bone marrow infusion (TCDBMI in preventing the occurrence of GVHD after small bowel transplantation (SBTx. METHODS: Heterotopic SBTX was performed with Lewis rats as recipients and DA as donors and distributed into 5 groups according to the irradiation, duration of immunossupression and the use of UBM or TCDBMI: G1 (n=6, without irradiation and G2 (n=9, G3 (n=4, G4 (n=5 and G5 (n=6 was given 250 rd of irradiation. Groups 1,2,4 and G3 and 5 were infused with 100 x 10(6 UBM and TCDBM respectively. Animals in G1, 2, 3 were immunossupressed with 1mg/ FK506/Kg/IM for 5 days and G4 and G5 for 15 days. Anti CD3 monoclonal antibodies and immunomagnetic beads were used for T-cell depletion.Animals were examined for rejection, GVHD, chimerism characterization and ileal and skin biopsies. RESULTS: Minimal to mild rejection was observed in all groups; however, GVHD were present only in irradiated groups. Long-term immunossupression changed the severity of GVHD in G4 and G5. Rejection was the cause of death in G1 while GVHD in G2, 3, 4 and 5, not avoided by the use of TCDBMI. Total chimerism and T-cell chimerism was statistically higher in irradiated groups when compared to G1. CONCLUSION: Extended immunossupression associated to low dose of irradiation decrease the severity of GVHD, not avoided by the use of TCDBMI.

  10. Establishment of a murine graft-versus-myeloma model using allogeneic stem cell transplantation.

    Directory of Open Access Journals (Sweden)

    Marilène Binsfeld

    Full Text Available Multiple myeloma (MM is a malignant plasma cell disorder with poor long-term survival and high recurrence rates. Despite evidence of graft-versus-myeloma (GvM effects, the use of allogeneic hematopoietic stem cell transplantation (allo-SCT remains controversial in MM. In the current study, we investigated the anti-myeloma effects of allo-SCT from B10.D2 mice into MHC-matched myeloma-bearing Balb/cJ mice, with concomitant development of chronic graft-versus-host disease (GvHD.Balb/cJ mice were injected intravenously with luciferase-transfected MOPC315.BM cells, and received an allogeneic (B10.D2 donor or autologous (Balb/cJ donor transplant 30 days later. We observed a GvM effect in 94% of the allogeneic transplanted mice, as the luciferase signal completely disappeared after transplantation, whereas all the autologous transplanted mice showed myeloma progression. Lower serum paraprotein levels and lower myeloma infiltration in bone marrow and spleen in the allogeneic setting confirmed the observed GvM effect. In addition, the treated mice also displayed chronic GvHD symptoms. In vivo and in vitro data suggested the involvement of effector memory CD4 and CD8 T cells associated with the GvM response. The essential role of CD8 T cells was demonstrated in vivo where CD8 T-cell depletion of the graft resulted in reduced GvM effects. Finally, TCR Vβ spectratyping analysis identified Vβ families within CD4 and CD8 T cells, which were associated with both GvM effects and GvHD, whereas other Vβ families within CD4 T cells were associated exclusively with either GvM or GvHD responses.We successfully established an immunocompetent murine model of graft-versus-myeloma. This is the first murine GvM model using immunocompetent mice that develop MM which closely resembles human MM disease and that are treated after disease establishment with an allo-SCT. Importantly, using TCR Vβ spectratyping, we also demonstrated the presence of GvM unique responses

  11. Wharton’s Jelly-Derived Mesenchymal Stromal Cells as a Promising Cellular Therapeutic Strategy for the Management of Graft-versus-Host Disease

    Directory of Open Access Journals (Sweden)

    Joseph P. McGuirk

    2015-04-01

    Full Text Available Allogeneic hematopoietic cell transplantation (allo-HCT, a treatment option in hematologic malignancies and bone marrow failure syndromes, is frequently complicated by Graft-versus-host disease (GVHD. The primary treatment for GVHD involves immune suppression by glucocorticoids. However, patients are often refractory to the steroid therapy, and this results in a poor prognosis. Therefore alternative therapies are needed to treat GVHD. Here, we review data supporting the clinical investigation of a novel cellular therapy using Wharton’s jelly (WJ-derived mesenchymal stromal cells (MSCs as a potentially safe and effective therapeutic strategy in the management of GVHD. Adult-derived sources of MSCs have demonstrated signals of efficacy in the management of GVHD. However, there are limitations, including: limited proliferation capacity; heterogeneity of cell sources; lengthy expansion time to clinical dose; expansion failure in vitro; and a painful, invasive, isolation procedure for the donor. Therefore, alternative MSC sources for cellular therapy are sought. The reviewed data suggests MSCs derived from WJ may be a safe and effective cellular therapy for GVHD. Laboratories investigated and defined the immune properties of WJ-MSCs for potential use in cellular therapy. These cells represent a more uniform cell population than bone marrow-derived MSCs, displaying robust immunosuppressive properties and lacking significant immunogenicity. They can be collected safely and painlessly from individuals at birth, rapidly expanded and stored cryogenically for later clinical use. Additionally, data we reviewed suggested licensing MSCs (activating MSCs by exposure to cytokines to enhance effectiveness in treating GVHD. Therefore, WJCs should be tested as a second generation, relatively homogeneous allogeneic cell therapy for the treatment of GVHD.

  12. Prevention of lethal murine graft versus host disease by treatment of donor cells with L-leucyl-L-leucine methyl ester

    International Nuclear Information System (INIS)

    Charley, M.; Thiele, D.L.; Bennett, M.; Lipsky, P.E.

    1986-01-01

    Graft vs. host disease (GVHD) remains one of the main problems associated with bone marrow transplantation. The current studies were undertaken to determine whether treatment of the donor inoculum with the anticytotoxic cell compound L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) would alter the development of GVHD in a murine model. Irradiated recipient mice transplanted with a mixture of control bone marrow and spleen cells from naive semiallogeneic donors died rapidly from GVHD, whereas the recipients of cells incubated with 250 microM Leu-Leu-OMe all survived. In addition, Leu-Leu-OMe treatment of cells obtained from donors immunized against host alloantigens resulted in significantly prolonged survival. Phenotypic characterization of spleen cells from the various groups of mice that had received Leu-Leu-OMe-treated cells and survived consistently revealed the donor phenotype. Treatment of marrow cells with 250 microM Leu-Leu-OMe appeared to have no adverse effects on stem cell function. Erythropoiesis was undiminished, as assayed by splenic 5-iodo-2'-deoxyuridine- 125 I uptake. Moreover, granulocytic and megakaryocytic regeneration were histologically equivalent in the spleens of recipients of control or Leu-Leu-OMe-treated cells. Treatment of the donor inoculum with Leu-Leu-OMe thus prevents GVHD in this murine strain combination with no apparent stem cell toxicity

  13. Graft-versus-leukemia, donor selection for adoptive immunotherapy in mice

    International Nuclear Information System (INIS)

    LeFeber, W.P.; Truitt, R.L.; Rose, W.C.; Bortin, M.M.

    1977-01-01

    The optimal donor for adoptive immunotherapy would exhibit great antitumor reactivity and no antihost reactivity. Immunocompetent cells from 11 strains of mice were tested in vivo for their reactivity against a long-passage AKR acute lymphoblastic leukemia and against immunosuppressed nonleukemic AKR mice. Donor mice were syngeneic, unprimed H-2 compatible, primed H-2 compatible, congenic, or H-2 incompatible with AKR. Bioassays were used to evaluate the relative graft-vs.-leukemia (GvL) reactivity and the relative graft-vs.-host (GvH) reactivity of transplanted bone marrow and lymph-node cells from the panel of donors. No significant GvL reactivity was found when cells from syngeneic, unprimed H-2 compatible, or congenic donors were tested. H-2 compatible donors that were immunized with γ-irradiated AKR leukemic spleen cells showed modest GvL reactivity, but associated with the immunization was a disproportionate increase in acute and delayed GvH mortality. Among the H-2 mismatched donors, mice of the SJL strain appeared to most closely approach the ideal because of least intense GvH reactivity and maximal GvL reactivity. As measured in these experiments there was no correlation between the severity of GvH disease and the efficacy of the GvL reaction; GvL reactivity in unprimed donors was always associated with H-2 incompatibility; disparity between donor and recipient at H-2 did not guarantee an effective GvL reaction; and the increase in GvL reactivity obtained by immunizing H-2 compatible donors was overshadowed by the increase in GvH disease

  14. HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse.

    Science.gov (United States)

    Martelli, Massimo F; Di Ianni, Mauro; Ruggeri, Loredana; Falzetti, Franca; Carotti, Alessandra; Terenzi, Adelmo; Pierini, Antonio; Massei, Maria Speranza; Amico, Lucia; Urbani, Elena; Del Papa, Beatrice; Zei, Tiziana; Iacucci Ostini, Roberta; Cecchini, Debora; Tognellini, Rita; Reisner, Yair; Aversa, Franco; Falini, Brunangelo; Velardi, Andrea

    2014-07-24

    Posttransplant relapse is still the major cause of treatment failure in high-risk acute leukemia. Attempts to manipulate alloreactive T cells to spare normal cells while killing leukemic cells have been unsuccessful. In HLA-haploidentical transplantation, we reported that donor-derived T regulatory cells (Tregs), coinfused with conventional T cells (Tcons), protected recipients against graft-versus-host disease (GVHD). The present phase 2 study investigated whether Treg-Tcon adoptive immunotherapy prevents posttransplant leukemia relapse. Forty-three adults with high-risk acute leukemia (acute myeloid leukemia 33; acute lymphoblastic leukemia 10) were conditioned with a total body irradiation-based regimen. Grafts included CD34(+) cells (mean 9.7 × 10(6)/kg), Tregs (mean 2.5 × 10(6)/kg), and Tcons (mean 1.1 × 10(6)/kg). No posttransplant immunosuppression was given. Ninety-five percent of patients achieved full-donor type engraftment and 15% developed ≥grade 2 acute GVHD. The probability of disease-free survival was 0.56 at a median follow-up of 46 months. The very low cumulative incidence of relapse (0.05) was significantly better than in historical controls. These results demonstrate the immunosuppressive potential of Tregs can be used to suppress GVHD without loss of the benefits of graft-versus-leukemia (GVL) activity. Humanized murine models provided insights into the mechanisms underlying separation of GVL from GVHD, suggesting the GVL effect is due to largely unopposed Tcon alloantigen recognition in bone marrow. © 2014 by The American Society of Hematology.

  15. The Genotype of the Donor for the (GTn Polymorphism in the Promoter/Enhancer of FOXP3 Is Associated with the Development of Severe Acute GVHD but Does Not Affect the GVL Effect after Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation.

    Directory of Open Access Journals (Sweden)

    Víctor Noriega

    Full Text Available The FOXP3 gene encodes for a protein (Foxp3 involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+, which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (≤(GT15 for the (GTn polymorphism in the promoter/enhancer of FOXP3 are associated with a higher expression of FOXP3, and hypothetically with an increase of regulatory T cell activity. This polymorphism has been related to the development of auto- or alloimmune conditions including type 1 diabetes or graft rejection in renal transplant recipients. However, its impact in the allo-transplant setting has not been analyzed. In the present study, which includes 252 myeloablative HLA-identical allo-transplants, multivariate analysis revealed a lower incidence of grade III-IV acute graft versus host disease (GVHD in patients transplanted from donors harboring short alleles (OR = 0.26, CI 0.08-0.82, p = 0.021; without affecting chronic GVHD or graft versus leukemia effect, since cumulative incidence of relapse, event free survival and overall survival rates are similar in both groups of patients.

  16. Application experience of extracorporeal photopheresis for treatment of acutegraft-versus-host” disease after allogeneic hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    A. V. Kozlov

    2014-07-01

    Full Text Available Extracorporeal photopheresis (ECP has been used as a component of combined immunosuppressive therapy in 53 patients with steroid-refractoryacute “graft-versus-host” disease. Overall response was observed in 35 patients (66 %; 95 % CI 52.6–77.3: complete response (CR in 15 pts (28.3 %; 95 % CI 18–41.6 and partial response (PR in 20 pts (37.7 %; 95 % CI 25.9–51.2. 3-year OS was 39 % in patients with clinical response (CR or PR; in the absence of clinical response OS was 8 % during the first year (p < 0.0001. Median methylprednisolone dose before ECP was 2 mg/kg/day, and at the end of ECP course – 0.7 mg/kg/day (p < 0.0001.

  17. Early and long-term outcomes of coronary artery bypass grafting in patients with acute coronary syndrome versus stable angina pectoris.

    Science.gov (United States)

    Fukui, Toshihiro; Tabata, Minoru; Morita, Satoshi; Takanashi, Shuichiro

    2013-06-01

    The aim of the present study was to determine the early and long-term outcomes of coronary artery bypass grafting in patients with acute coronary syndrome and stable angina pectoris. From September 2004 to September 2011, 382 patients with acute coronary syndrome (unstable angina pectoris and non-ST-segment elevation myocardial infarction) and 851 patients with stable angina pectoris underwent first-time isolated coronary artery bypass grafting at our institute. The early and long-term outcomes were compared between the 2 groups. Patients with acute coronary syndrome were older, were more likely to be women, had a smaller body surface area, and were more likely to have left main coronary artery disease. In both groups, bilateral internal thoracic artery grafts were used in approximately 89% of the patients, and off-pump techniques in approximately 97% of the patients. The acute coronary syndrome group had a greater operative death rate (2.6% vs 0.1%) and a greater incidence of low output syndrome (3.1% vs 1.2%) and hemodialysis requirement (2.9% vs 1.1%). Multivariate regression analysis demonstrated that age, acute coronary syndrome, lower ejection fraction, and higher creatinine level before surgery were independent predictors of operative death. However, among the hospital survivors, no differences were seen in freedom from all death (85.4% ± 2.5% vs 87.7% ± 2.0%), cardiac death (97.4% ± 0.9% vs 96.5% ± 0.9%), or major adverse cardiac and cerebrovascular events (78.0% ± 2.9% vs 78.1% ± 2.3%) at 7 years between the patients with acute coronary syndrome and stable angina pectoris. Although acute coronary syndrome is an independent predictor of early mortality in patients undergoing coronary artery bypass grafting, the long-term outcomes after surgery were similar between patients with acute coronary syndrome and stable angina pectoris who survived the early postoperative period. Copyright © 2013 The American Association for Thoracic Surgery. Published by

  18. Mesenchymal Stem Cells (MSCs) Attenuate Cutaneous Sclerodermatous Graft-Versus-Host Disease (Scl-GVHD) through Inhibition of Immune Cell Infiltration in a Mouse Model.

    Science.gov (United States)

    Lim, Ji-Young; Ryu, Da-Bin; Lee, Sung-Eun; Park, Gyeongsin; Min, Chang-Ki

    2017-09-01

    Human chronic graft-versus-host disease (GVHD) shares clinical characteristics with a murine sclerodermatous GVHD model that is characterized by skin thickening and lung fibrosis. A B10.D2 → BALB/c transplant model of sclerodermatous GVHD was used to address the therapeutic effect of mesenchymal stem cells (MSCs) on the development of chronic GVHD. The clinical and pathological severity of cutaneous sclerodermatous GVHD was significantly attenuated in MSC-treated recipients relative to sclerodermatous GVHD control subjects. After MSC treatment, skin collagen production was significantly reduced, with consistent down-regulation of Tgfb expression. Effects of MSCs on molecular markers implicated in persistent transforming growth factor-β signaling and fibrosis, such as PTEN, phosphorylated Smad-2/3, and matrix metalloproteinase-1, were observed in skin tissue. MSCs neither migrate to the skin nor affect the in vivo expansion of immune effector cells, but they inhibited the infiltration of immune effector cells into skin via down-regulation of CCR4 and CCR8 expression on CD4 + T cells and CCR1 on CD11b + monocyte/macrophages. MSCs diminished expression of chemokines such as CCL1, CCL3, CCL8, CCL17, and CCL22 in skin. MSCs were also dependent on stimulated splenocytes to suppress fibroblast proliferation. Our findings indicate that MSCs attenuate the cutaneous sclerodermatous GVHD by selectively blocking immune cell migration and down-regulating chemokines and chemokine receptors. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Use of telecobalt-therapy in transfusion-associated graft-versus-host disease; Uso da telecobaltoterapia na prevencao da doenca enxerto-versus-hospedeiro associada a transfusao

    Energy Technology Data Exchange (ETDEWEB)

    Goes, Evamberto Garcia de

    1999-08-01

    The transfusion-associated Graft-Versus-Host Disease (TA-GVHD) is prevented through the irradiation of blood components before transfusion. This work started with a diagnostic about blood irradiation practices in Brazil, through the application of a questionnaire to 56 regional blood centers, and showed that the majority of the regional blood centers have no means to irradiate their own blood components. This survey have also shown that 62,5% of the regional blood centers have local facilities to irradiate their own blood components, through the use of telecobalt-therapy services. Assuming the use of telecobalt-therapy equipment as an alternative solution to the Brazilian blood irradiation problem, the development of an appropriate technique allowed a good quality for irradiated blood. A prototype of a thermic box was made in acrylic and foam, and an automated system of data acquisition, kept the temperature of blood components bellow 6 deg C, during irradiation. Phantoms built using polystyrene plastic represented blood volume routinely irradiated by the regional blood centers. The distribution of doses on the phantoms volumes determined with LiF-100 thermoluminescent dosimeters, were represented in terms of isodoses curves. The doses distributions on the phantom with higher dimensions, 30 x 30 x 20 cm, changed from a minimum relative dose of 80% up to a maximum of 106%. An investigation concerning effects of Cobalt-60 gamma radiation on red blood cells, irradiated and stored, showed increase in potassium levels, up to the tenth day, in blood units irradiated at 3,00 cGy. Surveillance of the reduction in the capacity of T-Cells proliferation as a function of dose, using Limiting Dilution Analysis, showed that a minimum of 2,500 cGy is necessary to prevent TA-GVHD. Methodology developed in this work guarantee good quality for blood irradiated with telecobalt-therapy equipment, a valid alternative for Brazilian institutions which have available only this technique

  20. Role of mobile passenger lymphocytes in the rejection of renal and cardiac allografts in the rat. A passenger lymphocyte-mediated graft-versus-host reaction amplifies the host response

    International Nuclear Information System (INIS)

    van Vrieshilfgaarde, R.; Hermans, P.; Terpstra, J.L.; van Breda Viresman, P.J.

    1980-01-01

    It is demonstrated that passenger lymphocytes migrate out of rat renal allografts into host spleens in a radioresistant fashion. These mobile passenger lymphocytes within BN kidney and heart transplants are immunocompetent, since they elicit a graft-versus-host (GVH) reaction in the spleens of (LEW x BN)F2 hybrid hosts. The greater GVH reaction in (LEW x BN)F1 recipients of BN kidneys reflects the greater number of mobile passenger lymphocytes in the kidney when compared to the heart. The mobile passenger lymphocytes within BN renal allografts also cause a proliferative response in the spleens of the LEW hosts as well as an accelerated rejection of BN renal allografts when compared to BN cardiac allografts, for the differences between BN kidney and heart, both in terms of splenomegaly elicited in LEW as well as tempo of rejection, are abolished by total body x-irradiation of the donor with 900 rad. Results indicate that a mobile passenger lymphocyte mediated GVH reaction in the central lymphoid organs of the host augments the host response to allogenic kidneys and contributes materially to first-set renal allograft rejection; this GVH reaction on the other hand is not conspicuously present in LEW recipients of BN cardiac allografts and has therefore little effect on first-set cardiac allograft rejection

  1. Potential for Monitoring Gut Microbiota for Diagnosing Infections and Graft-versus-Host Disease in Cancer and Stem Cell Transplant Patients.

    Science.gov (United States)

    Koh, Andrew Y

    2017-11-01

    Gut microbiota, the collective community of microorganisms inhabiting the intestine, have been shown to provide many beneficial functions for the host. Recent advances in next-generation sequencing and advanced molecular biology approaches have allowed researchers to identify gut microbiota signatures associated with disease processes and, in some cases, establish causality and elucidate underlying mechanisms. This report reviews 3 commonly used methods for studying the gut microbiota and microbiome (the collective genomes of the gut microorganisms): 16S rRNA gene sequencing, bacterial group or species-specific quantitative polymerase chain reaction (qPCR), and metagenomic shotgun sequencing (MSS). The technical approaches and resources needed for each approach are outlined, and advantages and disadvantages for each approach are summarized. The findings regarding the role of the gut microbiota in the health of patients with cancer and stem cell transplant (SCT) patients (specifically in modulating the development of gut-derived bacterial infections and a posttransplant immune-mediated complication known as graft-vs-host-disease) are reviewed. Finally, there is discussion of the potential viability of these approaches in the actual clinical treatment of cancer and SCT patients. Advances in next-generation sequencing have revolutionized our understanding of the importance of the gut microbiome to human health. Both 16S rRNA gene sequencing and MSS are currently too labor-intensive or computationally burdensome to incorporate into real-time clinical monitoring of gut microbiomes. Yet, the lessons learned from these technologies could be adapted to currently used methods (e.g., qPCR) that could then be rigorously tested in the clinical care of these patients. © 2017 American Association for Clinical Chemistry.

  2. Quantitative evaluation of the hazards involved in transferring foreign cells and tissues to immunologically suppressed or deficient subjects

    Energy Technology Data Exchange (ETDEWEB)

    Bekkum, D.W. van

    1971-04-01

    It has already been pointed out in a preceding chapter that a successful take of allogenic bone marrow in primates inevitably entails a most severe early or acute form of secondary disease caused by a violent immunological reaction of the immune competent cells of the graft directed against the host. In mice and rats such an acute graft versus host disease is not seen following grafting of allogenic bone marrow, but only if substantial numbers of spleen or lymph node cells are transferred. Apparently, primate bone marrow is exceptionally aggressive compared to rodent bone marrow and it is not possible to prevent this reaction by decreasing the number of infused bone marrow cells without simultaneously eliminating the restorative effect of the graft. There are many reasons for assuming that the property to elicit a graft versus host reaction resides exclusively in the lymphoid cell series. These cells are normally to be found not only in the bone marrow and the lymphatic organs but also in the peripheral blood and in other tissues. Since surprisingly small numbers of lymphoid cells have been shown to cause graft versus host disease in completely non-reactive recipients, a calculation of the risks involved in transfusing sizable amounts of fresh blood or leukocyte concentrates to human recipients appears to be opportune. Moreover, the current attempts to restore immunological function in agammaglobulinaemic patients by implantations of allogenic foetal thymus tissue and by infusion of foetal liver and bone marrow cell suspensions (Dooren et al., 1968; Hong et al., 1968) require a critical analysis of the risks involved. Finally, the rapidly advancing clinical transplantation of organs - all of which contain scattered lymphoid cells - seems to necessitate a re-evaluation of this potential hazard in the light of the present knowledge of the induction of graft versus host disease. Most of our factual information concerning graft versus host reactions comes from

  3. Efficacy of two different doses of rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease in children with haematological malignancies transplanted from an unrelated donor: a multicentre, randomised, open-label, phase 3 trial.

    Science.gov (United States)

    Locatelli, Franco; Bernardo, Maria Ester; Bertaina, Alice; Rognoni, Carla; Comoli, Patrizia; Rovelli, Attilio; Pession, Andrea; Fagioli, Franca; Favre, Claudio; Lanino, Edoardo; Giorgiani, Giovanna; Merli, Pietro; Pagliara, Daria; Prete, Arcangelo; Zecca, Marco

    2017-08-01

    Although rabbit anti-T-lymphocyte globulin (ATLG) is largely used for the prevention of immune-mediated complications in patients given allogeneic haemopoietic stem-cell transplantation (HSCT) from an unrelated donor, the optimum dose of this drug in children is still undefined. We aimed to test whether a higher dose of ATLG was superior to a lower dose for prevention of grade II-IV acute graft-versus-host disease (GVHD). We conducted a multicentre, randomised, open-label, phase 3 trial in seven Italian centres comparing two different doses of ATLG (30 mg/kg vs 15 mg/kg, given intravenously over 3 days, from day -4 to -2) in children (aged 0-18 years) with haematological malignancies transplanted from an unrelated donor, selected using high-resolution typing for HLA-class I/II loci. All patients received a myeloablative regimen and cyclosporine-A plus short-term methotrexate as post-transplantation GVHD prophylaxis. Patients were randomly assigned (1:1) to either of the two groups and were stratified by the degree of HLA-compatibility with their donor, the source of haemopoietic stem cells used (bone marrow vs peripheral blood stem cells), and the disease risk category. The randomisation was open label; all investigators were aware of the treatment allocation. The primary endpoint of the study was 100-day cumulative incidence of grade II-IV acute GVHD. Statistical analyses were done according to the per-protocol principle. Other outcomes included cumulative incidence of chronic GVHD, non-relapse mortality, disease recurrence, and probability of overall survival and event-free survival. This study was registered with ClinicalTrials.gov, number NCT00934557. Between Jan 15, 2008, and Sept 25, 2012, 89 patients were randomly assigned to the 30 mg/kg ATLG group and 91 to the 15 mg/kg ATLG group; 84 patients in the 30 mg/kg ATLG group and 88 in the 15 mg/kg ATLG group were included in the analysis. The median follow-up for the whole study population was 3·4 years (IQR 1

  4. TNF Receptor Type II as an Emerging Drug Target for the Treatment of Cancer, Autoimmune Diseases, and Graft-Versus-Host Disease: Current Perspectives and In Silico Search for Small Molecule Binders

    Directory of Open Access Journals (Sweden)

    Faraz Shaikh

    2018-06-01

    Full Text Available There is now compelling evidence that TNF receptor type II (TNFR2 is predominantly expressed on CD4+Foxp3+ regulatory T cells (Tregs and myeloid-derived suppressor cells (MDSCs, and plays a major role in the expansion and function of Tregs and MDSCs. Consequently, targeting of TNFR2 by either antagonists or agonists may represent a novel strategy in the treatment of cancer and autoimmune diseases, by downregulating or upregulating suppressor cell activity. The advance in the understanding of complex structure of TNFR2 and its binding with TNF at molecular levels offers opportunity for structure-guided drug discovery. This article reviews the current evidences regarding the decisive role of TNFR2 in immunosuppressive function of Tregs and MDSCs, and the current effort to develop novel TNFR2-targeting therapeutic agents in the treatment of cancer, autoimmune diseases, and graft-versus-host disease. To shed light on the potential TNFR2-targeting small molecules, we for the first time performed virtual screening of 400,000 natural compounds against the two TNF-binding sites, regions 3 and 4, of TNFR2. Our result showed that the top hits at region 4 had slightly higher docking energies than those at region 3. Nevertheless, free energy calculation from the TNF–TNFR2 molecular dynamics simulation revealed that the binding strength of TNF in region 3 is only one-tenth of that in region 4. This suggests that region 3 is a potentially more viable binding site to be targeted by small molecules than region 4. Therefore, the effectiveness in targeting region 3 of TNFR2 deserves further investigation.

  5. Regulatory T Cells in Chronic Graft-Versus-Host Disease After Extracorporeal Photopheresis: Correlation With Skin and Global Organ Responses, and Ability to Taper Steroids.

    Science.gov (United States)

    Denney, Helen A; Whittle, Robert J; Lai, Jennifer; Jacques, Richard M; Taylor, Peter C

    2017-01-01

    Induction of immune tolerance by an increase in regulatory T (Treg) cells after extracorporeal photopheresis (ECP) is thought to contribute to how ECP exerts its therapeutic effect in patients with chronic graft-versus-host disease (cGvHD). We investigated whether percentages and absolute counts of Treg cells changed post-ECP, and examined correlation with response. Absolute counts and % of CD4+ T cells and Treg cells (CD4 + CD25 + FOXP3 + CD127dim/-) were evaluated using flow cytometry in 32 patients with cGvHD treated by ECP for a minimum of 3 months, and up to 12 months. CD4+ or Treg cells at baseline to 12 months post-ECP were compared with changes in skin disease scores or global organ involvement, or the ability to taper steroids, at 14, 28, and 56 weeks. Regulatory T cells % increased significantly above any overall changes in CD4+ % at 6, 9, and 12 months post-ECP. There was no statistically significant association between Treg cells and skin or steroid response, whereas a larger increase in CD4+ count from baseline to 1 to 3 months corresponded to increased odds of being able to reduce steroid dose by 50% or greater at 14 weeks. Skin and global organ responders at 28 weeks had higher median Treg cell counts 3 months post-ECP than nonresponders, as did steroid responders at 56 weeks who were 12 months post-ECP. Regulatory T cell counts and % varied greatly among cGvHD patients, and the increase post-ECP was not significant until 6 months. No clear correlation was found between Treg cells and clinical improvement, suggesting that increases in Treg cell numbers and/or proportions are not driving the mechanism leading to a response after ECP.

  6. Striatal grafts in a rat model of Huntington's disease

    DEFF Research Database (Denmark)

    Guzman, R; Meyer, M; Lövblad, K O

    1999-01-01

    Survival and integration into the host brain of grafted tissue are crucial factors in neurotransplantation approaches. The present study explored the feasibility of using a clinical MR scanner to study striatal graft development in a rat model of Huntington's disease. Rat fetal lateral ganglionic...... time-points graft location could not be further verified. Measures for graft size and ventricle size obtained from MR images highly correlated with measures obtained from histologically processed sections (R = 0.8, P fetal rat lateral ganglionic...

  7. Graft-Versus-Host-Disease

    Science.gov (United States)

    ... however you can Daughter's dying wish became mother's motivation Be The Match Blog Stories Anna, transplant recipient ... any symptoms of GVHD , tell your transplant doctor right away. Chronic GVHD: Usually develops 3-6 months ...

  8. Distribution and clonality of the vα and vβ T-cell receptor repertoire of regulatory T cells in leukemia patients with and without graft versus host disease.

    Science.gov (United States)

    Jin, Zhenyi; Wu, Xiuli; Chen, Shaohua; Yang, Lijian; Liu, Qifa; Li, Yangqiu

    2014-03-01

    Graft versus host disease (GVHD) is the main complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recent data indicated that regulatory T (Treg) cells might relate to GVHD, and such functions might be mediated by certain T-cell receptor (TCR) subfamily of Treg cells. Thus, we analyzed the distribution and clonality of the TCR Vα and Vβ repertoire of Treg cells from leukemia patients with and without GVHD after allo-HSCT. Numerous TCR Vα subfamilies, including Vα1, Vα9, Vα13, Vα16-19, and Vα24-29, were absent in Treg cells after allo-HSCT. The usage numbers for the TCR Vα and Vβ subfamilies in Treg cells from patients without GVHD appeared more widely. The expression frequencies of Vα10 or Vα20 between both groups were significantly different. Moreover, the expression frequency of TCR Vβ2 subfamily in patients without GVHD was significantly higher than that in patients with GVHD. Oligoclonally expanded TCR Vα and Vβ Treg cells were identified in a few samples in both groups. Restricted utilization of the Vα and Vβ subfamilies and the absence of some important TCR rearrangements in Treg cells may be related to GVHD due to a lower regulating function of Treg subfamilies.

  9. Induction of a glucocorticoid-sensitive F1-anti-parental mechanism that affects engraftment during graft-versus-host disease.

    Science.gov (United States)

    You-Ten, K E; Seemayer, T A; Wisse, B; Bertley, F M; Lapp, W S

    1995-07-01

    Studies have shown that graft-vs-host disease (GVHD) in animal models induces persistent elevated levels of circulating adrenal glucocorticoids. In this report, we investigated the effects of endogenous glucocorticoids on the outcome of GVHD by adrenalectomizing (ADX) unirradiated (C57BL/6 x A)F1 (B6AF1) mice before GVHD induction. GVHD was induced by injection of 20 x 10(6) A strain parental lymphoid cells into B6AF1 mice. Our results demonstrated that non-ADX recipient mice experienced features characteristic of GVHD on day 13, which became progressively more severe by days 18 to 21. The GVHD features included severe immunosuppression, reversal in the host splenic CD4+/CD8+ ratio, histopathologic lesions in different tissues, and high parental cell chimerism in the spleens and lymph nodes. In contrast, ADX F1 recipient mice experienced GVHD features on day 13 similar to their non-ADX counterparts; however, ADX animals recovered rapidly from GVHD by days 18 to 21. Flow cytometry showed that, although a relatively high frequency of parental cells was detected in the spleens and lymph nodes of ADX mice on day 13, nearly all of the parental cells in the peripheral lymphoid organs disappeared on days 18 to 21, the time of recovery from GVHD. The marked reduction of parental cells and recovery from GVHD were prevented by treating ADX F1 mice with either exogenous glucocorticoid, anti-asialoGM1, or anti-CD8, but not anti-NK1.1 Ab. These results suggest that a dramatic recovery from GVHD was induced by a cell-mediated, steroid-sensitive F1-anti-parental mechanism. The F1-anti-parental phenomenon described herein is different from classical hybrid resistance.

  10. Effect of selective T cell depletion of host and/or donor bone marrow on lymphopoietic repopulation, tolerance, and graft-vs-host disease in mixed allogeneic chimeras (B10 + B10.D2----B10)

    International Nuclear Information System (INIS)

    Ildstad, S.T.; Wren, S.M.; Bluestone, J.A.; Barbieri, S.A.; Stephany, D.; Sachs, D.H.

    1986-01-01

    Reconstitution of lethally irradiated mice with a mixture of T cell-depleted syngeneic plus T cell-depleted allogeneic bone marrow (B10 + B10.D2----B10) leads to the induction of mixed lymphopoietic chimerism, excellent survivals, specific in vivo transplantation tolerance to subsequent donor strain skin grafts, and specific in vitro unresponsiveness to allogeneic donor lymphoid elements as assessed by mixed lymphocyte reaction (MLR) proliferative and cell-mediated lympholysis (CML) cytotoxicity assays. When B10 recipient mice received mixed marrow inocula in which the syngeneic component had not been T cell depleted, whether or not the allogeneic donor marrow was treated, they repopulated exclusively with host-type cells, promptly rejected donor-type skin allografts, and were reactive in vitro to the allogeneic donor by CML and MLR assays. In contrast, T cell depletion of the syngeneic component of the mixed marrow inocula resulted in specific acceptance of allogeneic donor strain skin grafts. Such animals were specifically unreactive to allogeneic donor lymphoid elements in vitro by CML and MLR, but were reactive to third party. When both the syngeneic and allogeneic marrow were T cell depleted, variable percentages of host- and donor-type lymphoid elements were detected in the mixed reconstituted host. When only the syngeneic bone marrow was T cell depleted, animals repopulated exclusively with donor-type cells. Although these animals had detectable in vitro anti-host (B10) reactivity by CML and MLR and reconstituted as fully allogeneic chimeras, they exhibited excellent survival and had no in vivo evidence for graft-vs-host disease. Experiments in which untreated donor spleen cells were added to the inocula in this last group suggest that the presence of T cell-depleted syngeneic bone marrow cells diminishes graft-vs-host disease and the mortality from it

  11. Treatment of whole blood with riboflavin plus ultraviolet light, an alternative to gamma irradiation in the prevention of transfusion-associated graft-versus-host disease?

    Science.gov (United States)

    Fast, Loren D; Nevola, Martha; Tavares, Jennifer; Reddy, Heather L; Goodrich, Ray P; Marschner, Susanne

    2013-02-01

    Exposure of blood products to gamma irradiation is currently the standard of care in the prevention of transfusion-associated graft-versus-host disease (TA-GVHD). Regulatory, technical, and clinical challenges associated with the use of gamma irradiators are driving efforts to develop alternatives. Pathogen reduction methods were initially developed to reduce the risk of microbial transmission by blood components. Through modifications of nucleic acids, these technologies interfere with the replication of both pathogens and white blood cells (WBCs). To date, systems for pathogen and WBC inactivation of products containing red blood cells are less well established than those for platelets and plasma. In this study, the in vitro and in vivo function of WBCs present in whole blood after exposure to riboflavin plus ultraviolet light (Rb-UV) was examined and compared to responses of WBCs obtained from untreated or gamma-irradiated blood by measuring proliferation, cytokine production, activation, and antigen presentation and xenogeneic (X-)GVHD responses in an in vivo mouse model. In vitro studies demonstrated that treatment of whole blood with Rb-UV was as effective as gamma irradiation in preventing WBC proliferation, but was more effective in preventing antigen presentation, cytokine production, and T-cell activation. Consistent with in vitro findings, treatment with Rb-UV was as effective as gamma irradiation in preventing X-GVHD, a mouse model for TA-GVHD. The ability to effectively inactivate WBCs in fresh whole blood using Rb-UV, prior to separation into components, provides the transfusion medicine community with a potential alternative to gamma irradiation. © 2012 American Association of Blood Banks.

  12. [Skin biopsy in diagnosis of chronic graft-versus-host disease in patients after allogeneic haematopoietic stem cell transplantation: pathologist's point of view on quantitative scoring system].

    Science.gov (United States)

    Grzanka, Dariusz; Styczyński, Jan; Debski, Robert; Krenska, Anna; Pacholska, Małgorzata; Prokurat, Andrzej I; Wysocki, Mariusz; Marszałek, Andrzej

    2008-01-01

    Pathology diagnosis of chronic graft-versus-host-disease (GVHD) after allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an important issue in clinical follow-up, in spite of frequent difficulties in interpretation., related to dynamic changes occurring in the skin during the disease, as well as to sequelae of basic disease and immunosuppressive therapy. Recently presented Consensus NIH (National Health Institute, Bethesda, USA) of histopathologic (HP) analysis is still complex and intrinsically divergent, thus clinically difficult to implement. Analysis of clinical value of histological evaluation results of skin biopsy in children after allo-HSCT and its correlation with clinical status. Ten skin biopsies were taken from 7 patients (4 boys, 3 girls, age 3-15 years) after allo-HSCT (6 MFD, 1 MMUD) and analyzed after hematoxylin/eosine and immunohistochemical (CD3, CD45T, CD20) staining. Pathology analysis was based on commonly accepted criteria enabling simple and unambiguous interpretation. Results were compared with clinical data and indications for immunosuppressive therapy. It was found that reliable and coherent interpretation can be made when following parameters were taken into account: 1. in epithelium: the presence of apoptosis, archetypical changes and vacuolar degeneration in the basilar layer, presence of CD3/CD45 in the epidermis; 2. in the dermis: the extent of collagenization, presence of melanophages and lymphocyte infiltrations; 3. in the eccrine glands epithelium: eccrine glands atrophy and presence of lymphocytes. A new scoring system of skin biopsy analysis in patients with chronic GVHD based on the modified NIH Consensus was proposed. The preliminary clinical value of histological results was assessed. Skin biopsy evaluation based on limited qualitative and quantitative analysis of lymphocyte infiltrates together with studies on intensity of apoptosis, collagenization and archetypical changes is a valuable diagnostic method

  13. FTY720 ameliorates murine sclerodermatous chronic graft-versus-host disease by promoting expansion of splenic regulatory cells and inhibiting immune cell infiltration into skin.

    Science.gov (United States)

    Huu, Doanh Le; Matsushita, Takashi; Jin, Guihua; Hamaguchi, Yasuhito; Hasegawa, Minoru; Takehara, Kazuhiko; Fujimoto, Manabu

    2013-06-01

    Sphingosine 1-phosphate (S1P) exerts a variety of activities in immune, inflammatory, and vascular systems. S1P plays an important role in systemic sclerosis (SSc) pathogenesis. Regulation of S1P in fibrotic diseases as well as in SSc was recently reported. FTY720, an oral S1P receptor modulator, has been shown to be a useful agent for the prevention of transplant rejection and autoimmune diseases. Murine sclerodermatous chronic graft-versus-host disease (GVHD) is a model for human sclerodermatous chronic GVHD and SSc. We undertook this study to investigate the effects of FTY720 in murine sclerodermatous chronic GVHD. FTY720 was orally administered to allogeneic recipient mice from day 0 to day 20 (short-term, early-treatment group), from day 0 to day 42 (full-term, early-treatment group), or from day 22 to day 42 (delayed-treatment group) after bone marrow transplantation. Delayed administration of FTY720 attenuated, and early administration of FTY720 inhibited, the severity and fibrosis in murine sclerodermatous chronic GVHD. With early treatment, FTY720 induced expansion of splenic myeloid-derived suppressor cells, Treg cells, and Breg cells. Vascular damage in chronic GVHD was inhibited by FTY720 through down-regulating serum levels of S1P and soluble E-selectin. FTY720 inhibited infiltration of immune cells into skin. Moreover, FTY720 diminished the expression of messenger RNA for monocyte chemotactic protein 1, macrophage inflammatory protein 1α, RANTES, tumor necrosis factor α, interferon-γ, interleukin-6 (IL-6), IL-10, IL-17A, and transforming growth factor β1 in the skin. FTY720 suppressed the immune response by promoting the expansion of regulatory cells and reducing vascular damage and infiltration of immune cells into the skin. Taken together, these results have important implications for the potential use of FTY720 in the treatment of sclerodermatous chronic GVHD and SSc in humans. Copyright © 2013 by the American College of Rheumatology.

  14. HLA-Matched Sibling versus Unrelated versus Haploidentical Related Donor Allogeneic Hematopoietic Stem Cell Transplantation for Patients Aged Over 60 Years with Acute Myeloid Leukemia: A Single-Center Donor Comparison.

    Science.gov (United States)

    Devillier, Raynier; Legrand, Faezeh; Rey, Jérôme; Castagna, Luca; Fürst, Sabine; Granata, Angela; Charbonnier, Aude; Harbi, Samia; d'Incan, Evelyne; Pagliardini, Thomas; Faucher, Catherine; Lemarie, Claude; Saillard, Colombe; Calmels, Boris; Mohty, Bilal; Maisano, Valerio; Weiller, Pierre-Jean; Chabannon, Christian; Vey, Norbert; Blaise, Didier

    2018-02-12

    Haploidentical related donor (HRD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) was developed as a valid option for the treatment of acute myeloid leukemia (AML) in the absence of a matched donor. However, many investigators are reluctant to consider the use of this alternative in elderly patients, anticipating high morbidity. Here, we report a single-center comparison of HRD versus matched sibling donor (MSD) and unrelated donor (UD) allo-HSCT for patients with AML aged ≥60 years. Ninety-four patients (MSD: n = 31; UD: n = 30; HRD: n = 33) were analyzed. The median age was 65 (range, 60 to 73) years. We observed a higher cumulative incidence of grade 3 to 4 acute graft-versus-host disease (GVHD) after UD allo-HSCT (MSD versus UD versus HRD: 3% versus 33% versus 6%, respectively; P = .006). Two-year cumulative incidence of moderate or severe chronic GVHD was 17%, 27%, and 16% in the MSD, UD, and HRD groups, respectively (P = .487). No difference was observed in the 2-year cumulative incidence of relapse or nonrelapse mortality (NRM) (relapse: MSD versus UD versus HRD: 32% versus 25% versus 25%, respectively; P = .411; NRM: MSD versus UD versus HRD: 19% versus 27% versus 24%, respectively; P = .709). At 2 years, progression-free survival, overall survival, and GVHD- and relapse-free survival were 48%, 50%, and 39%, respectively, in the MSD group; 48%, 51%, and 23%, respectively, in the UD group; and 50%, 52%, and 32%, respectively, in the HRD group, without statistically significant differences between the groups. We conclude that HRD allo-HSCT is highly feasible and no less efficient than MSD or UD allo-HSCT in patients with AML aged ≥60 years. Thus, the absence of a HLA-identical donor should not limit the consideration of allo-HSCT for the treatment of AML. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  15. Relapsing acute myeloid leukemia presenting as hypopyon uveitis

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    Sapna P Hegde

    2011-01-01

    Full Text Available Anterior segment infiltration in acute myeloid leukemia (AML presenting as hypopyon uveitis is very rare. We report this case as an uncommon presentation in a patient on remission after bone marrow transplant for AML. In addition to the hypopyon, the patient presented with "red eye" caused by ocular surface disease due to concurrent graft-versus-host disease and glaucoma. The classical manifestations of masquerade syndrome due to AML were altered by concurrent pathologies. Media opacities further confounded the differential diagnosis. We highlight the investigations used to arrive at a definitive diagnosis. In uveitis, there is a need to maintain a high index of clinical suspicion, as early diagnosis in ocular malignancy can save sight and life.

  16. Prospective, Randomized, Double-Blind, Phase III Clinical Trial of Anti-T-Lymphocyte Globulin to Assess Impact on Chronic Graft-Versus-Host Disease-Free Survival in Patients Undergoing HLA-Matched Unrelated Myeloablative Hematopoietic Cell Transplantation.

    Science.gov (United States)

    Soiffer, Robert J; Kim, Haesook T; McGuirk, Joseph; Horwitz, Mitchell E; Johnston, Laura; Patnaik, Mrinal M; Rybka, Witold; Artz, Andrew; Porter, David L; Shea, Thomas C; Boyer, Michael W; Maziarz, Richard T; Shaughnessy, Paul J; Gergis, Usama; Safah, Hana; Reshef, Ran; DiPersio, John F; Stiff, Patrick J; Vusirikala, Madhuri; Szer, Jeff; Holter, Jennifer; Levine, James D; Martin, Paul J; Pidala, Joseph A; Lewis, Ian D; Ho, Vincent T; Alyea, Edwin P; Ritz, Jerome; Glavin, Frank; Westervelt, Peter; Jagasia, Madan H; Chen, Yi-Bin

    2017-12-20

    Purpose Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graft-versus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days -3, -2, -1 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P = .004) and moderate-severe cGVHD (12% v 33%; P < .001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P = .47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% [ P = .04] and 59% v 74% [ P = .034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P = .026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P = .01). Conclusion In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.

  17. Factors Associated with Long-Term Risk of Relapse after Unrelated Cord Blood Transplantation in Children with Acute Lymphoblastic Leukemia in Remission.

    Science.gov (United States)

    Page, Kristin M; Labopin, Myriam; Ruggeri, Annalisa; Michel, Gerard; Diaz de Heredia, Cristina; O'Brien, Tracey; Picardi, Alessandra; Ayas, Mouhab; Bittencourt, Henrique; Vora, Ajay J; Troy, Jesse; Bonfim, Carmen; Volt, Fernanda; Gluckman, Eliane; Bader, Peter; Kurtzberg, Joanne; Rocha, Vanderson

    2017-08-01

    For pediatric patients with acute lymphoblastic leukemia (ALL), relapse is an important cause of treatment failure after unrelated cord blood transplant (UCBT). Compared with other donor sources, relapse is similar or even reduced after UCBT despite less graft-versus-host disease (GVHD). We performed a retrospective analysis to identify risk factors associated with the 5-year cumulative incidence of relapse after UCBT. In this retrospective, registry-based study, we examined the outcomes of 640 children (leukemia-free survival (LFS), and relapse were 59%, 52%, and 23%, respectively. In multivariate analysis (MVA), acute GVHD (grades II to IV) and TBI protected against relapse. In patients in CR2, rates of 5-year OS, LFS, and the cumulative incidence of relapse were 46%, 44%, and 28%, respectively. In MVA, longer duration from diagnosis to UCBT (≥30 months) and TBI were associated with decreased relapse risk. Importantly, receiving a fully HLA matched graft was a strong risk factor for increased relapse in MVA. An exploratory analysis of all 640 patients supported the important association between the presence of acute GVHD and less relapse but also demonstrated an increased risk of nonrelapse mortality. In conclusion, the impact of GVHD as a graft-versus-leukemia marker is evident in pediatric ALL after UCBT. Strategies that promote graft-versus-leukemia while harnessing GVHD should be further investigated. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  18. Modeling conduction in host-graft interactions between stem cell grafts and cardiomyocytes.

    Science.gov (United States)

    Chen, Michael Q; Yu, Jin; Whittington, R Hollis; Wu, Joseph C; Kovacs, Gregory T A; Giovangrandi, Laurent

    2009-01-01

    Cell therapy has recently made great strides towards aiding heart failure. However, while transplanted cells may electromechanically integrate into host tissue, there may not be a uniform propagation of a depolarization wave between the heterogeneous tissue boundaries. A model using microelectrode array technology that maps the electrical interactions between host and graft tissues in co-culture is presented and sheds light on the effects of having a mismatch of conduction properties at the boundary. Skeletal myoblasts co-cultured with cardiomyocytes demonstrated that conduction velocity significantly decreases at the boundary despite electromechanical coupling. In an attempt to improve the uniformity of conduction with host cells, differentiating human embryonic stem cells (hESC) were used in co-culture. Over the course of four to seven days, synchronous electrical activity was observed at the hESC boundary, implying differentiation and integration. Activity did not extend far past the boundary, and conduction velocity was significantly greater than that of the host tissue, implying the need for other external measures to properly match the conduction properties between host and graft tissue.

  19. Donor T cells primed on leukemia lysate-pulsed recipient APCs mediate strong graft-versus-leukemia effects across MHC barriers in full chimeras.

    Science.gov (United States)

    Ghosh, Arnab; Koestner, Wolfgang; Hapke, Martin; Schlaphoff, Verena; Länger, Florian; Baumann, Rolf; Koenecke, Christian; Cornberg, Markus; Welte, Karl; Blazar, Bruce R; Sauer, Martin G

    2009-04-30

    Antigen-presenting cells (APCs) of host origin drive graft-versus-leukemia (GVL) effects but can also trigger life-threatening graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) across major histocompatibility complex (MHC) barriers. We show that in vitro priming of donor lymphocytes can circumvent the need of recipient-derived APCs in vivo for mediating robust GVL effects and significantly diminishes the risk of severe GVHD. In vitro, generated and expanded T cells (ETCs) mediate anti-leukemia effects only when primed on recipient-derived APCs. Loading of APCs in vitro with leukemia cell lysate, chimerism status of the recipient, and timing of adoptive transfer after HCT are important factors determining the outcome. Delayed transfer of ETCs resulted in strong GVL effects in leukemia-bearing full chimera (FC) and mixed chimera (MC) recipients, which were comparable with the GVL/GVHD rates observed after the transfer of naive donor lymphocyte infusion (DLI). Upon early transfer, GVL effects were more pronounced with ETCs but at the expense of significant GVHD. The degree of GVHD was most severe in MCs after transfer of ETCs that had been in vitro primed either on nonpulsed recipient-derived APCs or with donor-derived APCs.

  20. Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease.

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    Gideon Steinbach

    Full Text Available Severe intestinal graft-vs-host disease (GVHD after allogeneic hematopoietic cell transplantation (HCT causes mucosal ulceration and induces innate and adaptive immune responses that amplify and perpetuate GVHD and the associated barrier dysfunction. Pharmacological agents to target mucosal barrier dysfunction in GVHD are needed. We hypothesized that induction of Wnt signaling by lithium, an inhibitor of glycogen synthase kinase (GSK3, would potentiate intestinal crypt proliferation and mucosal repair and that inhibition of GSK3 in inflammatory cells would attenuate the deregulated inflammatory response to mucosal injury. We conducted an observational pilot study to provide data for the potential design of a randomized study of lithium. Twenty patients with steroid refractory intestinal GVHD meeting enrollment criteria were given oral lithium carbonate. GVHD was otherwise treated per current practice, including 2 mg/kg per day of prednisone equivalent. Seventeen patients had extensive mucosal denudation (extreme endoscopic grade 3 in the duodenum or colon. We observed that 8 of 12 patients (67% had a complete remission (CR of GVHD and survived more than 1 year (median 5 years when lithium administration was started promptly within 3 days of endoscopic diagnosis of denuded mucosa. When lithium was started promptly and less than 7 days from salvage therapy for refractory GVHD, 8 of 10 patients (80% had a CR and survived more than 1 year. In perspective, a review of 1447 consecutive adult HCT patients in the preceding 6 years at our cancer center showed 0% one-year survival in 27 patients with stage 3-4 intestinal GVHD and grade 3 endoscopic appearance in the duodenum or colon. Toxicities included fatigue, somnolence, confusion or blunted affect in 50% of the patients. The favorable outcomes in patients who received prompt lithium therapy appear to support the future conduct of a randomized study of lithium for management of severe GVHD with

  1. Localization of sclerotic-type chronic graft-vs-host disease to sites of skin injury: potential insight into the mechanism of isomorphic and isotopic responses.

    Science.gov (United States)

    Martires, Kathryn J; Baird, Kristin; Citrin, Deborah E; Hakim, Fran T; Pavletic, Steven Z; Cowen, Edward W

    2011-09-01

    The mechanisms responsible for the variable manifestations of chronic cutaneous graft-vs-host disease (cGVHD) are poorly understood. Localization of sclerotic-type chronic graft-vs-host disease to sites of skin injury (isomorphic and isotopic responses), a recognized phenomenon in morphea, suggests a potential common pathway between cGVHD and other sclerotic skin conditions. Four cases of sclerotic-type cGVHD developed at the site of disparate skin injuries (ionizing radiotherapy, repeated needle sticks, central catheter site, and varicella-zoster virus infection). We review the spectrum of previously reported cases of sclerotic and nonsclerotic cGVHD relating to external forces on the skin. Localization of sclerotic-type cGVHD may occur after many types of skin injury, including UV and ionizing radiotherapy, needle sticks, viral infection, and pressure or friction. Recognition of this phenomenon may be helpful for the early diagnosis of sclerotic disease. Recent insights into the immunological consequences of minor skin injury may provide important clues to the underlying pathogenesis of cGVHD-mediated skin disease.

  2. Vorinostat plus tacrolimus/methotrexate to prevent GVHD after myeloablative conditioning, unrelated donor HCT

    NARCIS (Netherlands)

    Choi, S.W.; Braun, T.; Henig, I.; Gatza, E.; Magenau, J.; Parkin, B.; Pawarode, A.; Riwes, M.; Yanik, G.; Dinarello, C.A.; Reddy, P.

    2017-01-01

    The oral histone deacetylase (HDAC) inhibitor (vorinostat) is safe and results in low incidence of acute graft-versus-host disease (GVHD) after reduced-intensity conditioning, related donor hematopoietic cell transplantation (HCT). However, its safety and efficacy in preventing acute GVHD in

  3. Comparison of long-term clinical outcome between patients with chronic versus acute type B aortic dissection treated by implantation of a stent graft: a single-center report

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    Chen SL

    2013-04-01

    Full Text Available Shao-Liang Chen, Jian-Cheng Zhu, Xiao-Bo Li, Fei Ye, Jun-Jie Zhang, Zhi-Zhong Liu, Nai-Liang Tian, Song Lin, Cheng-Yu Lv Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China Background: Stent grafting for treatment of type B aortic dissection has been extensively used. However, the difference in the long-term clinical outcome between patients with chronic versus acute type B aortic dissection remains unknown. This study aimed to analyze the difference in long-term clinical outcome after endovascular repair for patients with chronic (93% complete false-lumen thrombosis. Untreated tear and type I endoleak were predictors of clinical events during follow-up. Conclusion: Comparable long-term clinical results were achieved in patients with chronic or acute type B aortic dissection after implantation of a stent graft. Keywords: aortic dissection, endovascular repair, procedure-related events, propensity score matching

  4. Successful treatment of dry eye in two patients with chronic graft-versus-host disease with systemic administration of FK506 and corticosteroids.

    Science.gov (United States)

    Ogawa, Y; Okamoto, S; Kuwana, M; Mori, T; Watanabe, R; Nakajima, T; Yamada, M; Mashima, Y; Tsubota, K; Oguchi, Y

    2001-05-01

    We present two cases of severe dry eye in patients with chronic graft-versus-host disease (CGVHD) after hematopoietic stem cell transplantation (SCT) who were successfully treated by the systemic administration of FK506 and corticosteroids. A 29-year-old man with chronic myelogenous leukemia underwent SCT. Oral and lung CGVHD developed on approximately day 130, and dry eye associated with CGVHD was diagnosed on day 168. The patient began receiving cyclosporin A (150 mg/d) for the treatment of oral and lung CGVHD. Treatment with prednisolone (1 mg/kg/d) began on approximately day 300. Oral and lung GVHD improved slightly, but worsened again although systemic administration of cyclosporin A and prednisolone were continued. Cyclosporin A was discontinued, and systemic administration of FK506 was started on day 376. Forty-four days later, marked improvement in the ocular surface and other organs was observed. However, the dry eye worsened while tapering FK506, with no flare of other affected organs. A 43-year-old woman with myelodysplastic syndrome underwent SCT. She received FK506 for prophylaxis of CGVHD. She had mild dry eye before SCT. Oral and intestinal CGVHD developed, and the dry eye worsened significantly on approximately day 150 while tapering FK506. Treatment with prednisolone (1 mg/kg/d) began, and the dose of FK506 was increased. By day 240, the symptoms of dry eye and the findings of the ocular surface markedly improved, and CGVHD in other organs was completely resolved. However, the improvement in the dry eye was lost when FK506 was tapered for the second time. Systemic administration of FK506 with corticosteroids is an effective treatment of severe dry eye in patients with CGVHD, but long-term administration may be required to achieve a lasting response. These cases also suggest that further investigation into the use of topical FK506 and prednisolone as a maintenance therapy should be pursued.

  5. Animal experimental model of a graft-versus-host (GVH) reaction after allogenic transplantation of bone marrow in lethally irradiated mice

    International Nuclear Information System (INIS)

    Schwenke, H.; Muench, S.; Haubold, S.; Weber, B.

    1977-01-01

    The graft-versus-host (GVH) disease represents a serious still unsolved problem in the human allogenic transplantation of bone marrow. An experimental model of GVH reaction after an allogenic transplantation of bone marrow in the adult mouse has been worked out as a prerequisite for further studies on the therapeutic influence of this syndrome. 3 groups have been formed out of 82 lethally X-irradiated C57 Bl mice. The non-transplanted control group died to a hundred per cent within 12 days. While out of the 2nd group treated with syngenic bone marrow 55 per cent survived from the 22nd day, 30 per cent of the third animal group, allogenicly transplanted with histoincompatible AKR donor marrow developed a chronic GVH syndrome. The following symptoms were observed: retardation, alterations of the skin, diarrhea, edemas of the legs, failing increase of leukocytes in blood and proliferation of lymphocytes in bone marrow of about 60 per cent (18 per cent in syngenically transplanted animals), in lacking proliferation of hematopoiesis. The increase of liver and especially spleen index is not characteristic in comparison with the syngenically transplanted group, since in the latter there is also an increase of the values on account of a strong hematopoetic proliferation. The model is suitable and sufficiently well characterized for the performance of further experimental studies. (author)

  6. Patients with Treatment-Requiring Chronic Graft versus Host Disease after Allogeneic Stem Cell Transplantation Have Altered Metabolic Profiles due to the Disease and Immunosuppressive Therapy: Potential Implication for Biomarkers

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    Håkon Reikvam

    2018-01-01

    Full Text Available Chronic graft versus host disease (cGVHD is a common long-term complication after allogeneic hematopoietic stem cell transplantation. The objective of our study was to compare the metabolic profiles for allotransplant recipients and thereby identify metabolic characteristics of patients with treatment-requiring cGVHD. The study included 51 consecutive patients (29 men and 22 women; median age: 44 years, range: 15–66 years transplanted with peripheral blood stem cells derived from human leukocyte antigen-matched family donors. All serum samples investigated by global metabolomic profiling were collected approximately 1 year posttransplant (median 358 days. Thirty-one of the 51 patients (61% had cGVHD 1 year posttransplant. The affected organs were (number of patients liver/bile duct (23, eyes (15, gastrointestinal tract (14, skin (13, mouth (10, lungs (3, and urogenital tract (1. We compared the metabolic profile for patients with and without cGVHD, and a Random Forrest Classification Analysis then resulted in 75% accuracy in differentiating the two groups. The 30 top-ranked metabolites from this comparison included increased levels of bile acids, several metabolites from the cytokine-responsive kynurenine pathway for tryptophan degradation, pro-inflammatory lipid metabolites, phenylalanine and tyrosine metabolites derived from the gut microbial flora, and metabolites reflecting increased oxidative stress. However, nine of these 30 top-ranked metabolites were probably altered due to cyclosporine or steroid treatment, and we therefore did a hierarchical clustering analysis including all 51 patients but only based on the other 21 cGVHD-specific metabolites. This analysis identified three patient subsets: one cluster included mainly patients without cGVHD and had generally low metabolite levels; another cluster included mainly patients with cGVHD (most patients with at least three affected organs and high metabolite levels, and the last

  7. Graft Transit Time Has No Effect on Outcome of Unrelated Donor Hematopoietic Cell Transplants Performed in Australia and New Zealand: A Study from the Australasian Bone Marrow Transplant Recipient Registry.

    Science.gov (United States)

    Patton, William Nigel; Nivison-Smith, Ian; Bardy, Peter; Dodds, Anthony; Ma, David; Shaw, Peter John; Kwan, John; Wilcox, Leonie; Butler, Andrew; Carter, John M; Blacklock, Hilary; Szer, Jeffrey

    2017-01-01

    A previous study found that platelet recovery and mortality were worse in recipients of myeloablative bone marrow transplants where graft transit times were longer than 20 hours. This retrospective study of unrelated myeloablative allogeneic transplantation performed within Australia and New Zealand analyzed transplant outcomes according to graft transit times. Of 233 assessable cases, 76 grafts (33%) were sourced from bone marrow (BM) and 157 (67%) from peripheral blood. Grafts sourced from Australia and New Zealand (47% of total) were associated with a median transit time of 6 hours versus 32 hours for overseas sourced grafts (53% of total). Graft transit temperature was refrigerated in 85%, ambient in 6%, and unknown in 9% of cases, respectively. Graft transit times had no significant effect on neutrophil or platelet engraftment, treatment-related mortality, overall survival, and incidence of acute or chronic graft-versus-host disease. Separate analysis of BM grafts, although of reduced power, also showed no significant difference in either neutrophil or platelet engraftment or survival between short and longer transport times. This study gives reassurance that both peripheral blood stem cell and especially BM grafts subjected to long transit times and transported at refrigerated temperatures may not be associated with adverse recipient outcomes. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  8. Prolonged Survival of a Refractory Acute Myeloid Leukemia Patient after a Third Hematopoietic Stem Cell Transplantation with Umbilical Cord Blood following a Second Relapse

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    Suk-young Lee

    2014-01-01

    Full Text Available Although hematopoietic stem cell transplantation (HSCT has been considered to be the only way for potential cure of relapsed acute myeloid leukemia (AML, there has been no report on a third HSCT in patients with multiple relapsed AML. Here, we report a case of 53-year-old female who received a successful third allogeneic HSCT after relapse of AML following a second allogeneic HSCT. She was treated with a toxicity reduced conditioning regimen and received direct intrabone cord blood transplantation (CBT using a single unit of 5/6 HLA-matched cord blood as a graft source. Graft-versus-host disease prophylaxis was performed with a single agent of tacrolimus to increase graft-versus-leukemia effect. She is in remission for 8 months since the direct intrabone CBT. This report highlights not only the importance of individually adjusted approach but also the need for further investigation on the role of HSCT as a treatment modality in patients with refractory or multiple relapsed AML.

  9. Dexamethasone palmitate ameliorates macrophages-rich graft-versus-host disease by inhibiting macrophage functions.

    Science.gov (United States)

    Nishiwaki, Satoshi; Nakayama, Takayuki; Murata, Makoto; Nishida, Tetsuya; Terakura, Seitaro; Saito, Shigeki; Kato, Tomonori; Mizuno, Hiroki; Imahashi, Nobuhiko; Seto, Aika; Ozawa, Yukiyasu; Miyamura, Koichi; Ito, Masafumi; Takeshita, Kyosuke; Kato, Hidefumi; Toyokuni, Shinya; Nagao, Keisuke; Ueda, Ryuzo; Naoe, Tomoki

    2014-01-01

    Macrophage infiltration of skin GVHD lesions correlates directly with disease severity, but the mechanisms underlying this relationship remain unclear and GVHD with many macrophages is a therapeutic challenge. Here, we characterize the macrophages involved in GVHD and report that dexamethasone palmitate (DP), a liposteroid, can ameliorate such GVHD by inhibiting macrophage functions. We found that host-derived macrophages could exacerbate GVHD in a mouse model through expression of higher levels of pro-inflammatory TNF-α and IFN-γ, and lower levels of anti-inflammatory IL-10 than resident macrophages in mice without GVHD. DP significantly decreased the viability and migration capacity of primary mouse macrophages compared to conventional dexamethasone in vitro. DP treatment on day 7 and day 14 decreased macrophage number, and attenuated GVHD score and subsequent mortality in a murine model. This is the first study to provide evidence that therapy for GVHD should be changed on the basis of infiltrating cell type.

  10. Endovascular stent-graft management of thoracic aortic diseases

    International Nuclear Information System (INIS)

    Dake, Michael D.

    2001-01-01

    The traditional standard therapy for descending thoracic aortic aneurysm (TAA) is open operative repair with graft replacement of the diseased aortic segment. Despite important advances in surgical techniques, anesthetic management, and post-operative care over the last 30 years, the mortality and morbidity of surgery remains considerable, especially in patients at high risk for thoracotomy because of coexisting severe cardiopulmonary abnormalities or other medical diseases. The advent of endovascular stent-graft technology provides an alternative to open surgery for selected patients with TAA. The initial experience suggests that stent-graft therapy potentially may reduce the operative risk, hospital stay and procedural expenses of TAA repair. These potential benefits are especially attractive for patients at high risk for open TAA repair. Current results of endovascular TAA therapy document operative mortalities of between 0 and 4%, aneurysm thrombosis in 90 and 100% of cases, and paraplegia as a complication in 0 and 1.6% of patients. The early success of stent-graft repair of TAA has fostered the application of these devices for the management of a wide variety of thoracic aortic pathologies, including acute and chronic dissection, intramural hematoma, penetrating ulcer, traumatic injuries, and other diseases. The results of prospective controlled trials that compare the outcomes of stent-graft therapy with those of surgical treatment in patients with specific types of aortic disease are anxiously awaited before recommendations regarding the general use of these new devices can be made with confidence

  11. Graft versus host disease in the bone marrow, liver and thymus humanized mouse model.

    Directory of Open Access Journals (Sweden)

    Matthew B Greenblatt

    Full Text Available Mice bearing a "humanized" immune system are valuable tools to experimentally manipulate human cells in vivo and facilitate disease models not normally possible in laboratory animals. Here we describe a form of GVHD that develops in NOD/SCID mice reconstituted with human fetal bone marrow, liver and thymus (NS BLT mice. The skin, lungs, gastrointestinal tract and parotid glands are affected with progressive inflammation and sclerosis. Although all mice showed involvement of at least one organ site, the incidence of overt clinical disease was approximately 35% by 22 weeks after reconstitution. The use of hosts lacking the IL2 common gamma chain (NOD/SCID/γc(-/- delayed the onset of disease, but ultimately did not affect incidence. Genetic analysis revealed that particular donor HLA class I alleles influenced the risk for the development of GVHD. At a cellular level, GVHD is associated with the infiltration of human CD4+ T cells into the skin and a shift towards Th1 cytokine production. GVHD also induced a mixed M1/M2 polarization phenotype in a dermal murine CD11b+, MHC class II+ macrophage population. The presence of xenogenic GVHD in BLT mice both presents a major obstacle in the use of humanized mice and an opportunity to conduct preclinical studies on GVHD in a humanized model.

  12. Enfermedad injerto vs hospedero postransfusional en un paciente con leucemia linfoblástica aguda Graft vs host disease after transfusion in a patient with acute linfoblastic leukemia

    Directory of Open Access Journals (Sweden)

    TR Nijamin

    Full Text Available La enfermedad injerto vs hospedero (EICH es un proceso inmunológico, desencadenado por linfocitos T de un donante inmunocompetente, que reaccionan contra los tejidos de un receptor inmunocomprometido. Esto origina daño multiorgánico severo en el agente receptor. Las manifestaciones cutáneas son un signo clínico relevante en períodos tempranos. La EICH postranfusional (EICH-PT es una entidad poco frecuente y con alta tasa de mortalidad, que se observa en pacientes luego de transfusiones con hemoderivados no irradiados. Los corticoides son el pilar fundamental del tratamiento, una vez instalado el cuadro. La prevención con leucorreducción e irradiación de los componentes sanguíneos, constituye el sustento primordial para evitar su desarrollo. Presentamos un paciente de 5 años de edad, con un diagnóstico de leucemia linfoblástica aguda de alto riesgo, de múltiples transfusiones de glóbulos rojos sin tratamiento radiante previo, a quien se le realiza el diagnóstico dermatológico e histopatológico de EICH aguda postransfusional.Graft vs host disease (GVHD is a process triggered by immune T cells, that react immunocompetent donor tissue against a recipient immunocompromised. This causes severe multiorgan damage in the receiving agent. Cutaneous manifestations are an important clinical sign in early periods. Postranfusional GVHD (GVHD-PT is a rare entity with high mortality rate, observed in patients after transfusion with blood products not previously irradiated. Corticosteroids are the mainstay of treatment after installation of the box, however prevention with leukoreduction and irradiation of blood components remains the mainstay to prevent its development. We present a patient 5 years of age, diagnosed with acute lymphoblastic leukemia at high risk with a history of multiple transfusions of red blood cells without prior radiation treatment, who is performed dermatological and histopathological diagnosis posttransfusion acute GVHD.

  13. Tolerance induction between two different strains of parental mice prevents graft-versus-host disease in haploidentical hematopoietic stem cell transplantation to F1 mice

    International Nuclear Information System (INIS)

    Guo, Yixian; Zhang, Lanfang; Wan, Suigui; Sun, Xuejing; Wu, Yongxia; Yu, Xue-Zhong; Xia, Chang-Qing

    2014-01-01

    Highlights: • Injection of UVB-irradiated iDCs induces alloantigen tolerance. • This alloantigen tolerance may be associated regulatory T cell induction. • Tolerant mice serve as bone marrow donors reduces GVHD to their F1 recipients in allo-HSCT. • Tolerance is maintained in F1 recipients for long time post HSCT. - Abstract: Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) has been employed worldwide in recent years and led to favorable outcome in a group of patients who do not have human leukocyte antigen (HLA)-matched donors. However, the high incidence of severe graft-versus-host disease (GVHD) is a major problem for Haplo-HSCT. In the current study, we performed a proof of concept mouse study to test whether induction of allogeneic tolerance between two different parental strains was able to attenuate GVHD in Haplo-HSCT to the F1 mice. We induced alloantigen tolerance in C3H mice (H-2k) using ultraviolet B (UVB) irradiated immature dendritic cells (iDCs) derived from the cultures of Balb/c bone marrow cells. Then, we performed Haplo-HSCT using tolerant C3H mice as donors to F1 mice (C3H × Balb/c). The results demonstrated that this approach markedly reduced GVHD-associated death and significantly prolonged the survival of recipient mice in contrast to the groups with donors (C3H mice) that received infusion of non-UVB-irradiated DCs. Further studies showed that there were enhanced Tregs in the tolerant mice and alloantigen-specific T cell response was skewed to more IL-10-producing T cells, suggesting that these regulatory T cells might have contributed to the attenuation of GVHD. This study suggests that it is a feasible approach to preventing GVHD in Haplo-HSCT in children by pre-induction of alloantigen tolerance between the two parents. This concept may also lead to more opportunities in cell-based immunotherapy for GVHD post Haplo-HSCT

  14. Tolerance induction between two different strains of parental mice prevents graft-versus-host disease in haploidentical hematopoietic stem cell transplantation to F1 mice

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Yixian; Zhang, Lanfang; Wan, Suigui; Sun, Xuejing; Wu, Yongxia [Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Yu, Xue-Zhong [Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425 (United States); Xia, Chang-Qing, E-mail: cqx65@yahoo.com [Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China)

    2014-04-18

    Highlights: • Injection of UVB-irradiated iDCs induces alloantigen tolerance. • This alloantigen tolerance may be associated regulatory T cell induction. • Tolerant mice serve as bone marrow donors reduces GVHD to their F1 recipients in allo-HSCT. • Tolerance is maintained in F1 recipients for long time post HSCT. - Abstract: Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) has been employed worldwide in recent years and led to favorable outcome in a group of patients who do not have human leukocyte antigen (HLA)-matched donors. However, the high incidence of severe graft-versus-host disease (GVHD) is a major problem for Haplo-HSCT. In the current study, we performed a proof of concept mouse study to test whether induction of allogeneic tolerance between two different parental strains was able to attenuate GVHD in Haplo-HSCT to the F1 mice. We induced alloantigen tolerance in C3H mice (H-2k) using ultraviolet B (UVB) irradiated immature dendritic cells (iDCs) derived from the cultures of Balb/c bone marrow cells. Then, we performed Haplo-HSCT using tolerant C3H mice as donors to F1 mice (C3H × Balb/c). The results demonstrated that this approach markedly reduced GVHD-associated death and significantly prolonged the survival of recipient mice in contrast to the groups with donors (C3H mice) that received infusion of non-UVB-irradiated DCs. Further studies showed that there were enhanced Tregs in the tolerant mice and alloantigen-specific T cell response was skewed to more IL-10-producing T cells, suggesting that these regulatory T cells might have contributed to the attenuation of GVHD. This study suggests that it is a feasible approach to preventing GVHD in Haplo-HSCT in children by pre-induction of alloantigen tolerance between the two parents. This concept may also lead to more opportunities in cell-based immunotherapy for GVHD post Haplo-HSCT.

  15. Analysis of the results of allogeneic hematopoietic stem cell transplantation depending on HLA matching of the unrelated donor / recipient pair

    Directory of Open Access Journals (Sweden)

    Ye. V. Kuzmich

    2015-01-01

    Full Text Available HLA matching of the donor / recipient pair is a major factor associated with the outcome of allogeneic stem cell transplantation. In the presentstudy we analyzed the risk of severe acute graft-versus-host disease, graft failure, 2.year overall survival of the patients after allogeneic stem cell transplantation depending on HLA matching of the unrelated donor / recipient pair.

  16. Nogo-A Neutralization Improves Graft Function in a Rat Model of Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Stefanie eSeiler

    2016-04-01

    Full Text Available Transplantation of fetal human ventral mesencephalic dopaminergic neurons into the striatum is a promising strategy to compensate for the characteristic dopamine deficit observed in Parkinson’s disease. This therapeutic approach, however, is currently limited by the high number of fetuses needed for transplantation and the poor survival and functional integration of grafted dopaminergic neurons into the host brain. Accumulating evidence indicates that contrasting inhibitory signals endowed in the central nervous system might support neuronal regeneration. Hence, in the present study we aimed at improving survival and integration of grafted cells in the host brain by neutralizing Nogo-A, one of the most potent neurite growth inhibitors in the central nervous system. For that purpose, ventral mesencephalic tissue cultures were transplanted into rats with a partial 6-hydroxydopamine lesion causing a hemi-Parkinson’s disease model and concomitantly treated for two weeks with intra-ventricular infusion of neutralizing anti-Nogo-A antibodies. Motor behavior using the cylinder test was assessed prior to and after transplantation as functional outcome. At the end of the experimental period the number of dopaminergic fibers growing into the host brain, the number of surviving dopaminergic neurons in the grafts as well as graft size was examined. We found that anti-Nogo-A antibody infusion significantly improved the asymmetrical forelimb use observed after lesions as compared to controls. Importantly, a significantly three-fold higher dopaminergic fiber outgrowth from the transplants was detected in the Nogo-A antibody treated group as compared to controls. Furthermore, Nogo-A neutralization showed a tendency for increased survival of dopaminergic neurons (by two fold in the grafts. No significant differences were observed for graft volume and the number of dopaminergic neurons co-expressing G-protein-coupled inward rectifier potassium channel subunit

  17. Multiquadrant Subtenon Triamcinolone Injection for Acute Corneal Graft Rejection: A Case Report

    Directory of Open Access Journals (Sweden)

    Sunali Goyal

    2017-05-01

    Full Text Available Background: We report a case of reversal of an acute corneal graft rejection following multiquadrant subtenon triamcinolone injection. Case Presentation: A 19-year-old woman who had acute corneal graft rejection failed to show resolution of the graft rejection after standard treatment with systemic, intravenous, and topical steroids. The graft rejection, however, responded to injection of triamcinolone in multiple subtenon quadrants. Conclusions: For corneal graft rejection, multiquadrant subtenon triamcinolone injections may be a safe adjunct to systemic treatment.

  18. Allosuppression of B cells in vitro by graft-vs.-host reaction-derived T cells is caused by cytotoxic T lymphocytes

    NARCIS (Netherlands)

    Rozendaal, L.; Pals, S. T.; Schilham, M.; Melief, C. J.; Gleichmann, E.

    1989-01-01

    An acute graft-vs.-host reaction (GVHR) was induced by i.v. injection of 10(8) lymphoid cells from C57BL/10 (B10) donors (H-2b/b) into adult non-irradiated (B10 X DBA/2)F1 mice (H-2b/d). Previous experiments have established that spleen cells obtained from such GVHF1 mice suppress the primary

  19. A Single-Center Pilot Prospective Study of Topical Application of Platelet-Derived Eye Drops for Patients with Ocular Chronic Graft-versus-Host Disease.

    Science.gov (United States)

    Zallio, Francesco; Mazzucco, Laura; Monaco, Federico; Astori, Maria Rosa; Passera, Roberto; Drago, Giovanna; Tamiazzo, Stefania; Rapetti, Manuela; Dolcino, Daniela; Guaschino, Roberto; Pini, Massimo; Ladetto, Marco

    2016-09-01

    Ocular involvement of chronic graft-versus-host disease (cGVHD) is a complication that occurs in up to 60% of patients after allogeneic hematopoietic stem cell transplantation. Conventional therapeutic options include medical and surgical procedures that are administered depending on the severity of the condition, but most of them have provided unsatisfactory results and, to date, there is no consensus about treatment. We considered that topical application of a platelet lysate, administered as eye drops, might be considered an alternative worthwhile of investigation to treat ocular surface disorders in patients suffering from cGVHD. Therefore, we conducted a single-center prospective pilot study to assess the efficacy and safety of using eye drops made from reconstituted lysed platelet concentrate. Twenty-six patients with ocular cGVHD were eligible for the study; all but 2 completed their scheduled 1-year treatment and complied with the hematologic and ophthalmic regimen. At their first assessment interviews, after 30 days of treatment, 91% of patients reported an improvement in their symptoms and for 32%, substantive objective differences were measured. Remission of corneal damage was seen for 86% of our cohort, and improved National Institutes of Health scores for 73%, of whom 8% achieved the best score of 0 (ie, non-dry eye). Similar results were seen at later time points. Comparing outcomes for our patient cohort to those determined retrospectively for patients in our institutional database revealed a 5-year overall survival (OS) of 65%. This OS is comparable to patients with limited cGVHD (75%) and is superior to that of patients with nonocular extensive cGVHD or without cGVHD (30% and 59%, respectively) (P = .013). Our results suggest that platelet-derived eye drops are a safe, practical, and well-tolerated therapeutic option that offers substantial benefits for most patients affected by ocular cGVHD at onset. The favorable OS of our patient cohort

  20. Long-term engraftment, graft-vs.-host disease, and immunologic reconstitution after experimental transplantation of allogeneic peripheral blood cells from G-CSF-treated donors.

    Science.gov (United States)

    Pan, L; Bressler, S; Cooke, K R; Krenger, W; Karandikar, M; Ferrara, J L

    1996-10-01

    Peripheral blood cells (PBPC) are an alternative source of bone marrow for allogeneic transplantation. Reports from recent clinical trials granulocyte colony-stimulating factor (G-CSF)-mobilized PBPC for allogeneic transplantation show incidence and severity of graft-vs.-host disease (GVHD) similar to those observed in conventional bone marrow transplantation (BMT), despite the presence of 10- to 20-fold more T cell in the PBPC inoculum. In the present study, we examined the effects of pretreatment of donors with G-CSF on GVHD, long-term engraftment, and lymphocyte reconstitution in a murine parent-->F1 model (B6.Ly-5a-->B6d2F1) using splenocytes as a source of peripheral progenitor cells. Recipients of splenocytes from G-CSF-treated donors experienced less mortality from acute GVHD and showed sustained weight gain by day 100 after transplantation. At that time, there was no histological evidence od GVHD in either liver or gut. Recipients of splenocytes from G-CSF-treated donors showed complete donor engraftment within 1 month, which was sustained until the end of the observation period. In contrast, recipients of T cell-depleted splenocytes showed slower donor engraftment and persistent donor/host chimerism. In addition, lymphocyte phenotype and function in mice receiving splenocytes from G-CSF-treated donors was significantly restored by day 100 after transplantation. Thus, the use of G-CSF-mobilized PBPC may provide significant advantages to conventional BMT by reducing GVHD without impairing long-term engraftment and immunologic reconstruction.

  1. Osteonecrosis of the femoral head after bone marrow transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jeong Mi; Jun, Jeong Su; Park, Chang Suk; Kim, Yong Sik; Kwon, Soon Yong; Kim, Yoo Jin; Kim, Chun Choo [The Catholic University of Korea College of Medicine, Seoul (Korea, Republic of)

    2003-07-01

    To retrospectively review findings of osteonecrosis of the femoral head after bone marrow transplantation. We reviewed the clinical and MR findings of osteonecrosis of the femoral head in 23 of 1112 patients who underwent marrow transplantation during a five-year follow-up period lasting from 1996 to 2000. Mean age at the time of diagnosis was 31 (range, 20-47) years, and the mean time from transplant to diagnosis was 17 months. All patients developed variable graft-versus-host disease and seventeen were treated with high-dose prednisolone and/or cysclosporin for severe acute or extensive chronic graft versus host disease. Osteonecrosis was diagnosed by magnetic resonance (MR) imaging, which allowed early detection of disease assessment of its stage. At the time of diagnosis, 15 hips were at stage I, 28 at stage II, two at stage III, and none at stage IV, according to the international ARCO classification system. Osteonecrosis of femoral diaphyses, the lower lumbar spine, or pelvic bones in the MR field was also found to have occurred in 11 patients. Initial treatment was conservative: 21 hips underwent surgery [core decompression (n=10), vascularized fibular bone graft (n=5), and joint replacement (n=6)]. In patients receiving high-dose steroids for the treatment of graft-versus-host disease, MR screening might help detect osteonecrosis at an early stage.

  2. Graft-versus-host reaction in small-bowel transplantation and possibilities for its circumvention.

    Science.gov (United States)

    Watanabe, K; Yagi, T; Iwagaki, H; Kimura, Y; Mitsuoka, N; Inagaki, M; Tanaka, S; Tanaka, N

    2001-01-01

    To study graft-versus-host reaction (GVHR) in small-bowel transplantation and its underlying mechanisms and to find methods for circumventing GVHR, we used an unidirectional GVHR model in which F1 Lewis (LEW) x Wistar King A (WKA) hybrid rats received small-bowel transplants from either LEW or WKA parent rats. The survival time of F1 hybrid rats that received full-length small-bowel transplantation from LEW and WKA was 16.3+/-2.1 days and 18.2+/-3.4 days, respectively. When one-quarter of LEW small bowel was transplanted to an F1 hybrid recipient, the survival time was significantly longer at 44.0+/-23.4 days compared with rats that had received full-length LEW small-bowel transplantation. The survival time of F1 hybrid rats which received an injection of high-dose (5 x 10(8) cells) LEW or WKA spleen cells was 11.9+/-4.0 days and 13.1+/-3.6 days, respectively. However, when an injection containing a low dose (1 x 108 cells) of LEW spleen cells was used, survival was > 100 days, showing significance compared with the survival of rats receiving the higher dose LEW spleen-cell injection. Both small-bowel transplantation and spleen-cell injection were compared for the effective period of recipient resistance to donor cell or small-bowel transplantation as second challenge. When the F1 rats given a quarter LEW small-bowel transplant as first challenge were treated with a high-dose of spleen cells 30 days after transplantation, they survived for > 30 days without GVHR. F1 rats that were treated with a low-dose LEW spleen-cell injection, followed 30 days later by full LEW small-bowel transplantation, had a survival time of > 100 days. These results indicate that segmental small-bowel transplantation and spleen-cell injection as first challenge may facilitate the prevention of GVHR, resulting in resistance to subsequent immunological challenge.

  3. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation

    International Nuclear Information System (INIS)

    Thomas, E.D.; Buckner, C.D.; Banaji, M.

    1977-01-01

    One hundred patients, 54 with acute myelogenous leukemia (AML) and 46 with acute lymphoblastic leukemia (ALL), considered to be in the end stages of their disease, after combination chemotherapy were treated by marrow transplantation. All patients were given a marrow graft from an HLA-identical sibling after receiving 1000-rad total body irradiation (TBI). One group of 43 patients was given cyclophosphamide (CY), 60 mg/kg on each of 2 days, 5 and 4 days before TBI. In a second group of 31 patients, additional chemotherapy was given before CY and TBI. In a third group of 19 patients, BCNU was given before CY and TBI. A fourth group of 7 patients received other chemotherapy regimens before TBI. Six patients died 3 to 17 days after marrow infusion without evidence of engraftment. Ninety-four patients were engrafted rejected and only one patient rejected the graft. Thirteen patients are alive with a marrow graft, on no maintenance antileukemic therapy, and without recurrent leukemia 1--4 1 / 2 yr after transplantation. Three have chronic graft-versus-host disease (GVHD). The relapse rate appeared to be relatively constant over the first 2 yr and was extremely low after that time. Neither survival nor leukemic relapse appeared to be influenced by the type of leukemia nor by the preparative chemotherapy regimen given before TBI. Patients in fair clinical condition at the time of transplantation showed significantly longer survival times than patients in poor condition (p = 0.001). This observation, coupled with the observation that some patients may be cured of their disease, indicates that marrow transplantation should now be undertaken earlier in the management of patients with acute leukemia who have an HLA-matched sibling marrow donor

  4. Functional integration of grafted neural stem cell-derived dopaminergic neurons monitored by optogenetics in an in vitro Parkinson model

    DEFF Research Database (Denmark)

    Tønnesen, Jan; Parish, Clare L; Sørensen, Andreas T

    2011-01-01

    Intrastriatal grafts of stem cell-derived dopamine (DA) neurons induce behavioral recovery in animal models of Parkinson's disease (PD), but how they functionally integrate in host neural circuitries is poorly understood. Here, Wnt5a-overexpressing neural stem cells derived from embryonic ventral...... of post-synaptic currents, and functional expression of DA D₂ autoreceptors. These properties resembled those recorded from identical cells in acute slices of intrastriatal grafts in the 6-hydroxy-DA-induced mouse PD model and from DA neurons in intact substantia nigra. Optogenetic activation...... using optogenetics that ectopically grafted stem cell-derived DA neurons become functionally integrated in the DA-denervated striatum. Further optogenetic dissection of the synaptic wiring between grafted and host neurons will be crucial to clarify the cellular and synaptic mechanisms underlying...

  5. Expansion of donor-reactive host T cells in primary graft failure after allogeneic hematopoietic SCT following reduced-intensity conditioning.

    Science.gov (United States)

    Koyama, M; Hashimoto, D; Nagafuji, K; Eto, T; Ohno, Y; Aoyama, K; Iwasaki, H; Miyamoto, T; Hill, G R; Akashi, K; Teshima, T

    2014-01-01

    Graft rejection remains a major obstacle in allogeneic hematopoietic SCT following reduced-intensity conditioning (RIC-SCT), particularly after cord blood transplantation (CBT). In a murine MHC-mismatched model of RIC-SCT, primary graft rejection was associated with activation and expansion of donor-reactive host T cells in peripheral blood and BM early after SCT. Donor-derived dendritic cells are at least partly involved in host T-cell activation. We then evaluated if such an expansion of host T cells could be associated with graft rejection after RIC-CBT. Expansion of residual host lymphocytes was observed in 4/7 patients with graft rejection at 3 weeks after CBT, but in none of the 17 patients who achieved engraftment. These results suggest the crucial role of residual host T cells after RIC-SCT in graft rejection and expansion of host T cells could be a marker of graft rejection. Development of more efficient T cell-suppressive conditioning regimens may be necessary in the context of RIC-SCT.

  6. Host immune response and acute disease in a zebrafish model of francisella pathogenesis

    Science.gov (United States)

    Vojtech, L.N.; Sanders, G.E.; Conway, C.; Ostland, V.; Hansen, J.D.

    2009-01-01

    Members of the bacterial genus Francisella are highly virulent and infectious pathogens. New models to study Francisella pathogenesis in evolutionarily distinct species are needed to provide comparative insight, as the mechanisms of host resistance and pathogen virulence are not well understood. We took advantage of the recent discovery of a novel species of Francisella to establish a zebrafish/Francisella comparative model of pathogenesis and host immune response. Adult zebraflsh were susceptible to acute Francisella-induced disease and suffered mortality in a dose-dependent manner. Using immunohistochemical analysis, we localized bacterial antigens primarily to lymphoid tissues and livers of zebraflsh following infection by intraperitoneal injection, which corresponded to regions of local cellular necrosis. Francisella sp. bacteria replicated rapidly in these tissues beginning 12 h postinfection, and bacterial titers rose steadily, leveled off, and then decreased by 7 days postinfection. Zebraflsh mounted a significant tissue-specific proinflammatory response to infection as measured by the upregulation of interleukin-l?? (IL-1??), gamma interferon, and tumor necrosis factor alpha mRNA beginning by 6 h postinfection and persisting for up to 7 days postinfection. In addition, exposure of zebraflsh to heat-killed bacteria demonstrated that the significant induction of IL-?? was highly specific to live bacteria. Taken together, the pathology and immune response to acute Francisella infection in zebraflsh share many features with those in mammals, highlighting the usefulness of this new model system for addressing both general and specific questions about Francisella host-pathogen interactions via an evolutionary approach. Copyright ?? 2009, American Society for Microbiology. All Rights Reserved.

  7. Is the presence of 6 or fewer crypt apoptotic bodies sufficient for diagnosis of graft versus host disease? A decade of experience at a single institution.

    Science.gov (United States)

    Lin, Jingmei; Fan, Rong; Zhao, Zijin; Cummings, Oscar W; Chen, Shaoxiong

    2013-04-01

    Histopathology assessment is crucial for the diagnosis of graft versus host disease (GVHD), as the presence of crypt apoptosis is the cardinal criterion required. However, crypt apoptosis is not limited to GVHD; it also occurs in other conditions such as infection, drug reaction, or inflammatory reactions unrelated to GVHD. To better determine whether the presence of 6 or fewer apoptotic bodies is sufficient for the diagnosis of GVHD, we retrospectively reviewed 78 colon biopsies from 66 patients who received either hematopoietic stem cell (HSCT) or cord blood cell transplantation and whose colon biopsies exhibited apoptotic bodies. Among them, 41 cases contained 6 or fewer apoptotic bodies in the colon biopsy. These biopsies were compared with 141 colon biopsy controls that showed no significant pathologic changes as well as 16 colon biopsies with cytomegalovirus colitis from patients without a history of bone marrow transplantation. Among the 41 cases reviewed, 7 patients had coexisting GVHD in other organs (skin or liver). However, gastrointestinal symptoms of at least 4 HSCT patients whose colon biopsies contained 6 or fewer apoptotic bodies completely resolved in the absence of further intervention for GVHD. The discrepancy between pathologic findings and the clinical course may be due to confounding factors, such as infection or medication-induced injury. Our data suggest that identifying 6 or fewer crypt apoptotic bodies in colon biopsies from HSCT patients is worth reporting in order to alert the clinicians of the possibility of GVHD but not sufficient to render a diagnosis on the pathologic grounds alone. The colon biopsies containing 6 or fewer apoptotic bodies represent a heterogenous group. We suggest this group to be classified as indeterminate for GVHD, instead of diagnosing GVHD outright. Synthesis of all clinical, endoscopic, and pathologic information, including the status of infection, coexisting GVHD involvement in the other organs, and

  8. Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study.

    Science.gov (United States)

    Güngör, Tayfun; Teira, Pierre; Slatter, Mary; Stussi, Georg; Stepensky, Polina; Moshous, Despina; Vermont, Clementien; Ahmad, Imran; Shaw, Peter J; Telles da Cunha, José Marcos; Schlegel, Paul G; Hough, Rachel; Fasth, Anders; Kentouche, Karim; Gruhn, Bernd; Fernandes, Juliana F; Lachance, Silvy; Bredius, Robbert; Resnick, Igor B; Belohradsky, Bernd H; Gennery, Andrew; Fischer, Alain; Gaspar, H Bobby; Schanz, Urs; Seger, Reinhard; Rentsch, Katharina; Veys, Paul; Haddad, Elie; Albert, Michael H; Hassan, Moustapha

    2014-02-01

    In chronic granulomatous disease allogeneic haemopoietic stem-cell transplantation (HSCT) in adolescents and young adults and patients with high-risk disease is complicated by graft-failure, graft-versus-host disease (GVHD), and transplant-related mortality. We examined the effect of a reduced-intensity conditioning regimen designed to enhance myeloid engraftment and reduce organ toxicity in these patients. This prospective study was done at 16 centres in ten countries worldwide. Patients aged 0-40 years with chronic granulomatous disease were assessed and enrolled at the discretion of individual centres. Reduced-intensity conditioning consisted of high-dose fludarabine (30 mg/m(2) [infants HLA-matched related-donors or HLA-9/10 or HLA-10/10 matched unrelated-donors were infused. The primary endpoints were overall survival and event-free survival (EFS), probabilities of overall survival and EFS at 2 years, incidence of acute and chronic GVHD, achievement of at least 90% myeloid donor chimerism, and incidence of graft failure after at least 6 months of follow-up. 56 patients (median age 12·7 years; IQR 6·8-17·3) with chronic granulomatous disease were enrolled from June 15, 2003, to Dec 15, 2012. 42 patients (75%) had high-risk features (ie, intractable infections and autoinflammation), 25 (45%) were adolescents and young adults (age 14-39 years). 21 HLA-matched related-donor and 35 HLA-matched unrelated-donor transplants were done. Median time to engraftment was 19 days (IQR 16-22) for neutrophils and 21 days (IQR 16-25) for platelets. At median follow-up of 21 months (IQR 13-35) overall survival was 93% (52 of 56) and EFS was 89% (50 of 56). The 2-year probability of overall survival was 96% (95% CI 86·46-99·09) and of EFS was 91% (79·78-96·17). Graft-failure occurred in 5% (three of 56) of patients. The cumulative incidence of acute GVHD of grade III-IV was 4% (two of 56) and of chronic graft-versus-host disease was 7% (four of 56). Stable (≥90%) myeloid

  9. Hepatic artery stent-grafts for the emergency treatment of acute bleeding

    Energy Technology Data Exchange (ETDEWEB)

    Bellemann, Nadine, E-mail: nadine.bellemann@med.uni-heidelberg.de [Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, INF 110, 69120 Heidelberg (Germany); Sommer, Christof-Matthias; Mokry, Theresa; Kortes, Nikolas; Gnutzmann, Daniel; Gockner, Theresa; Schmitz, Anne [Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, INF 110, 69120 Heidelberg (Germany); Weitz, Jürgen [Department of Surgery, University Hospital Heidelberg, INF 110, 69120 Heidelberg (Germany); Department for Visceral, Thoracic and Vascular Surgery at the University Hospital, Technical University Dresden (Germany); Kauczor, Hans-Ulrich; Radeleff, Boris; Stampfl, Ulrike [Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, INF 110, 69120 Heidelberg (Germany)

    2014-10-15

    Highlights: • We report our experiences with stent-grafts for the treatment of acute hemorrhage from the hepatic artery or the stump of the gastroduodenal artery. • The technical success of stent-graft implantation was 88%. • The bleeding ceased immediately after stent-graft implantation in 88%. • The complication rate was 21%. - Abstract: Purpose: We evaluated the technical success and clinical efficacy of stent-graft implantation for the emergency management of acute hepatic artery bleeding. Methods: Between January 2010 and July 2013, 24 patients with hemorrhage from the hepatic artery were scheduled for emergency implantation of balloon expandable stent-grafts. The primary study endpoints were technical and clinical success, which were defined as successful stent-graft implantation with sealing of the bleeding site at the end of the procedure, and cessation of clinical signs of hemorrhage. The secondary study endpoints were complications during the procedure or at follow-up and 30-day mortality rate. Results: In 23 patients, hemorrhage occurred after surgery, and in one patient hemorrhage occurred after trauma. Eight patients had sentinel bleeding. In most patients (n = 16), one stent-graft was implanted. In six patients, two overlapping stent-grafts were implanted. The stent-grafts had a target diameter between 4 mm and 7 mm. Overall technical success was 88%. The bleeding ceased after stent-graft implantation in 21 patients (88%). The mean follow-up was 137 ± 383 days. In two patients, re-bleeding from the hepatic artery occurred during follow-up after 4 and 29 days, respectively, which could be successfully treated by endovascular therapy. The complication rate was 21% (minor complication rate 4%, major complication rate 17%). The 30-day mortality rate was 21%. Conclusions: Implantation of stent-grafts in the hepatic artery is an effective emergency therapy and has a good technical success rate for patients with acute arterial hemorrhage.

  10. Bone marrow transplantation in aplastic anaemia using cyclophosphamide and total lymphoid irradiation

    International Nuclear Information System (INIS)

    Jansen, J.; Zwaan, F.E.; Noordijk, E.M.

    1980-01-01

    Six patients with severe aplastic anaemia received a bone-marrow graft after conditioning with cyclophosphamide and total lymphoid irradiation (TLI). No rejections occurred. Acute graft-versus-host disease developed in 3 patients and was fatal in one. Another patient died from systemic aspergillus infection. Chronic GVHD of the skin developed in a patient who was grafted with bone marrow from her HLA-phenotypically identical father. These data suggest that conditioning with cyclophosphamide and TLI is a promising regimen. (orig.) [de

  11. Hematopoietic Stem Cell Transplantation—50 Years of Evolution and Future Perspectives

    Directory of Open Access Journals (Sweden)

    Israel Henig

    2014-10-01

    Full Text Available Hematopoietic stem cell transplantation is a highly specialized and unique medical procedure. Autologous transplantation allows the administration of high-dose chemotherapy without prolonged bone marrow aplasia. In allogeneic transplantation, donor-derived stem cells provide alloimmunity that enables a graft-versus-tumor effect to eradicate residual disease and prevent relapse. The first allogeneic transplantation was performed by E. Donnall Thomas in 1957. Since then the field has evolved and expanded worldwide. New indications beside acute leukemia and aplastic anemia have been constantly explored and now include congenital disorders of the hematopoietic system, metabolic disorders, and autoimmune disease. The use of matched unrelated donors, umbilical cord blood units, and partially matched related donors has dramatically extended the availability of allogeneic transplantation. Transplant-related mortality has decreased due to improved supportive care, including better strategies to prevent severe infections and with the incorporation of reduced-intensity conditioning protocols that lowered the toxicity and allowed for transplantation in older patients. However, disease relapse and graft-versus-host disease remain the two major causes of mortality with unsatisfactory progress. Intense research aiming to improve adoptive immunotherapy and increase graft-versus-leukemia response while decreasing graft-versus-host response might bring the next breakthrough in allogeneic transplantation. Strategies of graft manipulation, tumor-associated antigen vaccinations, monoclonal antibodies, and adoptive cellular immunotherapy have already proved clinically efficient. In the following years, allogeneic transplantation is likely to become more complex, more individualized, and more efficient.

  12. Superselective arterial embolisation with a liquid polyvinyl alcohol copolymer in patients with acute gastrointestinal haemorrhage

    Energy Technology Data Exchange (ETDEWEB)

    Lenhart, Markus; Schneider, Hans [Sozialstiftung Bamberg, Department of Diagnostic and Interventional Radiology, Bamberg (Germany); Paetzel, Christian [Klinikum Weiden, Department of Radiology, Weiden (Germany); Sackmann, Michael [Sozialstiftung Bamberg, Department of Gastroenterology, Bamberg (Germany); Jung, Ernst Michael; Schreyer, Andreas G.; Feuerbach, Stefan; Zorger, Niels [University of Regensburg, Department of Radiology, Regensburg (Germany)

    2010-08-15

    To evaluate the results of emergency embolisation in acute arterial bleeding of the gastrointestinal tract with a liquid polyvinyl alcohol copolymer from two centres. We retrospectively analysed 16 cases (15 patients) of acute arterial bleeding of the gastrointestinal tract where emergency embolotherapy was performed by using the copolymer when acute haemorrhage was not treatable with endoscopic techniques alone. Cause of haemorrhage and technical and clinical success were documented. Arterial embolotherapy was successful in all 16 cases. The technical success rate was 100%. The cause of bleeding was pancreatitis in four, graft-versus-host disease (GVHD) of the colon in three, malignancy in three, angiodysplasia in two, ulcer in two and panarteritis no dosa and trauma in one each. There were no procedure-related complications. No bowel necrosis occurred because of embolisation. In 13 cases, the patients were discharged in good condition (81%); the three patients with GVHD died because of the underlying disease. The copolymer seems to have great potential in embolotherapy of acute arterial gastrointestinal bleeding. In our series none of the patients had rebleeding at the site of embolisation and no clinically obvious bowel necrosis occurred. (orig.)

  13. Superselective arterial embolisation with a liquid polyvinyl alcohol copolymer in patients with acute gastrointestinal haemorrhage

    International Nuclear Information System (INIS)

    Lenhart, Markus; Schneider, Hans; Paetzel, Christian; Sackmann, Michael; Jung, Ernst Michael; Schreyer, Andreas G.; Feuerbach, Stefan; Zorger, Niels

    2010-01-01

    To evaluate the results of emergency embolisation in acute arterial bleeding of the gastrointestinal tract with a liquid polyvinyl alcohol copolymer from two centres. We retrospectively analysed 16 cases (15 patients) of acute arterial bleeding of the gastrointestinal tract where emergency embolotherapy was performed by using the copolymer when acute haemorrhage was not treatable with endoscopic techniques alone. Cause of haemorrhage and technical and clinical success were documented. Arterial embolotherapy was successful in all 16 cases. The technical success rate was 100%. The cause of bleeding was pancreatitis in four, graft-versus-host disease (GVHD) of the colon in three, malignancy in three, angiodysplasia in two, ulcer in two and panarteritis no dosa and trauma in one each. There were no procedure-related complications. No bowel necrosis occurred because of embolisation. In 13 cases, the patients were discharged in good condition (81%); the three patients with GVHD died because of the underlying disease. The copolymer seems to have great potential in embolotherapy of acute arterial gastrointestinal bleeding. In our series none of the patients had rebleeding at the site of embolisation and no clinically obvious bowel necrosis occurred. (orig.)

  14. Comparative study of navigated versus freehand osteochondral graft transplantation of the knee.

    Science.gov (United States)

    Koulalis, Dimitrios; Di Benedetto, Paolo; Citak, Mustafa; O'Loughlin, Padhraig; Pearle, Andrew D; Kendoff, Daniel O

    2009-04-01

    Osteochondral lesions are a common sports-related injury for which osteochondral grafting, including mosaicplasty, is an established treatment. Computer navigation has been gaining popularity in orthopaedic surgery to improve accuracy and precision. Navigation improves angle and depth matching during harvest and placement of osteochondral grafts compared with conventional freehand open technique. Controlled laboratory study. Three cadaveric knees were used. Reference markers were attached to the femur, tibia, and donor/recipient site guides. Fifteen osteochondral grafts were harvested and inserted into recipient sites with computer navigation, and 15 similar grafts were inserted freehand. The angles of graft removal and placement as well as surface congruity (graft depth) were calculated for each surgical group. The mean harvesting angle at the donor site using navigation was 4 degrees (standard deviation, 2.3 degrees ; range, 1 degrees -9 degrees ) versus 12 degrees (standard deviation, 5.5 degrees ; range, 5 degrees -24 degrees ) using freehand technique (P standard deviation, 2.1 degrees ; range, 0 degrees -9 degrees ) versus 10.7 degrees (standard deviation, 4.9 degrees ; range, 2 degrees -17 degrees ) in freehand (P standard deviation, 2.0 degrees ; range, 1 degrees -9 degrees ) versus 10.6 degrees (standard deviation, 4.4 degrees ; range, 3 degrees -17 degrees ) with freehand technique (P = .0001). The mean height of plug protrusion under navigation was 0.3 mm (standard deviation, 0.2 mm; range, 0-0.6 mm) versus 0.5 mm (standard deviation, 0.3 mm; range, 0.2-1.1 mm) using a freehand technique (P = .0034). Significantly greater accuracy and precision were observed in harvesting and placement of the osteochondral grafts in the navigated procedures. Clinical studies are needed to establish a benefit in vivo. Improvement in the osteochondral harvest and placement is desirable to optimize clinical outcomes. Navigation shows great potential to improve both harvest

  15. Effect of donor STAT4 polymorphism rs7574865 on clinical outcomes of pediatric acute leukemia patients after hematopoietic stem cell transplant.

    Science.gov (United States)

    Wun, Cheng Mun; Piao, Zhe; Hong, Kyung Taek; Choi, Jung Yoon; Hong, Che Ry; Park, June Dong; Park, Kyung Duk; Shin, Hee Young; Kang, Hyoung Jin

    2017-02-01

    STAT4 polymorphism, rs7574865 is linked to various autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Its T minor allele is associated with higher STAT4 mRNA and protein expression, indicating a stronger skewed immune response than the norm. Although widely studied in autoimmune disease patients and the general population, its effect on immunocompromised subjects is still unknown. Especially in situations, i.e. post-hematopoietic stem cell transplantation (post-HSCT), where control of the immune response is crucial. Hence, this study investigates if the presence of the T minor allele in donors would affect immunological response and clinical outcomes post-HSCT. Samples from 161 pediatric patients who underwent allogeneic HSCT for acute leukemia and showed complete chimerism by donor cells were obtained. Six clinical outcomes were investigated; hepatic veno-occlusive disease, acute graft-vs-host disease, chronic graft-vs-host disease, cytomegalovirus (CMV) infection, relapse and overall survival. The TT genotype was found to be significant in the occurrence of CMV infection (P=0.049), showing higher incidence of CMV infection compared to the others. Multivariate analysis confirmed that association of the TT genotype is independent from other variables in CMV infection occurrence (P=0.010). This is the first study on STAT4 polymorphism rs7574865 in allogeneic HSCT as well as immunocompromised patients. As the TT genotype is associated with autoimmune diseases, our results seem at a paradox with current evidence hinting at a different role of STAT4 in normal circumstances versus immunocompromised patients. Further investigation is needed to elicit the reason behind this and discover novel applications for better post-transplant outcomes. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Superior outcome using cyclosporin A alone versus cyclosporin A plus methotrexate for post-transplant immunosuppression in children with acute leukemia undergoing sibling hematopoietic stem cell transplantation.

    Science.gov (United States)

    Weiss, Melissa; Steinbach, Daniel; Zintl, Felix; Beck, James; Gruhn, Bernd

    2015-06-01

    The outcome of cyclosporin A (CSA) alone (n = 19) as graft-versus-host disease (GVHD) prophylaxis was compared to that of CSA combined with methotrexate (MTX) (n = 43) in children with acute leukemia who underwent hematopoietic stem cell transplantation. All respective donors were HLA-identical siblings. All patients received CSA at a dose of 3 mg/kg/day starting on day -1. A CSA level of 80-130 ng/ml was aimed for. The 43 patients in the historical control were given an additional 10 mg/m(2) dosage of MTX on days 1, 3, 6, and 11. Patients who received CSA alone had a significantly reduced cumulative incidence of relapse (5 vs. 40 %; p = 0.002), a significantly increased 5-year event-free survival (84 vs. 35 %; p = 0.001), and a significantly increased 5-year overall survival (84 vs. 42 %; p = 0.004). The incidence of acute GVHD grade II-IV and chronic GVHD in patients in the CSA group was equivalent to the CSA+MTX group (26 vs. 19 %; p = 0.440, and 32 vs. 23 %; p = 0.428). In conclusion, post-transplant immunosuppression consisting of CSA alone is well tolerated and may contribute to a superior outcome.

  17. Transcriptional portrait of Actinobacillus pleuropneumoniae during acute disease--potential strategies for survival and persistence in the host.

    Directory of Open Access Journals (Sweden)

    Kirstine Klitgaard

    Full Text Available BACKGROUND: Gene expression profiles of bacteria in their natural hosts can provide novel insight into the host-pathogen interactions and molecular determinants of bacterial infections. In the present study, the transcriptional profile of the porcine lung pathogen Actinobacillus pleuropneumoniae was monitored during the acute phase of infection in its natural host. METHODOLOGY/PRINCIPAL FINDINGS: Bacterial expression profiles of A. pleuropneumoniae isolated from lung lesions of 25 infected pigs were compared in samples taken 6, 12, 24 and 48 hours post experimental challenge. Within 6 hours, focal, fibrino hemorrhagic lesions could be observed in the pig lungs, indicating that A. pleuropneumoniae had managed to establish itself successfully in the host. We identified 237 differentially regulated genes likely to encode functions required by the bacteria for colonization and survival in the host. This group was dominated by genes involved in various aspects of energy metabolism, especially anaerobic respiration and carbohydrate metabolism. Remodeling of the bacterial envelope and modifications of posttranslational processing of proteins also appeared to be of importance during early infection. The results suggested that A. pleuropneumoniae is using various strategies to increase its fitness, such as applying Na+ pumps as an alternative way of gaining energy. Furthermore, the transcriptional data provided potential clues as to how A. pleuropneumoniae is able to circumvent host immune factors and survive within the hostile environment of host macrophages. This persistence within macrophages may be related to urease activity, mobilization of various stress responses and active evasion of the host defenses by cell surface sialylation. CONCLUSIONS/SIGNIFICANCE: The data presented here highlight the importance of metabolic adjustments to host conditions as virulence factors of infecting microorganisms and help to provide insight into the mechanisms

  18. Total lymph-node irradiation and pretreatment with cyclophosphamide in preparation for bone-marrow grafting for aplastic anaemia

    International Nuclear Information System (INIS)

    Jansen, J.; Zwaan, F.E.; Noordijk, E.M.

    1981-01-01

    Bone-marrow transplantation (BMT), using bone marrow from an HLA-identical brother or sister constitutes the treatment of choice in most young patients with severe aplastic amaemia. The cases are described of 6 patients who were prepared for grafting by administration of cyclophosphamide (4 days, 50 mg/kg body weight day) and total lymph-node irradiation (750 rad in a single dose). One patient died on the 26th day after BMT from a disseminated Aspergillus infection, and another on the 28th day from the consequences of graft-versus-host disease (GVH disease). One patient recovered after an episode of GVH disease. Two patients developed no complications after the grafting. One female patient, who for the lack of an HLA-identical brother or sister had been grafted with bone marrow of her father whose HLA-phenotype was identical, was normalized haematologically but developed chronic GVH disease of the skin. This method of preparation for BMT for aplastic anaemia reduces the risk of rejection of the bone marrow to a minimum, and may well reduce the frequency and severity of GVH disease. (Auth.)

  19. Fetal microchimeric cells in autoimmune thyroid diseases

    Science.gov (United States)

    Lepez, Trees; Vandewoestyne, Mado; Deforce, Dieter

    2013-01-01

    Autoimmune thyroid diseases (AITD) show a female predominance, with an increased incidence in the years following parturition. Fetal microchimerism has been suggested to play a role in the pathogenesis of AITD. However, only the presence of fetal microchimeric cells in blood and in the thyroid gland of these patients has been proven, but not an actual active role in AITD. Is fetal microchimerism harmful for the thyroid gland by initiating a Graft versus Host reaction (GvHR) or being the target of a Host versus Graft reaction (HvGR)? Is fetal microchimerism beneficial for the thyroid gland by being a part of tissue repair or are fetal cells just innocent bystanders in the process of autoimmunity? This review explores every hypothesis concerning the role of fetal microchimerism in AITD. PMID:23723083

  20. In vivo expansion of co-transplanted T cells impacts on tumor re-initiating activity of human acute myeloid leukemia in NSG mice.

    Directory of Open Access Journals (Sweden)

    Malte von Bonin

    Full Text Available Human cells from acute myeloid leukemia (AML patients are frequently transplanted into immune-compromised mouse strains to provide an in vivo environment for studies on the biology of the disease. Since frequencies of leukemia re-initiating cells are low and a unique cell surface phenotype that includes all tumor re-initiating activity remains unknown, the underlying mechanisms leading to limitations in the xenotransplantation assay need to be understood and overcome to obtain robust engraftment of AML-containing samples. We report here that in the NSG xenotransplantation assay, the large majority of mononucleated cells from patients with AML fail to establish a reproducible myeloid engraftment despite high donor chimerism. Instead, donor-derived cells mainly consist of polyclonal disease-unrelated expanded co-transplanted human T lymphocytes that induce xenogeneic graft versus host disease and mask the engraftment of human AML in mice. Engraftment of mainly myeloid cell types can be enforced by the prevention of T cell expansion through the depletion of lymphocytes from the graft prior transplantation.

  1. Allogeneic versus autologous derived cell sources for use in engineered bone-ligament-bone grafts in sheep anterior cruciate ligament repair.

    Science.gov (United States)

    Mahalingam, Vasudevan D; Behbahani-Nejad, Nilofar; Horine, Storm V; Olsen, Tyler J; Smietana, Michael J; Wojtys, Edward M; Wellik, Deneen M; Arruda, Ellen M; Larkin, Lisa M

    2015-03-01

    The use of autografts versus allografts for anterior cruciate ligament (ACL) reconstruction is controversial. The current popular options for ACL reconstruction are patellar tendon or hamstring autografts, yet advances in allograft technologies have made allogeneic grafts a favorable option for repair tissue. Despite this, the mismatched biomechanical properties and risk of osteoarthritis resulting from the current graft technologies have prompted the investigation of new tissue sources for ACL reconstruction. Previous work by our lab has demonstrated that tissue-engineered bone-ligament-bone (BLB) constructs generated from an allogeneic cell source develop structural and functional properties similar to those of native ACL and vascular and neural structures that exceed those of autologous patellar tendon grafts. In this study, we investigated the effectiveness of our tissue-engineered ligament constructs fabricated from autologous versus allogeneic cell sources. Our preliminary results demonstrate that 6 months postimplantation, our tissue-engineered auto- and allogeneic BLB grafts show similar histological and mechanical outcomes indicating that the autologous grafts are a viable option for ACL reconstruction. These data indicate that our tissue-engineered autologous ligament graft could be used in clinical situations where immune rejection and disease transmission may preclude allograft use.

  2. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease

    NARCIS (Netherlands)

    P.W.J.C. Serruys (Patrick); M-C. Morice (Marie-Claude); A.P. Kappetein (Arie Pieter); A. Colombo (Antonio); D.R. Holmes Jr (David); M.J. Mack (Michael); E. Stahle (Elisabeth); T.E. Feldman (Ted); M.J.B.M. van den Brand (Marcel); E.J. Bass (Eric); N. van Dyck (Nic); K. Leadly (Katrin); K.D. Dawkins (Keith); F.W. Mohr (Friedrich)

    2009-01-01

    textabstractBACKGROUND Percutaneous coronary intervention (PCI) involving drug-eluting stents is increasingly used to treat complex coronary artery disease, although coronary-artery bypass grafting (CABG) has been the treatment of choice historically. Our trial compared PCI and CABG for treating

  3. Functional integration of grafted neural stem cell-derived dopaminergic neurons monitored by optogenetics in an in vitro Parkinson model.

    Directory of Open Access Journals (Sweden)

    Jan Tønnesen

    Full Text Available Intrastriatal grafts of stem cell-derived dopamine (DA neurons induce behavioral recovery in animal models of Parkinson's disease (PD, but how they functionally integrate in host neural circuitries is poorly understood. Here, Wnt5a-overexpressing neural stem cells derived from embryonic ventral mesencephalon of tyrosine hydroxylase-GFP transgenic mice were expanded as neurospheres and transplanted into organotypic cultures of wild type mouse striatum. Differentiated GFP-labeled DA neurons in the grafts exhibited mature neuronal properties, including spontaneous firing of action potentials, presence of post-synaptic currents, and functional expression of DA D₂ autoreceptors. These properties resembled those recorded from identical cells in acute slices of intrastriatal grafts in the 6-hydroxy-DA-induced mouse PD model and from DA neurons in intact substantia nigra. Optogenetic activation or inhibition of grafted cells and host neurons using channelrhodopsin-2 (ChR2 and halorhodopsin (NpHR, respectively, revealed complex, bi-directional synaptic interactions between grafted cells and host neurons and extensive synaptic connectivity within the graft. Our data demonstrate for the first time using optogenetics that ectopically grafted stem cell-derived DA neurons become functionally integrated in the DA-denervated striatum. Further optogenetic dissection of the synaptic wiring between grafted and host neurons will be crucial to clarify the cellular and synaptic mechanisms underlying behavioral recovery as well as adverse effects following stem cell-based DA cell replacement strategies in PD.

  4. Graft rejection as a Th1-type process amenable to regulation by donor Th2-type cells through an interleukin-4/STAT6 pathway.

    Science.gov (United States)

    Mariotti, Jacopo; Foley, Jason; Ryan, Kaitlyn; Buxhoeveden, Nicole; Kapoor, Veena; Amarnath, Shoba; Fowler, Daniel H

    2008-12-01

    Graft rejection has been defined as the mirror image of graft-versus-host disease, which is biologically characterized primarily as a Th1-type process. As such, we reasoned that graft rejection would represent a Th1 response amenable to Th2 modulation. Indeed, adoptive transfer of host Th1-type cells mediated rejection of fully MHC-disparate murine bone marrow allografts more effectively than host Th2-type cells. Furthermore, STAT1-deficient host T cells did not differentiate into Th1-type cells in vivo and failed to mediate rejection. We next hypothesized that donor Th2 cell allograft augmentation would prevent rejection by modulation of the host Th1/Th2 balance. In the setting of donor Th2 cell therapy, host-anti-donor allospecific T cells acquired Th2 polarity, persisted posttransplantation, and did not mediate rejection. Abrogation of rejection required donor Th2 cell IL-4 secretion and host T-cell STAT6 signaling. In conclusion, T cell-mediated marrow graft rejection primarily resembles a Th1-type process that can be abrogated by donor Th2 cell therapy that promotes engraftment through a novel mechanism whereby cytokine polarization is transferred to host T cells.

  5. T Cell-Replete Peripheral Blood Haploidentical Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide Results in Outcomes Similar to Transplantation from Traditionally Matched Donors in Active Disease Acute Myeloid Leukemia.

    Science.gov (United States)

    How, Joan; Slade, Michael; Vu, Khoan; DiPersio, John F; Westervelt, Peter; Uy, Geoffrey L; Abboud, Camille N; Vij, Ravi; Schroeder, Mark A; Fehniger, Todd A; Romee, Rizwan

    2017-04-01

    Outcomes for patients with acute myeloid leukemia (AML) who fail to achieve complete remission remain poor. Hematopoietic cell transplantation (HCT) has been shown to induce long-term survival in AML patients with active disease. HCT is largely performed with HLA-matched unrelated or HLA-matched related donors. Recently, HCT with HLA-haploidentical related donors has been identified as a feasible option when HLA-matched donors are not immediately available. However, there are little data comparing outcomes for AML patients with active disease who receive haploidentical versus traditionally matched HCT. We retrospectively analyzed data from 99 AML patients with active disease undergoing allogeneic HCT at a single institution. Forty-three patients received unrelated donor HCT, 32 patients received matched related donor HCT, and 24 patients received peripheral blood haploidentical HCT with post-transplantation cyclophosphamide. We found no significant differences between treatment groups in terms of overall survival (OS), event-free survival, transplantation-related mortality, cumulative incidence of relapse, and cumulative incidence of acute and chronic graft-versus-host disease (GVHD). We performed univariate regression analysis of variables that modified OS in all patients and found only younger age at transplantation and development of chronic GVHD significantly improved outcome. Although limited by our relatively small sample size, these results indicate that haploidentical HCT in active AML patients have comparable outcomes to HCT with traditionally matched donors. Haploidentical HCT can be considered in this population of high-risk patients when matched donors are unavailable or when wait times for transplantation are unacceptably long. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  6. Bone marrow transplantation

    International Nuclear Information System (INIS)

    Storb, R.; Santos, G.W.

    1979-01-01

    Bone marrow transplantation has been increasingly used to treat patients with severe combined immunodeficiency diseases, severe aplastic anemia, and malignant hematologic diseases, especially leukemia. At the Workshop a number of problems were discussed, e.g., conditioning regimens aimed at overcoming the problem of marrow graft rejection and reducing the incidence of recurrent leukemia, prevention of graft-versus-host disease (GVHD), possible mechanisms involved in stable graft-host tolerance, graft-versus-leukemia effect in mice, and finally, the possible use of autologous marrow transplantation

  7. Five-Strand versus Four-Strand Hamstring Tendon Graft Technique for Anterior Cruciate Ligament Reconstruction: A Biomechanical Comparison.

    Science.gov (United States)

    Vaillant, Eric R; Parks, Brent G; Camire, Lyn M; Hinton, Richard Y

    2017-11-01

    The aim of this article is to compare diameter and stiffness, displacement, and strain in a five-strand versus four-strand hamstring graft for anterior cruciate ligament reconstruction. Eight matched pairs of lower extremities underwent four-strand or five-strand hamstring graft reconstruction. Diameter was significantly higher in the five-strand versus the four-strand construct ( p  = 0.002). No significant difference was found between the groups in construct displacement or stiffness. Significantly higher strain was observed in the inner limb versus the outer limb in the four-strand construct ( p  = 0.001) and in the inner limb versus the fifth limb in the 5-strand construct ( p  = 0.004). A fifth limb added to a four-strand hamstring graft significantly increased graft diameter but did not significantly change stiffness or displacement, suggesting that attachment of additional graft material via suture did not provide for full incorporation of the added limb into the graft at time zero. The inner limb in both constructs absorbed significantly greater load than did other limbs. The use of suture to attach additional material to a four-strand hamstring graft may not contribute to improved biomechanical qualities of the graft at time zero. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  8. Bone marrow transplantation after the Chernobyl nuclear accident

    International Nuclear Information System (INIS)

    Baranov, A.; Gale, R.P.; Guskova, A.

    1989-01-01

    On April 26, 1986, an accident at the Chernobyl nuclear power station in the Soviet Union exposed about 200 people to large doses of total-body radiation. Thirteen persons exposed to estimated total-body doses of 5.6 to 13.4 Gy received bone marrow transplants. Two transplant recipients, who received estimated doses of radiation of 5.6 and 8.7 Gy, are alive more than three years after the accident. The others died of various causes, including burns (the cause of death in five), interstitial pneumonitis (three), graft-versus-host disease (two), and acute renal failure and adult respiratory distress syndrome (one). There was hematopoietic (granulocytic) recovery in nine transplant recipients who could be evaluated, six of whom had transient partial engraftment before the recovery of their own marrow. Graft-versus-host disease was diagnosed clinically in four persons and suspected in two others. Although the recovery of endogenous hematopoiesis may occur after exposure to radiation doses of 5.6 to 13.4 Gy, we do not know whether it is more likely after the transient engraftment of transplanted stem cells. Because large doses of radiation affect multiple systems, bone marrow recovery does not necessarily ensure survival. Furthermore, the risk of graft-versus-host disease must be considered when the benefits of this treatment are being weighed

  9. CHALLENGES IN TREATMENT OF RENAL GRAFT ACUTE ANTIBODY-MEDIATED REJECTION

    Directory of Open Access Journals (Sweden)

    A. I. Sushkov

    2016-01-01

    Full Text Available Diagnostic criteria and treatment protocols for acute antibody-mediated rejection (AMR of kidney allograft remain controversial. We report the case of early severe AMR after primary kidney transplantation. The graft removal was considered in the absence of treatment efficacy and in the presence of systemic infl ammatory response syndrome. However, at surgery the graft looked normal and it was not removed. The repeated treatment course (plasmapheresis, antithymocyte globulin, intravenous immunoglobulin and rituximab was effective. The patient has good and stable graft function in 1 year after transplantation. 

  10. Intravital imaging of donor allogeneic effector and regulatory T cells with host dendritic cells during GVHD.

    Science.gov (United States)

    Lin, Kaifeng Lisa; Fulton, LeShara M; Berginski, Matthew; West, Michelle L; Taylor, Nicholas A; Moran, Timothy P; Coghill, James M; Blazar, Bruce R; Bear, James E; Serody, Jonathan S

    2014-03-06

    Graft-versus-host disease (GVHD) is a systemic inflammatory response due to the recognition of major histocompatibility complex disparity between donor and recipient after hematopoietic stem cell transplantation (HSCT). T-cell activation is critical to the induction of GVHD, and data from our group and others have shown that regulatory T cells (Tregs) prevent GVHD when given at the time of HSCT. Using multiphoton laser scanning microscopy, we examined the single cell dynamics of donor T cells and dendritic cells (DCs) with or without Tregs postallogeneic transplantation. We found that donor conventional T cells (Tcons) spent very little time screening host DCs. Tcons formed stable contacts with DCs very early after transplantation and only increased velocity in the lymph node at 20 hours after transplant. We also observed that Tregs reduced the interaction time between Tcons and DCs, which was dependent on the generation of interleukin 10 by Tregs. Imaging using inducible Tregs showed similar disruption of Tcon-DC contact. Additionally, we found that donor Tregs induce host DC death and down-regulate surface proteins required for donor T-cell activation. These data indicate that Tregs use multiple mechanisms that affect host DC numbers and function to mitigate acute GVHD.

  11. A 10-year institutional experience with open branched graft reconstruction of aortic aneurysms in connective tissue disorders versus degenerative disease.

    Science.gov (United States)

    Hicks, Caitlin W; Lue, Jennifer; Glebova, Natalia O; Ehlert, Bryan A; Black, James H

    2017-11-01

    Aortic reconstruction for complex thoracoabdominal aortic aneurysms (TAAAs) can be challenging, especially in patients with connective tissue disorders (CTDs) in whom tissue fragility is a major concern. Branched graft reconstruction is a more complex operation compared with inclusion patch repair of the aorta but is frequently necessary in patients with CTDs or other pathologies because of anatomic reasons. We describe our institutional experience with open branched graft reconstruction of aortic aneurysms and compare outcomes for patients with CTDs vs degenerative pathologies. We retrospectively analyzed all patients undergoing open aortic reconstruction using branched grafts at our institution between July 2006 and December 2015. Postoperative outcomes, including perioperative morbidity and mortality, midterm graft patency, and the development of new aneurysms, were compared for patients with CTD vs degenerative disease. During the 10-year study period, 137 patients (CTD, 29; degenerative, 108) underwent aortic repair with branched graft reconstruction. CTD patients were significantly younger (39 ± 1.9 vs 68 ± 1.0 years; P disease, coronary artery disease; P degenerative disease. Perioperative mortality (CTD: 10% [n = 3] vs degenerative: 6% [n = 6]; P = .40) and any complication (62% vs 55%; P = .47) were similar between groups. At a median follow-up time of 14.5 months (interquartile range: 6.5, 43.9 months), CTD patients were more likely to develop both new aortic (21%) and nonaortic (14%) aneurysms compared with the degenerative group (7% and 4% for aortic and nonaortic aneurysms, respectively; P = .02). Loss of branch graft patency occurred in 0 of 99 grafts (0%) in CTD patients and in 13 of 167 grafts (7.8%) in degenerative disease patients (P = .005). Loss of branch graft patency occurred most commonly in left renal artery bypass grafts (77%) and was clinically asymptomatic (creatinine: 1.77 ± 0.13 mg/dL currently vs 1.41 ± 0

  12. A comparison between allogeneic stem cell transplantation from unmanipulated haploidentical and unrelated donors in acute leukemia

    Directory of Open Access Journals (Sweden)

    Simona Piemontese

    2017-01-01

    Full Text Available Abstract Background In the absence of a HLA-matched related or matched unrelated donor, allogeneic stem cell transplantation (allo-SCT from mismatched unrelated donors or haploidentical donors are potential alternatives for patients with acute leukemia with an indication to allo-SCT. The objective of this study was to compare the outcome of allo-SCT from T cell-replete haploidentical (Haplo versus matched (MUD 10/10 or mismatched unrelated donor at a single HLA-locus (MMUD 9/10 for patients with acute leukemia in remission. Methods Two hundred sixty-five adult patients with de novo acute leukemia in first or second remission that received a Haplo-SCT between January 2007 and December 2013 were compared with 2490 patients receiving a MUD 10/10 and 813 receiving a MMUD 9/10. Propensity score weighted analysis was conducted in order to control for disease risk imbalances between the groups. Results The weighted 3-year non-relapse mortality and relapse incidence were 29 and 30% for Haplo, 21 and 29% for MUD 10/10, and 29 and 25% for MMUD 9/10, respectively. The weighted 3-year leukemia-free survival (LFS and overall survival (OS were 41 and 46% for Haplo, 50 and 56% for MUD 10/10, and 46 and 48% for MMUD 9/10, respectively. Using weighted Cox model, both LFS and OS were significantly higher in transplants from MUD 10/10 compared from those in Haplo but not different between transplants from MMUD 9/10 and Haplo. The type of donor was not significantly associated with neither acute nor chronic graft-versus-host disease. Conclusions Patients with acute leukemia in remission have better outcomes if transplanted from a MUD 10/10. We did not find any significant difference in outcome between transplants from MMUD 9/10 and Haplo, suggesting that both can be equally used in the absence of a 10/10 MUD. Key point 1 Better outcomes using fully (10/10 matched unrelated donor for allo-SCT in acute leukemia in remission. Key point 2 Similar outcomes after allo

  13. Nursing challenges caring for bone marrow transplantation patients with graft versus host disease.

    Science.gov (United States)

    Neumann, Joyce

    2017-12-01

    Nursing care of blood and marrow transplantation (BMT) patients is complicated. Nursing considerations of BMT patients with GVHD require an additional set of skills and knowledge that include side effects, both expected and less common, assessment skills, treatment administration, both standard and novel, and acute or intensive care. Nursing care of BMT patients with skin GVHD will be determined by the degree of skin alteration with distinct decisions made about hygiene, both topical and systemic treatment, infection prevention, relief of discomfort, functional ability (ADL) and body image alteration. The nurse needs to have knowledge about assessment criteria for acute and chronic (NIH) assessment with special attention to skin (presence of rash, texture, mobility), joint mobility, mouth care, dressings, and skin care products. Nursing consideration of gastrointestinal GVHD includes importance of accurate intake and output, obtaining culture, fluid and electrolyte imbalance, nutrition, treatment, and skin care. Complication of GVHD treatment, namely effects of steroids require experts from many disciplines to provide comprehensive care. Caring and advocating for GVHD patients may include preparing for outcomes that are undesirable and impact the patient's quality of life and mortality. BMT survivorship programs are a major source of patient education about chronic GVHD for patients after treatment. Caring for BMT patients, especially those experiencing GVHD, takes a knowledgeable, committed, and caring team of healthcare providers. Workshops like this are vital in providing information and networking to keep providers around the region and globe engaged in this critical work. Copyright © 2017. Published by Elsevier B.V.

  14. T-regulatory cells in chronic rejection versus stable grafts.

    Science.gov (United States)

    Al-Wedaie, Fatima; Farid, Eman; Tabbara, Khaled; El-Agroudy, Amgad E; Al-Ghareeb, Sumaya M

    2015-04-01

    Studying regulatory T cells in kidney allograft acceptance versus chronic rejection may help in the understanding of more mechanisms of immune tolerance and, in the future, may enable clinicians to induce immune tolerance and decrease the use of immunosuppressive drugs. The aim of the current study was to evaluate regulatory T cells in kidney transplant patients with stable graft versus transplant with biopsy-proven chronic rejection. The 3 groups that were studied included: kidney transplanted patients with no rejection episodes (n = 43); transplanted patients with biopsy-proven renal rejection (n = 27); and healthy age-matched nontransplanted individuals as controls (n = 42).The percentage of regulatory T cells (CD4+CD25+Foxp3+) in blood was determined by flow cytometry. The regulatory T cell percentage was significantly lower in chronic rejection patients than control or stable graft groups. No significant difference was observed in regulatory T cell percentage between the stable graft and control groups. In the stable graft group, patients on rapamycin had a significantly higher regulatory T cell percentage than patients on cyclosporine. No effect of donor type, infection, or duration after transplant was observed on regulatory T cell percentage. The results of the current study are consistent with previous studies addressing the function of regulatory T cells in inducing immunotolerance after kidney transplant. Considering the established role of regulatory T cells in graft maintenance and our observation of high regulatory T cell percentage in patients receiving rapamycin than cyclosporine, we recommend including rapamycin when possible in immunosuppressive protocols. The findings from the current study on the chronic rejection group support ongoing research of having treatment with regulatory T cells, which may constitute a novel, efficient antirejection therapy in the future.

  15. Off-Pump Versus On-Pump Coronary Artery Bypass Grafting

    DEFF Research Database (Denmark)

    Møller, Christian H; Steinbrüchel, Daniel A

    2014-01-01

    Coronary artery bypass grafting (CABG) remains the preferred treatment in patients with complex coronary artery disease. However, whether the procedure should be performed with or without the use of cardiopulmonary bypass, referred to as off-pump and on-pump CABG, is still up for debate....... Intuitively, avoidance of cardiopulmonary bypass seems beneficial as the systemic inflammatory response from extracorporeal circulation is omitted, but no single randomized trial has been able to prove off-pump CABG superior to on-pump CABG as regards the hard outcomes death, stroke or myocardial infarction....... In contrast, off-pump CABG is technically more challenging and may be associated with increased risk of incomplete revascularization. The purpose of the review is to summarize the current literature comparing outcomes of off-pump versus on-pump coronary artery bypass surgery....

  16. Treatment of inflammatory diseases with mesenchymal stem cells.

    Science.gov (United States)

    Newman, Robert E; Yoo, Dana; LeRoux, Michelle A; Danilkovitch-Miagkova, Alla

    2009-06-01

    Human mesenchymal stem cells (hMSCs) are rare progenitor cells present in adult bone marrow that have the capacity to differentiate into a variety of tissue types, including bone, cartilage, tendon, fat, and muscle. In addition to multilineage differentiation capacity, MSCs regulate immune and inflammatory responses, providing therapeutic potential for treating diseases characterized by the presence of an inflammatory component. The availability of bone marrow and the ability to isolate and expand hMSCs ex vivo make these cells an attractive candidate for drug development. The low immunogenicity of these cells suggests that hMSCs can be transplanted universally without matching between donors and recipients. MSCs universality, along with the ability to manufacture and store these cells long-term, present a unique opportunity to produce an "off-the-shelf" cellular drug ready for treatment of diseases in acute settings. Accumulated animal and human data support MSC therapeutic potential for inflammatory diseases. Several phase III clinical trials for treatment of acute Graft Versus Host Disease (GVHD) and Crohn's disease are currently in progress. The current understanding of cellular and molecular targets underlying the mechanisms of MSCs action in inflammatory settings as well as clinical experience with hMSCs is summarized in this review.

  17. Fetal liver transplantation in 2 patients with acute leukaemia after total body irradiation

    International Nuclear Information System (INIS)

    Lucarelli, G.; Izzi, T.; Porcellini, A.; Delfini, C.; Galimberti, M.; Moretti, L.; Polchi, P.; Agostinelli, F.; Andreani, M.; Manna, M.; Dallapiccola, B.

    1982-01-01

    2 patients with acute leukaemia in relapse were transplanted with fetal liver cells following a conditioning regimen of cyclophosphamide (120 mg/kg) and total body irradiation (1000 r). Each patient achieved a remission with haematopoietic recovery that was rapid in one case and delayed in the other. In one case there was evidence of chimerism as demonstrated by the presence of the XYY karyotype of the donor fetus in 20 % of marrow metaphases, by the presence of double Y bodies in the peripheral blood, by the appearance of new HLA-antigens, and by red cell isoenzyme phenotypes of donor origin. In the second case there was prompt haemotopoietic recovery and the appearance of red cell isoenzyme phenotypes of donor origin. Survival was 153 and 30 d, respectively, and both patients died of interstitial pneumonia without evidence of graft versus host disease. (author)

  18. Stent grafting of acute hepatic artery bleeding following pancreatic head resection

    International Nuclear Information System (INIS)

    Stoupis, Christoforos; Ludwig, Karin; Triller, Juergen; Inderbitzin, Daniel; Do, Dai-Do

    2007-01-01

    The purpose of this study was to report the potential of hepatic artery stent grafting in cases of acute hemorrhage of the gastroduodenal artery stump following pancreatic head resection. Five consecutive male patients were treated because of acute, life-threatening massive bleeding. Instead of re-operation, emergency angiography, with the potential of endovascular treatment, was performed. Because of bleeding from the hepatic artery, a stent graft (with the over-the-wire or monorail technique) was implanted to control the hemmorhage by preserving patency of the artery. The outcome was evaluated. In all cases, the hepatic artery stent grafting was successfully performed, and the bleeding was immediately stopped. Clinically, immediately after the procedure, there was an obvious improvement in the general patient condition. There were no immediate procedure-related complications. Completion angiography (n=5) demonstrated control of the hemorrhage and patency of the hepatic artery and the stent graft. Although all patients recovered hemodynamically, three individuals died 2 to 10 days after the procedure. The remaining two patients survived, without the need for re-operation. Transluminal stent graft placement in the hepatic artery is a safe and technically feasible solution to control life-threatening bleeding of the gastroduodenal artery stump. (orig.)

  19. Maternally acquired runt disease.

    Science.gov (United States)

    Beer, A E; Billingham, R E

    1973-01-19

    propounded as to how maternally transmitted graft-versus-host reactivity might lead to the development of these tumors. In mice it has been established that graft-versus-host reactivity may result in a high incidence of lymphomas (18). Recent analysis indicates that this graft-versus-host reactivity unmasks and activates normally latent and undemonstrable oncogenic viruses (19). The work we describe in this article may have some relevance to the possible clinical significance of transplacental cellular mobility in man. We suggest that the relatively high incidence of lymphomas in children might also be, in part at least, due to unmasking of oncogenic viruses by subclinical graft-versus-host reactivity mediated by immunocompetent cells of maternal origin. The statistical evidence that male infants are at greater risk than females (20) is concordant with our observation that maternally induced runts include a significantly higher proportion of males than females (10).

  20. Dutch randomized trial comparing standard catheter-directed thrombolysis versus Ultrasound-accElerated Thrombolysis for thromboembolic infrainguinal disease (DUET: design and rationale

    Directory of Open Access Journals (Sweden)

    Fioole Bram

    2011-01-01

    Full Text Available Abstract Background The use of thrombolytic therapy in the treatment of thrombosed infrainguinal native arteries and bypass grafts has increased over the years. Main limitation of this treatment modality, however, is the occurrence of bleeding complications. Low intensity ultrasound (US has been shown to accelerate enzymatic thrombolysis, thereby reducing therapy time. So far, no randomized trials have investigated the application of US-accelerated thrombolysis in the treatment of thrombosed infra-inguinal native arteries or bypass grafts. The DUET study (Dutch randomized trial comparing standard catheter-directed thrombolysis versus Ultrasound-accElerated Thrombolysis for thrombo-embolic infrainguinal disease is designed to assess whether US-accelerated thrombolysis will reduce therapy time significantly compared with standard catheter-directed thrombolysis. Methods/design Sixty adult patients with recently (between 1 and 7 weeks thrombosed infrainguinal native arteries or bypass grafts with acute limb ischemia class I or IIa, according to the Rutherford classification for acute ischemia, will be randomly allocated to either standard thrombolysis (group A or US-accelerated thrombolysis (group B. Patients will be recruited from 5 teaching hospitals in the Netherlands during a 2-year period. The primary endpoint is the duration of catheter-directed thrombolysis needed for uninterrupted flow in the thrombosed infrainguinal native artery or bypass graft, with outflow through at least 1 crural artery. Discussion The DUET study is a randomized controlled trial that will provide evidence of whether US-accelerated thrombolysis will significantly reduce therapy time in patients with recently thrombosed infrainguinal native arteries or bypass grafts, without an increase in complications. Trial registration Current Controlled Trials ISRCTN72676102

  1. Revision Vaginoplasty: A Comparison of Surgical Outcomes of Laparoscopic Intestinal versus Perineal Full-Thickness Skin Graft Vaginoplasty.

    Science.gov (United States)

    Van der Sluis, Wouter B; Bouman, Mark-Bram; Buncamper, Marlon E; Mullender, Margriet G; Meijerink, Wilhelmus J

    2016-10-01

    Vaginal (re)construction can greatly improve the quality of life of indicated patients. If primary vaginoplasty fails, multiple surgical approaches exist for revision. The authors compared surgical results of laparoscopic intestinal versus full-thickness skin graft revision vaginoplasty. A retrospective chart review of patients who underwent revision vaginoplasty at the authors' institution was conducted. Patient demographics, surgical characteristics, complications, hospitalization, reoperations, and neovaginal depth for both surgical techniques were recorded and compared. The authors studied a consecutive series of 50 transgender and three biological women who underwent revision vaginoplasty, of which 21 were laparoscopic intestinal and 32 were perineal full-thickness skin graft vaginoplasties, with a median clinical follow-up of 3.2 years (range, 0.5 to 19.7 years). Patient demographics did not differ significantly. There was no mortality. Two intraoperative rectal perforations (10 percent) occurred in the intestinal group versus six (19 percent) in the full-thickness skin graft group. Operative time was shorter for the full-thickness skin graft vaginoplasty group (131 ± 35 minutes versus 191 ± 45 minutes; p skin graft (81 percent) vaginoplasty procedures. A deeper neovagina was achieved with intestinal vaginoplasty (15.9 ± 1.4 cm versus 12.5 ± 2.8 cm; p skin graft vaginoplasty can be used as secondary vaginal reconstruction. Intraoperative and postoperative complications do not differ significantly, but rectal perforation was more prevalent in the full-thickness skin graft vaginoplasty group. Although the operative time of laparoscopic intestinal vaginoplasty is longer, adequate neovaginal depth was more frequently achieved than in secondary perineal full-thickness skin graft vaginoplasty. Therapeutic, III.

  2. Successful haploidentical stem cell transplantation with prophylactic administration of liposomal amphotericin B after invasive pulmonary zygomycosis

    Directory of Open Access Journals (Sweden)

    Testuro Ochi

    2017-12-01

    Full Text Available A 54-year-old woman with acute myeloid leukemia (AML achieved complete remission by induction chemotherapy, but developed zygomycosis after consolidation therapy. As zygomycosis could not be cured by liposomal amphotericin B and micafungin, left lower lobectomy was performed. As AML relapsed 7 months after onset, she received haploidentical stem cell transplantation under administration of liposomal amphotericin B. Despite experiencing severe acute graft-versus-host disease, she remains alive with no relapse of either zygomycosis or AML. Keywords: Zygomycosis, Acute myeloid leukemia, Liposomal amphotericin B, Stem cell transplantation

  3. Pretransplant soluble CD30 level has limited effect on acute rejection, but affects graft function in living donor kidney transplantation.

    Science.gov (United States)

    Kim, Myoung Soo; Kim, Hae Jin; Kim, Soon Il; Ahn, Hyung Joon; Ju, Man Ki; Kim, Hyun Jung; Jeon, Kyung Ock; Kim, Yu Seun

    2006-12-27

    Serum soluble CD30 (sCD30) levels might be a useful marker of immunologic status in pre transplant (Tx) recipients. We retrospectively correlated preTx sCD30 levels (high versus low) on postTx graft survival, incidence of acute rejection, and graft function using stored preTx serum. Of 254 recipients who underwent kidney Tx, 120 recipients were enrolled under the uniform criteria (living donor, age >25 years, viral hepatitis free, diabetes free). The preTx sCD30 was not significantly associated with differences in graft survival rate during 47.5+/-11.4 months of follow-up (P = 0.5901). High sCD30 (> or =115 U/ml) was associated with a higher incidence of clinically or pathologically defined acute rejection than low sCD30, but the difference was not statistically significant (33.9% vs. 22.4%, P = 0.164). The response rate to antirejection therapy in patients with high sCD30 was inferior to those with low sCD30, but also was not statistically significant (33.3% vs. 7.7%, P = 0.087). However, mean serum creatinine levels in high sCD30 patients at one month, one year, and three years postTx were significantly different from those with low sCD30 (P acute rejection episodes, donor age, kidney weight/recipient body weight ratio, and preTx sCD30 levels were independent variables affecting the serum creatinine level three years postTx. PreTx sCD30 level has a limited effect on the incidence of acute rejection and response to antirejection treatment, but inversely and independently affects serum creatinine level after living donor kidney transplantation.

  4. In vitro regulation of immunoglobulin synthesis after human marrow transplantation. II. Deficient T and non-T lymphocyte function within 3-4 months of allogeneic, syngeneic, or autologous marrow grafting for hematologic malignancy

    International Nuclear Information System (INIS)

    Witherspoon, R.P.; Lum, L.G.; Storb, R.; Thomas, E.D.

    1982-01-01

    Immunoglobulin secretion was studied in 37 patients between 19 and 106 days after allogeneic HLA-identical (30 patients), allogeneic one HLA-haplotype-identical (three patients), syngeneic (three patients), or autologous (one patient) marrow grafting. E rosette-positive (T) and E rosette-negative (non-T) peripheral blood mononuclear cells were cocultured with pokeweed mitogen for 6 days. Polyvalent immunoglobulin secretion was determined by counting plaque forming cells in a reverse hemolytic plaque assay. The number of antibody secreting cells in cocultures of autologous T and non-T lymphocytes was low in 40 of 44 tests conducted on samples from the 37 patients. Mononuclear or non-T cells from 38 of 40 tests failed to produce antibody when cultured with normal helper T cells. T cells from 23 of 37 tests failed to help normal non-T cells secrete antibody. T lymphocytes from 23 of 41 tests suppressed antibody production greater than 80% by normal T and non-T cells. The suppressor cells were radiosensitive in 17 of the 25 tests. The abnormal function of lymphocyte subpopulations in patients during the first 3 mo after syngeneic, allogeneic or autologous marrow grafting was similar regardless of the type of graft or the presence of acute graft versus host disease

  5. HLA-DP and bonemarrow transplantation: DP-incompatibility and severe acute graft versus host disease

    DEFF Research Database (Denmark)

    Ødum, Niels; Platz, P; Jakobsen, B K

    1987-01-01

    The presence of activated T cells as judged from the reaction with monoclonal antibodies (MoAb) against (a) a late stage T cell activation antigen (VLA-1), (b) the interleukin 2 (IL2) receptor (CD25), and (c) four different HLA class II molecules (HLA-DR, DRw52, DQ, and DP) was studied in 15...

  6. Personalized Prognostic Risk Score for Long-Term Survival for Children with Acute Leukemia after Allogeneic Transplantation.

    Science.gov (United States)

    Bitan, Menachem; Ahn, Kwang Woo; Millard, Heather R; Pulsipher, Michael A; Abdel-Azim, Hisham; Auletta, Jeffery J; Brown, Valerie; Chan, Ka Wah; Diaz, Miguel Angel; Dietz, Andrew; Vincent, Marta González; Guilcher, Gregory; Hale, Gregory A; Hayashi, Robert J; Keating, Amy; Mehta, Parinda; Myers, Kasiani; Page, Kristin; Prestidge, Tim; Shah, Nirali N; Smith, Angela R; Woolfrey, Ann; Thiel, Elizabeth; Davies, Stella M; Eapen, Mary

    2017-09-01

    We studied leukemia-free (LFS) and overall survival (OS) in children with acute myeloid (AML, n = 790) and acute lymphoblastic leukemia (ALL, n = 1096) who underwent transplantation between 2000 and 2010 and who survived for at least 1 year in remission after related or unrelated donor transplantation. Analysis of patient-, disease-, and transplantation characteristics and acute and chronic graft-versus-host disease (GVHD) was performed to identify factors with adverse effects on LFS and OS. These data were used to develop risk scores for survival. We did not identify any prognostic factors beyond 4 years after transplantation for AML and beyond 3 years for ALL. Risk score for survival for AML includes age, disease status at transplantation, cytogenetic risk group, and chronic GVHD. For ALL, the risk score includes age at transplantation and chronic GVHD. The 10-year probabilities of OS for AML with good (score 0, 1, or 2), intermediate (score 3), and poor risk (score 4, 5, 6, or 7) were 94%, 87%, and 68%, respectively. The 10-year probabilities of OS for ALL were 89% and 80% for good (score 0 or 1) and poor risk (score 2), respectively. Identifying children at risk for late mortality with early intervention may mitigate some excess late mortality. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  7. Keratocyte apoptosis and not myofibroblast differentiation mark the graft/host interface at early time-points post-DSAEK in a cat model.

    Directory of Open Access Journals (Sweden)

    Adam J Weis

    Full Text Available To evaluate myofibroblast differentiation as an etiology of haze at the graft-host interface in a cat model of Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK.DSAEK was performed on 10 eyes of 5 adult domestic short-hair cats. In vivo corneal imaging with slit lamp, confocal, and optical coherence tomography (OCT were performed twice weekly. Cats were sacrificed and corneas harvested 4 hours, and 2, 4, 6, and 9 days post-DSAEK. Corneal sections were stained with the TUNEL method and immunohistochemistry was performed for α-smooth muscle actin (α-SMA and fibronectin with DAPI counterstain.At all in vivo imaging time-points, corneal OCT revealed an increase in backscatter of light and confocal imaging revealed an acellular zone at the graft-host interface. At all post-mortem time-points, immunohistochemistry revealed a complete absence of α-SMA staining at the graft-host interface. At 4 hours, extracellular fibronectin staining was identified along the graft-host interface and both fibronectin and TUNEL assay were positive within adjacent cells extending into the host stroma. By day 2, fibronectin and TUNEL staining diminished and a distinct acellular zone was present in the region of previously TUNEL-positive cells.OCT imaging consistently showed increased reflectivity at the graft-host interface in cat corneas in the days post-DSAEK. This was not associated with myofibroblast differentiation at the graft-host interface, but rather with apoptosis and the development of a subsequent acellular zone. The roles of extracellular matrix changes and keratocyte cell death and repopulation should be investigated further as potential contributors to the interface optical changes.

  8. Fetal microchimeric cells in autoimmune thyroid diseases: harmful, beneficial or innocent for the thyroid gland?

    Science.gov (United States)

    Lepez, Trees; Vandewoestyne, Mado; Deforce, Dieter

    2013-01-01

    Autoimmune thyroid diseases (AITD) show a female predominance, with an increased incidence in the years following parturition. Fetal microchimerism has been suggested to play a role in the pathogenesis of AITD. However, only the presence of fetal microchimeric cells in blood and in the thyroid gland of these patients has been proven, but not an actual active role in AITD. Is fetal microchimerism harmful for the thyroid gland by initiating a Graft versus Host reaction (GvHR) or being the target of a Host versus Graft reaction (HvGR)? Is fetal microchimerism beneficial for the thyroid gland by being a part of tissue repair or are fetal cells just innocent bystanders in the process of autoimmunity? This review explores every hypothesis concerning the role of fetal microchimerism in AITD.

  9. A randomized comparison of the Saphenous Vein Versus Right Internal Thoracic Artery as a Y-Composite Graft (SAVE RITA) trial: early results.

    Science.gov (United States)

    Hwang, Ho Young; Kim, Jun Sung; Oh, Se Jin; Kim, Ki-Bong

    2012-11-01

    The Saphenous Vein Versus Right Internal Thoracic Artery as a Y-Composite Graft trial was designed to evaluate the saphenous vein compared with the right internal thoracic artery as a Y-composite graft anastomosed to the side of the left internal thoracic artery. In this early analysis, we compared early angiographic patency rates and clinical outcomes. From September 2008 to October 2011, 224 patients with multivessel coronary artery disease were randomized prospectively to undergo off-pump revascularization using the saphenous vein group (n = 112) or the right internal thoracic artery group (n = 112) as Y-composite grafts. Early postoperative (1.4 ± 1.1 days) angiographic patency and clinical outcomes were compared. There was 1 operative death in the right internal thoracic artery group. No statistically significant differences in postoperative morbidities, including atrial fibrillation and acute renal failure, were observed between the groups. The number of distal anastomoses using the side-arm Y-composite graft (saphenous vein vs right internal thoracic artery) were 2.3 ± 0.8 and 1.9 ± 0.7 in the saphenous vein and right internal thoracic artery groups, respectively (P < .001). A third conduit was used in 44 patients (saphenous vein group vs right internal thoracic artery group, 4/109 vs 40/110; P < .001) to extend the side-arm Y-composite graft for complete revascularization. Early angiography demonstrated an overall patency rate of 99.4% (771 of 776 distal anastomoses). Patency rates of the side-arm Y-composite graft (saphenous vein vs right internal thoracic artery) were 98.8% (245 of 248) and 99.5% (207 of 208) in the saphenous vein and right internal thoracic artery groups, respectively (P = .629). A third conduit was needed to extend the right internal thoracic artery composite graft and reach the target vessels in 36.4% (40/110) of the patients. The saphenous vein composite graft was comparable with the right internal thoracic artery composite graft

  10. Secondary Disease in Radiation Chimeras

    Energy Technology Data Exchange (ETDEWEB)

    Congdon, C. C. [Biology Division, Oak Ridge National Laboratory, Oak Ridge, TN (United States)

    1969-07-15

    A review of research dealing directly or indirectly with the development of bidirectional tolerance in radiation chimeras has been made, emphasizing some of the contemporary research on this subject in Oak Ridge and Knoxville. By controlling such factors as cell dose, age of donor animal and day of cell injection, it was possible to achieve bidirectional tolerance. Attempts to reduce bidirectional tolerance in favour of increasing the graft-versus-host reaction were less successful. Hypoxic caging demonstrated a new approach to achieving bidirectional tolerance through physiological competition for growth. Graft-versus-host reactions have a lower growth priority than marrow regeneration or erythropoietic hyperplasia. Study of pathologic processes, immunologic capability and the-biochemical lesions in radiation chimeras all lead to new ideas that involve bidirectional tolerance. The investigations on dose rate in radiation suppression of the immune response and on LD{sub 50} (30- to 90-day)values after injection of different numbers of marrow cells all have a bearing on control of the host-versus-graft response and therefore are important in understanding bidirectional tolerance. (author)

  11. Gene Map of the HLA Region, Graves' Disease and Hashimoto Thyroiditis, and Hematopoietic Stem Cell Transplantation.

    Science.gov (United States)

    Sasazuki, Takehiko; Inoko, Hidetoshi; Morishima, Satoko; Morishima, Yasuo

    2016-01-01

    The human leukocyte antigen (HLA) genomic region spanning about 4 Mb is the most gene dense and the polymorphic stretches in the human genome. A total of the 269 loci were identified, including 145 protein coding genes mostly important for immunity and 50 noncoding RNAs (ncRNAs). Biological function of these ncRNAs remains unknown, becoming hot spot in the studies of HLA-associated diseases. The genomic diversity analysis in the HLA region facilitated by next-generation sequencing will pave the way to molecular understanding of linkage disequilibrium structure, population diversity, histocompatibility in transplantation, and associations with autoimmune diseases. The 4-digit DNA genotyping of HLA for six HLA loci, HLA-A through DP, in the patients with Graves' disease (GD) and Hashimoto thyroiditis (HT) identified six susceptible and three resistant HLA alleles. Their epistatic interactions in controlling the development of these diseases are shown. Four susceptible and one resistant HLA alleles are shared by GD and HT. Two HLA alleles associated with GD or HT control the titers of autoantibodies to thyroid antigens. All these observations led us to propose a new model for the development of GD and HT. Hematopoietic stem cell transplantation from unrelated donor (UR-HSCT) provides a natural experiment to elucidate the role of allogenic HLA molecules in immune response. Large cohort studies using HLA allele and clinical outcome data have elucidated that (1) HLA locus, allele, and haplotype mismatches between donor and patient, (2) specific amino acid substitution at specific positions of HLA molecules, and (3) ethnic background are all responsible for the immunological events related to UR-HSCT including acute graft-versus-host disease (GVHD), chronic GVHD, graft-versus-leukemia (GvL) effect, and graft failure. © 2016 Elsevier Inc. All rights reserved.

  12. Outcomes of coronary artery bypass grafting versus percutaneous coronary intervention with drug-eluting stents for patients with multivessel coronary artery disease.

    Science.gov (United States)

    Javaid, Aamir; Steinberg, Daniel H; Buch, Ashesh N; Corso, Paul J; Boyce, Steven W; Pinto Slottow, Tina L; Roy, Probal K; Hill, Peter; Okabe, Teruo; Torguson, Rebecca; Smith, Kimberly A; Xue, Zhenyi; Gevorkian, Natalie; Suddath, William O; Kent, Kenneth M; Satler, Lowell F; Pichard, Augusto D; Waksman, Ron

    2007-09-11

    Advances in coronary artery bypass grafting (CABG) surgery and percutaneous coronary intervention (PCI) with drug-eluting stents have dramatically improved results of these procedures. The optimal treatment for patients with multivessel coronary artery disease is uncertain given the lack of prospective, randomized data reflecting current practice. This study represents a "real-world" evaluation of current technology in the treatment of multivessel coronary artery disease. A total of 1680 patients undergoing revascularization for multivessel coronary artery disease were identified. Of these, 1080 patients were treated for 2-vessel disease (196 CABG and 884 PCI) and 600 for 3-vessel disease (505 CABG and 95 PCI). One-year mortality, cerebrovascular events, Q-wave myocardial infarction, target vessel failure, and composite major adverse cardiovascular and cerebrovascular events were compared between the CABG and PCI cohorts. Outcomes were adjusted for baseline covariates and reported as hazard ratios. The unadjusted major adverse cardiovascular and cerebrovascular event rate was reduced with CABG for patients with 2-vessel disease (9.7% CABG versus 21.2% PCI; P<0.001) and 3-vessel disease (10.8% CABG versus 28.4% PCI; P<0.001). Adjusted outcomes showed increased major adverse cardiovascular and cerebrovascular event with PCI for patients with 2-vessel (hazard ratio 2.29; 95% CI 1.39 to 3.76; P=0.01) and 3-vessel disease (hazard ratio 2.90; 95% CI 1.76 to 4.78; P<0.001). Adjusted outcomes for the nondiabetic subpopulation demonstrated equivalent major adverse cardiovascular and cerebrovascular event with PCI for 2-vessel (hazard ratio 1.77; 95% CI 0.96 to 3.25; P=0.07) and 3-vessel disease (hazard ratio 1.70; 95% CI 0.77 to 3.61; P=0.19). Compared with PCI with drug-eluting stents, CABG resulted in improved major adverse cardiovascular and cerebrovascular event in patients with 2- and 3-vessel coronary artery disease, primarily in those with underlying diabetes

  13. [Immunological mechanisms of graft versus tumor effect].

    Science.gov (United States)

    Ine, Shoji; Yamada, Minami; Miyamura, Koichi; Sasaki, Takeshi

    2003-09-01

    Lesson from hematopoietic stem cell transplantation demonstrated that donor immuno-surveillance system can eradicate tumor cells. This is so-call graft versus tumor(GVT) effect. Antigen presenting cells show peptide from minor antigen rather leukemic specific antigen in the context of major histocompatibility complex. The effector cells composed of CD8 T lymphocyte, CD4 T lymphocyte, natural killer cell and natural killer T cell. Death signal was transmitted from effector cells via granzyme/perforin system and FasL/Fas system, and recently TRAIL system seems most important for GVT effect.

  14. Long-term outcomes of coronary artery bypass grafting versus stent-PCI for unprotected left main disease: a meta-analysis.

    Science.gov (United States)

    De Rosa, Salvatore; Polimeni, Alberto; Sabatino, Jolanda; Indolfi, Ciro

    2017-09-06

    Coronary artery bypass graft (CABG) surgery has traditionally represented the standard of care for left main coronary artery (LMCA) disease. However, percutaneous coronary intervention with stent implantation (PCI) has more recently emerged as a valuable alternative. The long-time awaited results of the largest randomized trials on the long-term impact of PCI versus CABG in LMCA disease, the newly published NOBLE and EXCEL studies, revealed contrasting results. Thus, aim of the present meta-analysis was to review the most robust evidence from randomized comparisons of CABG versus PCI for revascularization of LMCA. Randomized studies comparing long-term clinical outcomes of CABG or Stent-PCI for the treatment of LMCA disease were searched for in PubMed, the Chochrane Library and Scopus electronic databases. A total of 5 randomized studies were selected, including 4499 patients. No significant difference between CABG and PCI was found in the primary analysis on the composite endpoint of death, stroke and myocardial infarction (OR = 1·06 95% CI 0·80-1·40; p = 0·70). Similarly, no differences were observed between CABG and PCI for all-cause death (OR = 1·03 95% CI 0·81-1·32; p = 0·81). Although not statistically significant, a lower rate of stroke was registered in the PCI arm (OR = 0·86; p = 0·67), while a lower rate of myocardial infarction was found in the CABG arm (OR = 1·43; p = 0·17). On the contrary, a significantly higher rate of repeat revascularization was registered in the PCI arm (OR = 1·76 95% CI 1·45-2·13; p PCI and CABG for the treatment of LMCA disease in the composite endpoint of death, stroke and myocardial infarction. Hence, a large part of patients with unprotected left main coronary artery disease can be managed equally well by means of both these revascularization strategies.

  15. Haploidentical hematopoietic stem cell transplant with umbilical cord-derived multipotent mesenchymal cell infusion for the treatment of high-risk acute leukemia in children.

    Science.gov (United States)

    Zhu, Ling; Wang, Zhidong; Zheng, Xiaoli; Ding, Li; Han, Dongmei; Yan, Hongmin; Guo, Zikuan; Wang, Hengxiang

    2015-05-01

    In this study, 25 children with high-risk acute leukemia received haploidentical hematopoietic stem cell transplant (haplo-HSCT) with co-transfusion of umbilical cord multipotent mesenchymal cells (UC-MSCs). Adverse effects, hematopoietic recovery, complications and outcome were observed during a median follow-up of 12.8 months (range: 3-25 months). Myeloid engraftment was rapid, and the median time to neutrophil and platelet recovery was 15.12 days and 20.08 days, respectively. Eight patients developed grade I skin acute graft-versus-host disease (aGVHD) that responded well to standard steroid therapy. Of note, cytomegalovirus viremia was observed in most patients (23/25 cases). Patients died mainly of leukemia relapse and pulmonary complication. Fourteen patients are currently alive and remain with full donor chimerism at the time of reporting. The present results suggest further clinical trials to testify the effectiveness of UC-MSCs to prevent aGVHD in haplo-HSCT for treating children with high-risk leukemia.

  16. Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE)

    DEFF Research Database (Denmark)

    Mäkikallio, Timo; Holm, Niels R; Lindsay, Mitchell

    2016-01-01

    Background Coronary artery bypass grafting (CABG) is the standard treatment for revascularisation in patients with left main coronary artery disease, but use of percutaneous coronary intervention (PCI) for this indication is increasing. We aimed to compare PCI and CABG for treatment of left main...... coronary artery disease. Methods In this prospective, randomised, open-label, non-inferiority trial, patients with left main coronary artery disease were enrolled in 36 centres in northern Europe and randomised 1: 1 to treatment with PCI or CABG. Eligible patients had stable angina pectoris, unstable......, and 5% versus 2% (2 . 25, 0 . 93-5 . 48, p= 0 . 073) for stroke. Interpretation The findings of this study suggest that CABG might be better than PCI for treatment of left main stem coronary artery disease....

  17. All-cause mortality and major cardiovascular outcomes comparing percutaneous coronary angioplasty versus coronary artery bypass grafting in the treatment of unprotected left main stenosis

    DEFF Research Database (Denmark)

    Laukkanen, Jari A; Kunutsor, Setor K; Niemelä, Matti

    2017-01-01

    Objective: We compared percutaneous coronary intervention (PCI) with coronary artery bypass grafting (CABG) for the treatment of left main coronary artery (LMCA) disease by conducting a systematic review and meta-analysis of randomised controlled trials (RCTs). Methods: RCTs of PCI versus CABG in...

  18. Vitamin D levels and their associations with survival and major disease outcomes in a large cohort of patients with chronic graft-vs-host disease

    Science.gov (United States)

    Katić, Mašenjka; Pirsl, Filip; Steinberg, Seth M.; Dobbin, Marnie; Curtis, Lauren M.; Pulanić, Dražen; Desnica, Lana; Titarenko, Irina; Pavletic, Steven Z.

    2016-01-01

    Aim To identify the factors associated with vitamin D status in patients with chronic graft-vs-host disease (cGVHD) and evaluate the association between serum vitamin D (25(OH)D) levels and cGVHD characteristics and clinical outcomes defined by the National Institutes of Health (NIH) criteria. Methods 310 cGVHD patients enrolled in the NIH cGVHD natural history study (clinicaltrials.gov: NCT00092235) were analyzed. Univariate analysis and multiple logistic regression were used to determine the associations between various parameters and 25(OH)D levels, dichotomized into categorical variables: ≤20 and >20 ng/mL, and as a continuous parameter. Multiple logistic regression was used to develop a predictive model for low vitamin D. Survival analysis and association between cGVHD outcomes and 25(OH)D as a continuous as well as categorical variable: ≤20 and >20 ng/mL; <50 and ≥50 ng/mL, and among three ordered categories: ≤20, 20-50, and ≥50 ng/mL, was performed. PMID:27374829

  19. Allogeneic hematopoietic cell transplantation in first remission abrogates poor outcomes associated with high-risk pediatric acute myeloid leukemia.

    Science.gov (United States)

    Burke, Michael J; Wagner, John E; Cao, Qing; Ustun, Celalettin; Verneris, Michael R

    2013-07-01

    Despite remission rates of approximately 85% for children diagnosed with acute myeloid leukemia (AML), greater than 40% will die from relapsed disease. Patients with poor-risk molecular/cytogenetics and/or inadequate response to up-front therapy are typically considered high-risk (HR) and historically have poor outcomes with chemotherapy alone. We investigated whether allogeneic hematopoietic cell transplantation (allo-HCT) with best available donor in first remission (CR1) would abrogate the poor outcomes associated with HR AML in children and young adults treated with chemotherapy. We reviewed the outcomes of 50 consecutive children and young adults (ages 0 to 30 years) with AML who received a myeloablative allo-HCT between 2001 and 2010. Thirty-six patients (72%) were HR, defined as having FLT3-ITD mutations, 11q23 MLL rearrangements, chromosome 5 or 7 abnormalities, induction failure, and/or having persistent disease. The majority of patients received cyclophosphamide and total body irradiation conditioning, and graft-versus-host-disease (GVHD) prophylaxis was cyclosporine based. Transplantation outcomes for HR patients were compared to standard-risk patients, with no significant differences observed in overall survival (72% versus 78%, P = .72), leukemia-free survival (69% versus 79%, P = .62), relapse (11% versus 7%, P = .71), or treatment-related mortality (17% versus 14%, P = .89). Children and young adults with HR-AML have comparable outcomes to standard-risk patients following allo-HCT in CR1. Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  20. Evaluation of Low- Versus High-dose Valganciclovir for Prevention of Cytomegalovirus Disease in High-risk Renal Transplant Recipients.

    Science.gov (United States)

    Gabardi, Steven; Asipenko, Natalya; Fleming, James; Lor, Kevin; McDevitt-Potter, Lisa; Mohammed, Anisa; Rogers, Christin; Tichy, Eric M; Weng, Renee; Lee, Ruth-Ann

    2015-07-01

    Despite proven efficacy of prolonged cytomegalovirus (CMV) prophylaxis using valganciclovir 900 mg/day, some centers use 450 mg/day due to reported success and cost savings. This multicenter, retrospective study compared the efficacy and safety of 6 months of low-dose versus high-dose valganciclovir prophylaxis in high-risk, donor-positive/recipient-negative, renal transplant recipients (RTR). Two hundred thirty-seven high-risk RTR (low-dose group = valganciclovir 450 mg/day [n = 130]; high-dose group = valganciclovir 900 mg/day [n = s7]) were evaluated for 1-year CMV disease prevalence. Breakthrough CMV, resistant CMV, biopsy-proven acute rejection (BPAR), graft loss, opportunistic infections (OI), new-onset diabetes after transplantation (NODAT), premature valganciclovir discontinuation, renal function and myelosuppression were also assessed. Patient demographics and transplant characteristics were comparable. Induction and maintenance immunosuppression were similar, except for more early steroid withdrawal in the high-dose group. Similar proportions of patients developed CMV disease (14.6% vs 24.3%; P = 0.068); however, controlling CMV risk factor differences through multivariate logistic regression revealed significantly lower CMV disease in the low-dose group (P = 0.02; odds ratio, 0.432, 95% confidence interval, 0.211-0.887). Breakthrough and resistant CMV occurred at similar frequencies. There was no difference in renal function or rates of biopsy-proven acute rejection, graft loss, opportunistic infections, or new-onset diabetes after transplantation. The high-dose group had significantly lower mean white blood cell counts at months 5 and 6; however, premature valganciclovir discontinuation rates were similar. Low-dose and high-dose valganciclovir regimens provide similar efficacy in preventing CMV disease in high-risk RTR, with a reduced incidence of leukopenia associated with the low-dose regimen and no difference in resistant CMV. Low-dose valganciclovir

  1. Cerebrospinal Fluid Proteome of Patients with Acute Lyme Disease

    Energy Technology Data Exchange (ETDEWEB)

    Angel, Thomas E.; Jacobs, Jon M.; Smith, Robert P.; Pasternack, Mark S.; Elias, Susan; Gritsenko, Marina A.; Shukla, Anil K.; Gilmore, Edward C.; McCarthy, Carol; Camp, David G.; Smith, Richard D.

    2012-10-05

    Acute Lyme disease results from transmission of and infection by the bacterium Borrelia burgdorferi following a tick bite. During acute infection, bacteria can disseminate to the central nervous system (CNS) leading to the development of Lyme meningitis. Here we have analyzed pooled cerebrospinal fluid (CSF) allowing for a deep view into the proteome for a cohort of patients with early-disseminated Lyme disease and CSF inflammation leading to the identification of proteins that reflect host responses, which are distinct for subjects with acute Lyme disease. Additionally, we analyzed individual patient samples and quantified changes in protein abundance employing label-free quantitative mass spectrometry based methods. The measured changes in protein abundances reflect the impact of acute Lyme disease on the CNS as presented in CSF. We have identified 89 proteins that differ significantly in abundance in patients with acute Lyme disease. A number of the differentially abundant proteins have been found to be localized to brain synapse and thus constitute important leads for better understanding of the neurological consequence of disseminated Lyme disease.

  2. Humanized mouse models: Application to human diseases.

    Science.gov (United States)

    Ito, Ryoji; Takahashi, Takeshi; Ito, Mamoru

    2018-05-01

    Humanized mice are superior to rodents for preclinical evaluation of the efficacy and safety of drug candidates using human cells or tissues. During the past decade, humanized mouse technology has been greatly advanced by the establishment of novel platforms of genetically modified immunodeficient mice. Several human diseases can be recapitulated using humanized mice due to the improved engraftment and differentiation capacity of human cells or tissues. In this review, we discuss current advanced humanized mouse models that recapitulate human diseases including cancer, allergy, and graft-versus-host disease. © 2017 Wiley Periodicals, Inc.

  3. Epstein-Barr Virus-positive T-cell Lymphoproliferative Disease Following Umbilical Cord Blood Transplantation for Acute Myeloid Leukemia.

    Science.gov (United States)

    Yui, Shunsuke; Yamaguchi, Hiroki; Imadome, Ken-ichi; Arai, Ayako; Takahashi, Mikiko; Ohashi, Ryuji; Tamai, Hayato; Moriya, Keiichi; Nakayama, Kazutaka; Shimizu, Akira; Inokuchi, Koiti

    2016-01-01

    We report a case of the extremely rare condition Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease (LPD) which occurred after umbilical cord blood transplantation. A 25-year-old Japanese man underwent cord blood transplantation from a male human leukocyte antigen 4/6-matched donor due to acute myeloid leukemia with trisomy 8. Bone marrow examination on day 30 showed chimerism with at least 90% donor cells and complete hematological response. Chronic symptoms of graft-versus-host disease appeared only on the skin and were successfully treated with cyclosporine alone. Three years later, however, the patient experienced repeated cold-like symptoms and was hospitalized with liver dysfunction. A high fever developed and was followed by significant edema of the right side of the face. The EBV DNA copy number in whole peripheral blood was 2×10(4)/mL. Liver biopsy showed invasion of EBV-infected CD8-positive T cells. Southern blotting analysis of the whole peripheral blood showed that the T-cell receptor Cβ1 rearrangement was positive. On the basis of these results, EBV-positive T-cell LPD was diagnosed and treated with prednisolone, cyclosporine, and etoposide, followed by cyclophosphamide, doxorubicin, vincristine, and prednisone. However, the patient died of cardiac function failure, pneumonia, and pulmonary hemorrhage, all of unidentified cause. Most cases of EBV-related LPD after hematopoietic stem cell transplantation consist of EBV-positive B-cell LPD, and, to our knowledge, de novo EBV-positive T-cell LPD subsequent to transplantation has not been previously reported.

  4. Descemet Stripping Automated Endothelial Keratoplasty for Failed Penetrating Keratoplasty: Influence of the Graft-Host Junction on the Graft Survival Rate.

    Science.gov (United States)

    Omoto, Takashi; Sakisaka, Toshihiro; Toyono, Tetsuya; Yoshida, Junko; Shirakawa, Rika; Miyai, Takashi; Yamagami, Satoru; Usui, Tomohiko

    2018-04-01

    To investigate the clinical results of Descemet stripping automated endothelial keratoplasty (DSAEK) for failed penetrating keratoplasty (PK) and the influence of the graft-host junction (GHJ) on the graft survival rate. Data were retrospectively collected on patient demographics, visual outcomes, complications, and graft survival rate for 17 eyes of 16 patients who underwent DSAEK for failed PK. The graft survival rate was compared between the eyes when divided into a bump group and a well-aligned group according to the shape of the GHJ detected on anterior segment optical coherence tomography. The most common indication for initial PK was bullous keratopathy after glaucoma surgery (35.3%). Seven eyes (41.2%) were classified into the bump group and 10 eyes (58.8%) into the well-aligned group. The mean best-ever documented visual acuity (BDVA) after DSAEK was 0.33 logMAR. Postoperatively, almost 70% of eyes achieved a BDVA that was within 0.2 logMAR of their preoperative BDVA. Graft detachment occurred in 29.4% of eyes and primary graft failure in 17.6%. All primary failures occurred in the bump group. The cumulative graft survival rate was 82.3% at 1 year, 73.2% at 2 years, and 58.6% at 3 years. Graft failure was more likely in eyes in the bump group than in those in the well-aligned group (P = 0.037, Wilcoxon test). DSAEK for failed PK had a favorable outcome in this study. However, the GHJ should be assessed carefully before performing the procedure.

  5. Bone marrow transplantation (1958-1978): conditioning and graft-versus-host disease, indications in aplasias and leukemias

    International Nuclear Information System (INIS)

    Mathe, G.; Schwarzenberg, L.

    1979-01-01

    Bone marrow transplantation (BMT), which stimulated great hope for treatment of aplasias and leukemias in 1958 following our first success in grafting this tissue, is, after a long period of study and development, experiencing renewed interest since it is now possible to obtain, in case of transplantation with genotypically matched sibling donors, 70% long survival (cures) in aplasia (under the condition that the recipient is not sensitized by previous transfusions) and in leukemia (under the condition that the recipient is transplanted in a period of remission and is not sensitized by transfusions). When the patient does not possess any genotypically matched donor, a trial of incompatible bone marrow transplantation after conditioning with antilymphocyte serum is reasonable, since we have obtained good, although unexplained, results with this method, which should be pursued. In any case, these transplants must be done in intensive care units in hemato-oncology departments

  6. Bone marrow transplantation (1958-1978): conditioning and graft-versus-host disease, indications in aplasias and leukemias

    Energy Technology Data Exchange (ETDEWEB)

    Mathe, G; Schwarzenberg, L [Hopital Paul Brousse, 94 - Villejuif (France)

    1979-06-01

    Bone marrow transplantation (BMT), which stimulated great hope for treatment of aplasias and leukemias in 1958 following our first success in grafting this tissue, is, after a long period of study and development, experiencing renewed interest since it is now possible to obtain, in case of transplantation with genotypically matched sibling donors, 70% long survival (cures) in aplasia (under the condition that the recipient is not sensitized by previous transfusions) and in leukemia (under the condition that the recipient is transplanted in a period of remission and is not sensitized by transfusions). When the patient does not possess any genotypically matched donor, a trial of incompatible bone marrow transplantation after conditioning with antilymphocyte serum is reasonable, since we have obtained good, although unexplained, results with this method, which should be pursued. In any case, these transplants must be done in intensive care units in hemato-oncology departments.

  7. PTFE grafts versus tunneled cuffed catheters for hemodialysis: which is the second choice when arteriovenous fistula is not feasible?

    Science.gov (United States)

    Donati, Gabriele; Cianciolo, Giuseppe; Mauro, Raffaella; Rucci, Paola; Scrivo, Anna; Marchetti, Antonio; Giampalma, Emanuela; Golfieri, Rita; Panicali, Laura; Iorio, Mario; Stella, Andrea; La Manna, Gaetano; Stefoni, Sergio

    2015-02-01

    Vascular access-related complications are still one of the leading causes of morbidity in hemodialysis patients. The aim of this study was to compare polytetrafluoroethylene (PTFE) grafts versus tunneled cuffed permanent catheters (TCCs) in terms of vascular access and patients' survival. An observational study was carried out with a 2-year follow-up. Eighty-seven chronic hemodialysis patients were enrolled: 31 with a PTFE graft as vascular access for hemodialysis versus 56 with a TCC. Patients' mean age was 63.8 ± 14.6 (grafts) versus 73.5 ± 11.3 years (TCCs), P = 0.001. Significantly more patients with TCC had atrial fibrillation than patients with grafts (30.3% versus 6.5%, P = 0.01). In an unadjusted Kaplan-Meier analysis, median TCC survival at 24 months was 5.4 months longer than that of PTFE grafts but not significantly (log-rank test = 1.3, P = ns). In a Cox regression analysis adjusted for age, gender, number of previous vascular accesses, diabetes, atrial fibrillation, smoking, and any complication, this lack of significant difference in survival of the vascular access between TCC and PTFE groups was confirmed and diabetes proved to be an independent risk factor for the survival of both vascular accesses considered (P = 0.02). In an unadjusted Kaplan-Meier analysis, a higher mortality was found in the TCC group than in the PTFE group at 24 months (log-rank test = 10.07, P PTFE grafts. When an arteriovenous fistula (AVF) is not possible, PTFE grafts can be considered the vascular access of second choice, whereas TCCs can be used when an AVF or PTFE graft are not feasible or as a bridge to AVF or PTFE graft creation. Copyright © 2014 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

  8. Characterization of host lymphoid cells in antibody-facilitated bone marrow chimeras

    International Nuclear Information System (INIS)

    McCarthy, S.A.; Griffith, I.J.; Gambel, P.; Francescutti, L.H.; Wegmann, T.G.

    1985-01-01

    The authors have produced stable murine antibody-facilitated (AF) chimeras by the simultaneous injection of P1 bone marrow cells and anti-P2 monoclonal antibody into normal (unirradiated) adult (P1 X P2)F1 recipients. These AF chimeras are healthy, long-lived, and exhibit no overt signs of graft-versus-host disease. They are immunocompetent and tolerant of host, P2-encoded alloantigens. Donor cell engraftment and takeover, monitored by glucosephosphate isomerase isozyme patterns, is usually complete (greater than 95%) in the peripheral blood, bone marrow, and hemopoietic stem cell compartments of long-term (greater than 3 months posttransplantation) AF chimeras. The authors report here, however, that splenic, lymph node, and thymic leukocytes of AF chimeras represent donor/host chimeric populations. Spleen cell populations of AF chimeras exhibit substantial chimera-to-chimera variation in the preponderant residual host cell type(s) present. Interpretations of the implications of these findings are discussed

  9. Outcome of allogeneic hematopoietic stem cell transplantation for childhood acute lymphoblastic leukemia in second complete remission: a single institution study

    Directory of Open Access Journals (Sweden)

    Eun-Jung Lee

    2012-03-01

    Full Text Available Purpose : The survival rate for childhood acute lymphoblastic leukemia (ALL has improved significantly. However, overall prognosis for the 20 to 25% of patients who relapse is poor, and allogeneic hematopoietic stem cell transplantation (HSCT offers the best chance for cure. In this study, we identified significant prognostic variables by analyzing the outcomes of allogeneic HSCT in ALL patients in second complete remission (CR. Methods : Fifty-three ALL patients (42 men, 79% who received HSCT in second CR from August 1991 to February 2009 were included (26 sibling donor HSCTs, 49%; 42 bone marrow transplantations, 79%. Study endpoints included cumulative incidence of acute and chronic graft-versus-host disease (GVHD, relapse, 1-year transplant-related mortality (TRM, disease-free survival (DFS, and overall survival (OS. Results : Cumulative incidences of acute GVHD (grade 2 or above and chronic GVHD were 45.3% and 28.5%, respectively. The estimated 5-year DFS and OS for the cohort was 45.2¡?#?.8%; and 48.3¡?#?%,; respectively. Only donor type, i.e., sibling versus unrelated, showed significant correlation with DFS in multivariate analysis (P=0.010. The rates of relapse and 1 year TRM were 28.9¡?#?.4%; and 26.4¡?#?.1%;, respectively, and unrelated donor HSCT (P=0.002 and HLA mismatch (P =0.022 were significantly correlated with increased TRM in univariate analysis. Conclusion : In this single institution study spanning more than 17 years, sibling donor HSCT was the only factor predicting a favorable result in multivariate analysis, possibly due to increased TRM resulting from unrelated donor HSCT.

  10. Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation

    DEFF Research Database (Denmark)

    Storb, Rainer; Gyurkocza, Boglarka; Storer, Barry E

    2013-01-01

    We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the pures...

  11. Clostridium difficile infection in Chilean patients submitted to hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Javier Pilcante

    2015-12-01

    -value = 0.71. In the allogeneic transplant group, the median time to acute graft-versus- host disease was similar between the two groups (p-value = 0.08, as was the incidence of grades 1-4 acute graft-versus-host disease (40% vs. 48%; p-value >0.05. Conclusion: The incidence of C. difficile infection after hematopoietic stem cell transplantation was low, with a significant number of cases occurring shortly after transplantation. Allogeneic transplants had a three-time higher risk of infection compared to autologous transplants, but this was not associated with increased mortality, decreased overall survival or higher risk of acute graft-versus-host disease.

  12. Mechanism of donor to host tolerance in rat bone marrow chimeras

    International Nuclear Information System (INIS)

    Tutschka, P.; Schwerdtfeger, R.; Slavin, R.; Santos, G.

    1977-01-01

    Lewis rats were conditioned with cyclophosphamide and grafted with AgB incompatible bone marrow. They were examined 250 days after transplantation and demonstrated to be healthy complete chimeras. Marrow cells from these chimeras were infused into lethally irradiated ACI, Lewis and BN recipients. Graft-versus-host disease occurred only in the BN rats. Other chimeric rats were given no treatment, busulfan, CY, or total body irradiation prior to the infusion of normal ACI BM. GvHD occurred only in animals given CY or TBI. Normal Lewis rats were conditioned with TBI and given ACI BM. In addition, they received whole blood, irradiated blood, or serum from chimeric rats. GvHD developed in all animals except those given unirradiated chimeric blood. These studies suggest that suppressor cell populations, sensitive to immunosuppression, are likely the fundamental mechanism of recovery from GvHD

  13. Unrelated hematopoietic stem cell transplantation in the pediatric population: single institution experience

    Directory of Open Access Journals (Sweden)

    Daniela Hespanha Marinho

    2015-08-01

    Full Text Available OBJECTIVE: Hematopoietic stem cell transplantation has been successfully used to treat the pediatric population with malignant and non-malignant hematological diseases. This paper reports the results up to 180 days after the procedure of all unrelated hematopoietic stem cell transplantations in pediatric patients that were performed in one institution.METHODS: A retrospective review was performed of all under 18-year-old patients who received unrelated transplantations between 1995 and 2009. Data were analyzed using the log-rank test, Cox stepwise model, Kaplan-Meier method, Fine and Gray model and Fisher's exact test.RESULTS: This study included 118 patients (46.8% who received bone marrow and 134 (53.2% who received umbilical cord blood transplants. Engraftment occurred in 89.47% of the patients that received bone marrow and 65.83% of those that received umbilical cord blood (p-value < 0.001. Both neutrophil and platelet engraftments were faster in the bone marrow group. Acute graft-versus-host disease occurred in 48.6% of the patients without statistically significant differences between the two groups (p-value = 0.653. Chronic graft-versus-host disease occurred in 9.2% of the patients with a higher incidence in the bone marrow group (p-value = 0.007. Relapse occurred in 24% of the 96 patients with malignant disease with 2-year cumulative incidences of 45% in the bone marrow group and 25% in the umbilical cord blood group (p-value = 0.117. Five-year overall survival was 47%, with an average survival time of 1207 days, and no significant differences between the groups (p-value = 0.4666.CONCLUSION: Despite delayed engraftment in the umbilical cord blood group, graft-versus-host disease, relapse and survival were similar in both groups.

  14. Combined cord blood and bone marrow transplantation from the same human leucocyte antigen-identical sibling donor for children with malignant and non-malignant diseases.

    Science.gov (United States)

    Tucunduva, Luciana; Volt, Fernanda; Cunha, Renato; Locatelli, Franco; Zecca, Marco; Yesilipek, Akif; Caniglia, Maurizio; Güngör, Tayfun; Aksoylar, Serap; Fagioli, Franca; Bertrand, Yves; Addari, Maria Carmen; de la Fuente, Josu; Winiarski, Jacek; Biondi, Andrea; Sengeloev, Henrik; Badell, Isabel; Mellgren, Karin; de Heredia, Cristina Díaz; Sedlacek, Petr; Vora, Ajay; Rocha, Vanderson; Ruggeri, Annalisa; Gluckman, Eliane

    2015-04-01

    Umbilical cord blood (UCB) from an human leucocyte antigen (HLA)-identical sibling can be used for transplantation of patients with malignant and non-malignant diseases. However, the low cellular content of most UCB units represents a limitation to this approach. An option to increase cell dose is to harvest bone marrow (BM) cells from the same donor and infuse them along with the UCB. We studied 156 children who received such a combined graft between 1992 and 2011. Median age was 7 years and 78% of patients (n = 122) were transplanted for non-malignant diseases, mainly haemoglobinopathies. Acute leukaemia (n = 26) was the most frequent malignant diagnosis. Most patients (91%) received myeloablative conditioning. Median donor age was 1·7 years, median infused nucleated cell dose was 24·4 × 10(7) /kg and median follow-up was 41 months. Sixty-days neutrophil recovery occurred in 96% of patients at a median of 17 d. The probabilities of grade-II-IV acute and chronic graft-versus-host disease (GVHD) were 19% and 10%, respectively. Four-year overall survival was 90% (68% malignant; 97% non-malignant diseases) with 3% probability of death. In conclusion, combined UCB and BM transplantation from an HLA-identical sibling donor is an effective treatment for children with malignant and non-malignant disorders with high overall survival and low incidence of GVHD. © 2014 John Wiley & Sons Ltd.

  15. Effects of total body irradiation-based conditioning allogenic sem cell transplantation for pediatric acute leukemia: A single-institution study

    International Nuclear Information System (INIS)

    Park, Jong Moo; Choi, Eun Kyung; Kim, Jong Hoon

    2014-01-01

    To evaluate the effects of total body irradiation (TBI), as a conditioning regimen prior to allogeneic stem cell transplantation (allo-SCT), in pediatric acute leukemia patients. From January 2001 to December 2011, 28 patients, aged less than 18 years, were treated with TBI-based conditioning for allo-SCT in our institution. Of the 28 patients, 21 patients were diagnosed with acute lymphoblastic leukemia (ALL, 75%) and 7 were diagnosed with acute myeloid leukemia (AML, 25%). TBI was completed 4 days or 1 day before stem cell infusion. Patients underwent radiation therapy with bilateral parallel opposing fields and 6-MV X-rays. The Kaplan-Meier method was used to calculate survival outcomes. The 2-year event-free survival and overall survival rates were 66% and 56%, respectively (71.4% and 60.0% in AML patients vs. 64.3% and 52.4% in ALL patients, respectively). Treatment related mortality rate were 25%. Acute and chronic graft-versus-host disease was a major complication; other complications included endocrine dysfunction and pulmonary complications. Common complications from TBI were nausea (89%) and cataracts (7.1%). The efficacy and toxicity data in this study of TBI-based conditioning to pediatric acute leukemia patients were comparable with previous studies. However, clinicians need to focus on the acute and chronic complications related to allo-SCT.

  16. Effects of total body irradiation-based conditioning allogenic sem cell transplantation for pediatric acute leukemia: A single-institution study

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jong Moo; Choi, Eun Kyung; Kim, Jong Hoon [Dept.of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); and others

    2014-09-15

    To evaluate the effects of total body irradiation (TBI), as a conditioning regimen prior to allogeneic stem cell transplantation (allo-SCT), in pediatric acute leukemia patients. From January 2001 to December 2011, 28 patients, aged less than 18 years, were treated with TBI-based conditioning for allo-SCT in our institution. Of the 28 patients, 21 patients were diagnosed with acute lymphoblastic leukemia (ALL, 75%) and 7 were diagnosed with acute myeloid leukemia (AML, 25%). TBI was completed 4 days or 1 day before stem cell infusion. Patients underwent radiation therapy with bilateral parallel opposing fields and 6-MV X-rays. The Kaplan-Meier method was used to calculate survival outcomes. The 2-year event-free survival and overall survival rates were 66% and 56%, respectively (71.4% and 60.0% in AML patients vs. 64.3% and 52.4% in ALL patients, respectively). Treatment related mortality rate were 25%. Acute and chronic graft-versus-host disease was a major complication; other complications included endocrine dysfunction and pulmonary complications. Common complications from TBI were nausea (89%) and cataracts (7.1%). The efficacy and toxicity data in this study of TBI-based conditioning to pediatric acute leukemia patients were comparable with previous studies. However, clinicians need to focus on the acute and chronic complications related to allo-SCT.

  17. Low Body Mass Index Is Associated with Increased Risk of Acute GVHD after Umbilical Cord Blood Transplantation in Children and Young Adults with Acute Leukemia: A Study on Behalf of Eurocord and the EBMT Pediatric Disease Working Party.

    Science.gov (United States)

    Paviglianiti, Annalisa; Dalle, Jean Hugues; Ayas, Mouhab; Boelens, Jan Jaap; Volt, Fernanda; Iori, Anna Paola; de Souza, Mair Pedro; Diaz, Miguel Angel; Michel, Gerard; Locatelli, Franco; Jubert, Charlotte; Yakoub-Agha, Ibrahim; Bittencourt, Henrique; Bertrand, Yves; Kenzey, Chantal; Tozatto Maio, Karina; Hayashi, Hiromi; Rocha, Vanderson; Bader, Peter; Gluckman, Eliane; Ruggeri, Annalisa

    2018-04-01

    Body mass index (BMI) may influence outcomes after allogeneic hematopoietic stem cell transplantation (HSCT). However, the impact of BMI on survival in children undergoing HSCT is not well defined, with conflicting results being reported on this issue. We analyzed 855 patients age 2 to 20 years with diagnosis of acute leukemia who underwent umbilical cord blood transplantation (UCBT) from 1990 to 2015. Patients were classified according to BMI as normal (fifth to 85th percentile), underweight (less than fifth percentile), overweight (85th to 95th percentile), and obese (>95th percentile) using growth charts for age and sex. All patients received single-unit UCBT after a myeloablative conditioning regimen. Diagnosis was acute lymphoblastic leukemia in 68% of the patients. Sixty-one percent of patients (n = 523) were in the normal BMI category, 11% (n = 96) were underweight, 16% (n = 137) overweight, and 12% (n = 99) obese. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was 35% (32% to 38%). According to pretransplantation BMI, aGVHD was 46% (33% to 59%) for underweight, 34% (31% to 42%) for normal, 36% (18% to 38%) for overweight, and 27% (15% to 37%) for obese (P = .04). In multivariate analysis, a BMI less than the fifth percentile was associated with higher incidence of acute grade II to IV GVHD compared with normal-BMI patients (hazard ratio,  1.61; 95% confidence interval, 1.15 to 2.26; P = .006). Our results show that being underweight at the time of transplantation is associated with an increased risk of aGVHD, highlighting the importance of nutritional status before UCBT. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  18. Towards effective and safe immunotherapy after allogeneic stem cell transplantation: identification of hematopoietic-specific minor histocompatibility antigen UTA2-1

    NARCIS (Netherlands)

    Oostvogels, R.; Minnema, M. C.; van Elk, M.; Spaapen, R. M.; te Raa, G. D.; Giovannone, B.; Buijs, A.; van Baarle, D.; Kater, A. P.; Griffioen, M.; Spierings, E.; Lokhorst, H. M.; Mutis, T.

    2013-01-01

    Donor T cells directed at hematopoietic system-specific minor histoconnpatibility antigens (mHags) are considered important cellular tools to induce therapeutic graft-versus-tumor (GvT) effects with low risk of graft-versus-host disease after allogeneic stem cell transplantation. To enable the

  19. Obesity in pediatric kidney transplant recipients and the risks of acute rejection, graft loss and death.

    Science.gov (United States)

    Ladhani, Maleeka; Lade, Samantha; Alexander, Stephen I; Baur, Louise A; Clayton, Philip A; McDonald, Stephen; Craig, Jonathan C; Wong, Germaine

    2017-08-01

    Obesity is prevalent in children with chronic kidney disease (CKD), but the health consequences of this combination of comorbidities are uncertain. The aim of this study was to evaluate the impact of obesity on the outcomes of children following kidney transplantation. Using data from the ANZDATA Registry (1994-2013), we assessed the association between age-appropriate body mass index (BMI) at the time of transplantation and the subsequent development of acute rejection (within the first 6 months), graft loss and death using adjusted Cox proportional hazards models. Included in our analysis were 750 children ranging in age from 2 to 18 (median age 12) years with a total of 6597 person-years of follow-up (median follow-up 8.4 years). Overall, at transplantation 129 (17.2%) children were classified as being overweight and 61 (8.1%) as being obese. Of the 750 children, 102 (16.2%) experienced acute rejection within the first 6 months of transplantation, 235 (31.3%) lost their allograft and 53 (7.1%) died. Compared to children with normal BMI, the adjusted hazard ratios (HR) for graft loss in children who were underweight, overweight or diagnosed as obese were 1.05 [95% confidence interval (CI) 0.70-1.60], 1.03 (95% CI 0.71-1.49) and 1.61 (95% CI 1.05-2.47), respectively. There was no statistically significant association between BMI and acute rejection [underweight: HR 1.07, 95% CI 0.54-2.09; overweight: HR 1.42, 95% CI 0.86-2.34; obese: HR 1.83, 95% CI 0.95-3.51) or patient survival (underweight: HR 1.18, 95% CI 0.54-2.58, overweight: HR 0.85, 95% CI 0.38-1.92; obese: HR 0.80, 95% CI 0.25-2.61). Over 10 years of follow-up, pediatric transplant recipients diagnosed with obesity have a substantially increased risk of allograft failure but not acute rejection of the graft or death.

  20. Application of MultiStem® allogeneic cells for immunomodulatory therapy: clinical progress and pre-clinical challenges in prophylaxis for graft vs host disease

    Directory of Open Access Journals (Sweden)

    Bart eVaes

    2012-11-01

    Full Text Available The last decade has seen much progress in adjunctive cell therapy for immune disorders. Both corporate and institutional Phase III studies have been run using mesenchymal stromal cells (MSC for treatment of Graft vs Host Disease (GvHD, and product approval has been achieved for treatment of pediatric GvHD in Canada and New Zealand (Prochymal®; Osiris Therapeutics. This effectiveness has prompted the prophylactic use of adherent stem cells at the time of allogeneic hematopoietic stem cell transplantation (HSCT to prevent occurrence of GvHD and possibly provide stromal support for hematopoietic recovery. The MultiStem® product is an adult adherent stem cell product derived from bone marrow which has significant clinical exposure. MultiStem cells are currently in phase II clinical studies for treatment of ischemic stroke and ulcerative colitis, with Phase I studies completed in acute myocardial infarction and for GvHD prophylaxis in allogeneic HSCT, demonstrating that MultiStem administration was well tolerated while the incidence and severity of GvHD was reduced. In advancing this clinical approach, it is important to recognize that alternate models exist based on clinical manufacturing strategies. Corporate sponsors exploit the universal donor properties of adherent stem cells and manufacture at large scale, with many products obtained from one or limited donors and used across many patients. In Europe, institutional sponsors often produce allogeneic product in a patient designated context. For this approach, disposable bioreactors producing <10 products per donor in a closed system manner are very well suited. In this review, the use of adherent stem cells for GvHD prophylaxis is summarized and the suitability of disposable bioreactors for MultiStem production is presented, with an emphasis on quality control parameters, which are critical with a multiple donor approach for manufacturing.

  1. Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation in First Complete Remission Can Abrogate the Poor Outcomes of Children with Acute Myeloid Leukemia Resistant to the First Course of Induction Chemotherapy.

    Science.gov (United States)

    Mo, Xiao-Dong; Zhang, Xiao-Hui; Xu, Lan-Ping; Wang, Yu; Yan, Chen-Hua; Chen, Huan; Chen, Yu-Hong; Han, Wei; Wang, Feng-Rong; Wang, Jing-Zhi; Liu, Kai-Yan; Huang, Xiao-Jun

    2016-12-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is an important therapy option for children with acute myeloid leukemia (AML) resistant to the first course of induction chemotherapy (IC 1st ). We aimed to identify the efficacy of unmanipulated haploidentical HSCT (haplo-HSCT) in children with AML in the first complete remission and whether children resistant (IC 1st -resistant; n = 38) or sensitive (IC 1st -sensitive; n = 59) to the IC 1st can achieve comparable outcomes. The cumulative incidence of grades III to IV acute graft-versus-host disease (GVHD) and severe chronic GVHD was .0% versus 20.1% (P = .038) and 21.7% versus 13.2% (P = .238), respectively, for the IC 1st -resistant and IC 1st -sensitive groups. The 3-year cumulative incidence of relapse and nonrelapse mortality was 22.2% versus 7.6% (P = .061) and 5.3% versus 10.8% (P = .364), respectively, for the IC 1st -resistant and IC 1st -sensitive groups. The 3-year probability of overall survival and disease-free survival was 76.3% versus 83.0% (P = .657) and 72.5% versus 81.6% (P = .396), respectively, for the IC 1st -resistant and IC 1st -sensitive groups. Multivariate analysis failed to show significant differences in survival rates between the groups. Thus, our results show that unmanipulated haplo-HSCT may overcome the poor prognostic significance of IC 1st -resistance in children with AML, and it is valid as a postremission treatment for children with IC 1st -resistant AML lacking an HLA-matched donor. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  2. Probiotics: their role in the treatment and prevention of disease.

    Science.gov (United States)

    Doron, Shira; Gorbach, Sherwood L

    2006-04-01

    A probiotic is a "live microbial food ingredients that, when ingested in sufficient quantities, exerts health benefits on the consumer". Probiotics exert their benefits through several mechanisms; they prevent colonization, cellular adhesion and invasion by pathogenic organisms, they have direct antimicrobial activity and they modulate the host immune response. The strongest evidence for the clinical effectiveness of probiotics has been in their use for the prevention of symptoms of lactose intolerance, treatment of acute diarrhea, attenuation of antibiotic-associated gastrointestinal side effects and the prevention and treatment of allergy manifestations. More research needs to be carried out to clarify conflicting findings on the use of probiotics for prevention of travelers' diarrhea, infections in children in daycare and dental caries, and elimination of nasal colonization with potentially pathogenic bacteria. Promising ongoing research is being conducted on the use of probiotics for the treatment of Clostridium difficile colitis, treatment of Helicobacter pylori infection, treatment of inflammatory bowel disease and prevention of relapse, treatment of irritable bowel syndrome, treatment of intestinal inflammation in cystic fibrosis patients, and prevention of necrotizing enterocolitis in premature infants. Finally, areas of future research include the use of probiotics for the treatment of rheumatoid arthritis, prevention of cancer and the treatment of graft-versus-host disease in bone marrow transplant recipients.

  3. Degree of Predicted Minor Histocompatibility Antigen Mismatch Correlates with Poorer Clinical Outcomes of Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation

    DEFF Research Database (Denmark)

    Larsen, Malene Erup; Kornblit, B; Larsen, Mette Voldby

    2010-01-01

    In fully HLA-matched allogeneic hematopoietic cell transplantations (HCT), the main mechanism of the beneficial graft-versus-tumor (GVT) effect and of the detrimental graft-versus-host disease (GVHD) is believed to be caused by donor cytotoxic T cells directed against disparate recipient minor hi...

  4. Angiostrongylus spp. in the Americas: geographical and chronological distribution of definitive hosts versus disease reports.

    Science.gov (United States)

    Valente, Romina; Robles, Maria Del Rosario; Navone, Graciela T; Diaz, Julia I

    2018-03-01

    Angiostrongyliasis is an infection caused by nematode worms of the genus Angiostrongylus. The adult worms inhabit the pulmonary arteries, heart, bronchioles of the lung, or mesenteric arteries of the caecum of definitive host. Of a total of 23 species of Angiostrongylus cited worldwide, only nine were registered in the American Continent. Two species, A. cantonensis and A. costaricensis, are considered zoonoses when the larvae accidentally parasitise man. In the present study, geographical and chronological distribution of definitive hosts of Angiostrongylus in the Americas is analysed in order to observe their relationship with disease reports. Moreover, the role of different definitive hosts as sentinels and dispersers of infective stages is discussed. The study area includes the Americas. First records of Angiostrongylus spp. in definitive or accidental hosts were compiled from the literature. Data were included in tables and figures and were matched to geographic information systems (GIS). Most geographical records of Angiostrongylus spp. both for definitive and accidental hosts belong to tropical areas, mainly equatorial zone. In relation to those species of human health importance, as A. cantonensis and A. costaricensis, most disease cases indicate a coincidence between the finding of definitive host and disease record. However, in some geographic site there are gaps between report of definitive host and disease record. In many areas, human populations have invaded natural environments and their socioeconomic conditions do not allow adequate medical care. Consequently, many cases for angiostrongyliasis could have gone unreported or unrecognised throughout history and in the nowadays. Moreover, the population expansion and the climatic changes invite to make broader and more complete range of observation on the species that involve possible epidemiological risks. This paper integrates and shows the current distribution of Angiostrongylus species in America

  5. Angiostrongylus spp. in the Americas: geographical and chronological distribution of definitive hosts versus disease reports

    Science.gov (United States)

    Valente, Romina; Robles, Maria del Rosario; Navone, Graciela T; Diaz, Julia I

    2018-01-01

    BACKGROUND Angiostrongyliasis is an infection caused by nematode worms of the genus Angiostrongylus. The adult worms inhabit the pulmonary arteries, heart, bronchioles of the lung, or mesenteric arteries of the caecum of definitive host. Of a total of 23 species of Angiostrongylus cited worldwide, only nine were registered in the American Continent. Two species, A. cantonensis and A. costaricensis, are considered zoonoses when the larvae accidentally parasitise man. OBJECTIVES In the present study, geographical and chronological distribution of definitive hosts of Angiostrongylus in the Americas is analysed in order to observe their relationship with disease reports. Moreover, the role of different definitive hosts as sentinels and dispersers of infective stages is discussed. METHODS The study area includes the Americas. First records of Angiostrongylus spp. in definitive or accidental hosts were compiled from the literature. Data were included in tables and figures and were matched to geographic information systems (GIS). FINDINGS Most geographical records of Angiostrongylus spp. both for definitive and accidental hosts belong to tropical areas, mainly equatorial zone. In relation to those species of human health importance, as A. cantonensis and A. costaricensis, most disease cases indicate a coincidence between the finding of definitive host and disease record. However, in some geographic site there are gaps between report of definitive host and disease record. In many areas, human populations have invaded natural environments and their socioeconomic conditions do not allow adequate medical care. MAIN CONCLUSIONS Consequently, many cases for angiostrongyliasis could have gone unreported or unrecognised throughout history and in the nowadays. Moreover, the population expansion and the climatic changes invite to make broader and more complete range of observation on the species that involve possible epidemiological risks. This paper integrates and shows the

  6. Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion.

    Science.gov (United States)

    Locatelli, Franco; Merli, Pietro; Pagliara, Daria; Li Pira, Giuseppina; Falco, Michela; Pende, Daniela; Rondelli, Roberto; Lucarelli, Barbarella; Brescia, Letizia Pomponia; Masetti, Riccardo; Milano, Giuseppe Maria; Bertaina, Valentina; Algeri, Mattia; Pinto, Rita Maria; Strocchio, Luisa; Meazza, Raffaella; Grapulin, Lavinia; Handgretinger, Rupert; Moretta, Alessandro; Bertaina, Alice; Moretta, Lorenzo

    2017-08-03

    Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children with acute leukemia (AL) either relapsed or at high-risk of treatment failure. We developed a novel method of graft manipulation based on negative depletion of αβ T and B cells and conducted a prospective trial evaluating the outcome of children with AL transplanted with this approach. Eighty AL children, transplanted between September 2011 and September 2014, were enrolled in the trial. All children were given a fully myeloablative preparative regimen. Anti-T-lymphocyte globulin from day -5 to -3 was used for preventing graft rejection and graft-versus-host disease (GVHD); no patient received any posttransplantation GVHD prophylaxis. Two children experienced primary graft failure. The cumulative incidence of skin-only, grade 1-2 acute GVHD was 30%; no patient developed extensive chronic GVHD. Four patients died, the cumulative incidence of nonrelapse mortality being 5%, whereas 19 relapsed, resulting in a 24% cumulative incidence of relapse. With a median follow-up of 46 months for surviving patients, the 5-year probability of chronic GVHD-free, relapse-free survival (GRFS) is 71%. Total body irradiation-containing preparative regimen was the only variable favorably influencing relapse incidence and GRFS. The outcomes of these 80 patients are comparable to those of 41 and 51 children given transplantation from an HLA-identical sibling or a 10/10 allelic-matched unrelated donor in the same period. These data indicate that haplo-HSCT after αβ T- and B-cell depletion represents a competitive alternative for children with AL in need of urgent allograft. This trial was registered at www.clinicaltrials.gov as #NCT01810120. © 2017 by The American Society of Hematology.

  7. Recent progress of applying mesenchymal stem cells in therapy of urgent radiation damage

    International Nuclear Information System (INIS)

    Liu Jiangong; Guo Wanlong; Zhang Shuxian; Duan Zhikai

    2010-01-01

    At present, Cytokine therapy is the main strategy capable of preventing and reducing the acute radiation syndrome (ARS). With the problem of difficult match and severe graft versus host disease, haemopoietic stem cells can be used to find some effective approaches to treat acute radiation damage. Mesenchymal stem cells are of great therapeutic potential due to their particular characteristics including secretion of hematopoietic cytokine, reconstruction hemopoietic microenvironment, poor-immunogenicity, ease of reception ectogenic gene transfection and expression. This paper is to summarize the studies of biological characteristics of MSC and its application prospects in urgent radiation damage. (authors)

  8. Evaluation of early coronary graft patency after coronary artery bypass graft surgery using multislice computed tomography angiography

    Directory of Open Access Journals (Sweden)

    Raissi Kamal

    2009-12-01

    Full Text Available Abstract Background Coronary artery bypass graft (CABG surgery is the standard of care in the treatment of advanced coronary artery disease, and its long-term results are affected by the failure of bypass grafts. The aim of the present study was to evaluate the early patency rate in coronary bypass grafts. Methods A total of 107 consecutive patients who underwent CABG were included in this study. Early graft patency was evaluated via computed tomography (CT angiography in the first week after surgery. Results There were a total of 366 grafts, comprised of 250 venous grafts and 116 arterial grafts. Multi-slice CT detected acute graft occlusions in 32 (8.7% of all the grafts, including 26 (10% of the 250 venous grafts and 6 (5% of the 116 arterial grafts. The patency rates obtained were 97.3% for the left internal mammary (IMA grafts, 50% for the radial artery grafts, and 50% for the right IMA grafts. Additionally, 107 (96.4% grafts to the left anterior descending artery (LAD were classified as patent, whereas 1 (30% of the 3 grafts in the left circumflex (LCX region and 1 (50% of the 2 grafts in the right coronary artery (RCA territory were found to be occluded. In the venous category, 8 (13.7% of the 58 grafts to LAD were found to be occluded. In the LCX region, 9 (8.5% of the 106 grafts were classified as occluded, while the remaining 97 (91.5% grafts were patent. The venous grafts to RCA were occluded in 9 (10.4% of the 86 grafts. Amongst the multiple preoperative, intraoperative, and postoperative factors, pump time was significantly longer in the patients with occluded grafts than in those with patent grafts (P = 0.04. Conclusion The IMA grafts had the highest early patency rate amongst the coronary bypass grafts. However, the other arterial grafts were associated with a high rate of acute occlusions.

  9. Mannose-binding lectin deficiency and acute exacerbations of chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Woodruff PG

    2012-11-01

    Full Text Available Richard K Albert,1 John Connett,2 Jeffrey L Curtis,3,4 Fernando J Martinez,3 MeiLan K Han,3 Stephen C Lazarus,5 Prescott G Woodruff51Medicine Service, Denver Health and Department of Medicine, University of Colorado Denver, Denver, CO, 2Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, 3Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan, Ann Arbor, MI, 4Pulmonary and Critical Care Medicine, VA Medical Center, Ann Arbor, MI, 5Pulmonary and Critical Care Medicine, Department of Medicine, and Cardiovascular Research Institute, University of California, San Francisco, CA, USABackground: Mannose-binding lectin is a collectin involved in host defense against infection. Whether mannose-binding lectin deficiency is associated with acute exacerbations of chronic obstructive pulmonary disease is debated.Methods: Participants in a study designed to determine if azithromycin taken daily for one year decreased acute exacerbations had serum mannose-binding lectin concentrations measured at the time of enrollment.Results: Samples were obtained from 1037 subjects (91% in the trial. The prevalence of mannose-binding lectin deficiency ranged from 0.5% to 52.2%, depending on how deficiency was defined. No differences in the prevalence of deficiency were observed with respect to any demographic variable assessed, and no differences were observed in time to first exacerbation, rate of exacerbations, or percentage of subjects requiring hospitalization for exacerbations in those with deficiency versus those without, regardless of how deficiency was defined.Conclusion: In a large sample of subjects with chronic obstructive pulmonary disease selected for having an increased risk of experiencing an acute exacerbation of chronic obstructive pulmonary disease, only 1.9% had mannose-binding lectin concentrations below the normal range and we found no association between mannose-binding lectin

  10. Long-term outcomes of internal carotid artery disease treated using radial artery graft

    International Nuclear Information System (INIS)

    Murai, Yasuo; Teramoto, Akira; Mizunari, Takayuki; Kobayashi, Shiro; Umeoka, Katsuya; Tateyama, Kojiro

    2009-01-01

    Complex internal carotid artery disease presents a surgical challenge because limitations and difficulty are encountered with either clipping or endovascular treatment. Our review of previous reports suggests that no current vascular assessment can accurately predict occurrence of ischemic complications after internal carotid artery ligation. The present study concerns long-term clinical outcome of radial artery grafting followed by parent artery trapping or proximal occlusion for management of these difficult lesions. Between September 1997 and October 2007, we performed radial artery grafting followed immediately by parent artery occlusion in 20 sides of 19 patients with complex internal carotid arteries disease with follow-up for more than 36 months (5 men, 14 women; mean follow-up duration, 62 months). All patients underwent postoperative MRI and MR angiography (MRA) every year to assess graft patency, ischemic complications, and de novo aneurysm. Another 20 carotid aneurysms with visual disturbance were assessed concerning outcome. Among 13 patients with cranial nerve (III and VI) disturbances, all dysfunctions were improved in cases treated within 8 months of onset to operation. On the other hand, patients with second cranial nerve disturbances were not improved in cases treated after 4 months of onset. No long-term complications were discovered with MRI and MRA. With appropriate attention to surgical technique, radial artery grafting followed by acute parent artery occlusion is a safe treatment for complex internal carotid artery aneurysms. Long-term safety is satisfactory, with no delayed complications such as graft stenosis, ischemic complications or de novo aneurysm formations in follow-up periods of more than 3 years. Good clinical outcome of cranial nerve palsy was achieved in patients treated within 8 months of onset for cranial nerve (CN) III and VI, and 4 of CN II palsy. (author)

  11. Comparison of outcomes after unrelated cord blood and unmanipulated haploidentical stem cell transplantation in adults with acute leukemia

    DEFF Research Database (Denmark)

    Ruggeri, A; Labopin, M; Sanz, G

    2015-01-01

    outcomes after UCBT and Haplo in adults with de novo acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Median follow-up was 24 months. Analysis was performed separately for patients with AML, n=918 (Haplo=360, UCBT=558) and ALL, n=528 (Haplo=158 and UCBT=370). UCBT was associated......Outcomes after unmanipulated haploidentical stem cell transplantation (Haplo) and after unrelated cord blood transplantation (UCBT) are encouraging and have become alternative options to treat patients with high-risk acute leukemia without human leukocyte antigen (HLA) matched donor. We compared...... with delayed engraftment and higher graft failure in both AML and ALL recipients. In multivariate analysis, UCBT was associated with lower incidence of chronic graft-vs-host disease both in the AML group (hazard ratio (HR)=0.63, P=0.008) and in the ALL group (HR=0.58, P=0.01). Not statistically significant...

  12. Disease-specific hematopoietic stem cell transplantation in children with inherited bone marrow failure syndromes.

    Science.gov (United States)

    Li, Qian; Luo, Changying; Luo, Chengjuan; Wang, Jianmin; Li, Benshang; Ding, Lixia; Chen, Jing

    2017-08-01

    Hematopoietic stem cell transplantation (HSCT) using an optimized conditioning regimen is essential for the long-term survival of patients with inherited bone marrow failure syndromes (IBMFS). We report HSCT in 24 children with Fanconi anemia (FA, n = 12), Diamond-Blackfan anemia (DBA, n = 7), and dyskeratosis congenita (DC, n = 5) from a single HSCT center. The graft source was peripheral blood stem cells (n = 19) or cord blood stem cells (n = 5). FA and DC patients received reduced-intensity conditioning, while DBA patients had myeloablative conditioning. The median numbers of infused mononuclear cells and CD34+ cells were 14.20 × 10 8 /kg and 4.3 × 10 6 /kg, respectively. The median time for neutrophil and platelet recovery was 12 and 18 days, respectively. Complete donor engraftment was achieved in 23 of 24 patients. There was one primary graft failure. During a median follow-up of 27.5 months (range, 2-130 months), the overall survival in all patients was 95.8%. The incidence of grade II-III acute graft versus host disease (GvHD) and chronic GvHD was 29.2% and 16.7%, respectively. We conclude that HSCT can be a curative option for patients with IBMFS. Modification of the conditioning regimen based on the type of disease may lead to encouraging long-term outcomes.

  13. Immune competence of splenic lymphocytes following graft-vs-host disease in mouse allogeneic radiation chimeras

    International Nuclear Information System (INIS)

    Urso, P.; Gengozian, N.

    1977-01-01

    The abnormal immune response of long-term mouse allogeneic chimeras is reflected by qualitative deficiencies in either T or B lymphocytes. The present study was undertaken to determine if a relationship existed between the severity of graft-vs-host disease (GVHD) that these animals had experienced and a functional defect in either the T or B cell population. The in vitro PFC response of chimera spleen cells to sheep red blood cells (SRBC) was evaluated in the presence of normal T or B lymphocytes 4 to 8 months after marrow transplantation and well beyond the GVHD period. In an analysis of several different allogeneic radiation chimeras, our results showed no relationship between the severity of GVHD experienced and the immunologic capacity of either T or B cells. Thus, different chimera combinations showing similar degrees of GVHD were functionally deficient in one or the other of these two cells types or both with no apparent predilection for abnormality in either population. In examining the quantitative in vitro PFC response to sheep RBC by spleen cells from individual chimeras, we found that the number of PFC formed was related to the severity of GVHD experienced by that animal. A general relationship between severity of GVHD and PFC capacity may also exist between chimeras of different genetic combinations. However, this relationship is not precise since gross exceptions occur. Our results, although documenting further the qualitative abnormalities in T and/or B lymphocytes of radiation chimeras, do not reveal the factor or mechanisms by which these cells are made unresponsive. It is suggested that the tolerance-inducing mechanism of these animals, whether it be humoral blocking factors or suppressor cells, is in some way interfering with the collaboration of T and B cells for antibody production

  14. Successful generation of primary virus-specific and anti-tumor T-cell responses from the naive donor T-cell repertoire is determined by the balance between antigen-specific precursor T cells and regulatory T cells.

    NARCIS (Netherlands)

    Jedema, I.; Meent, M. van de; Pots, J.M.; Kester, M.G.; Beek, M.T. van der; Falkenburg, J.H.F.

    2011-01-01

    BACKGROUND: One of the major challenges in allogeneic stem cell transplantation is to find a balance between the harmful induction of graft-versus-host disease and the beneficial graft-versus-leukemia and pathogen-specific immune responses. Adoptive transfer of in-vitro generated donor T cells with

  15. Arterial grafts balance survival between incomplete and complete revascularization: a series of 1000 consecutive coronary artery bypass graft patients with 98% arterial grafts.

    Science.gov (United States)

    Kieser, Teresa M; Curran, Helen J; Rose, M Sarah; Norris, Colleen M; Graham, Michelle M

    2014-01-01

    Coronary artery bypass grafting (CABG) with incomplete revascularization (ICR) is thought to decrease survival. We studied the survival of patients with ICR undergoing total arterial grafting. In a consecutive series of all-comer 1000 patients with isolated CABG, operative and midterm survival were assessed for patients undergoing complete versus ICR, with odds ratios and hazard ratios, adjusted for European System for Cardiac Operative Risk Evaluation category, CABG urgency, age, and comorbidities. In this series of 1000 patients with 98% arterial grafts (2922 arterial, 59 vein grafts), 73% of patients with multivessel disease received bilateral internal mammary artery grafts. ICR occurred in 140 patients (14%). Operative mortality was 3.8% overall, 8.6% for patients with ICR, and 3.2% for patients with complete revascularization (P = .008). For operative mortality using multivariable logistic regression, after controlling for European System for Cardiac Operative Risk Evaluation category (P System for Cardiac Operative Risk Evaluation category (P reserved.

  16. Maintenance of host leukocytes in peripheral immune compartments following lethal irradiation and bone marrow reconstitution: implications for graft versus host disease.

    Science.gov (United States)

    Staley, Elizabeth M; Tanner, Scott M; Daft, Joseph G; Stanus, Andrea L; Martin, Steven M; Lorenz, Robin G

    2013-03-01

    Bone marrow reconstitution is utilized as a tool for disease treatment and as a research technique to elucidate the function of bone marrow derived cells. Clinically successful engraftment is indicated by the development of a functioning immune repertoire. In research, reconstitution is considered successful if >85% of splenic leukocytes are of donor origins. Previous work suggests that splenic reconstitution may not be indicative of reconstitution in the mucosa. We sought to evaluate mucosal reconstitution in animals following a standard bone marrow eradication and reconstitution technique. Bone marrow was harvested from adult B6.SJL donor mice (CD45.1) and injected via either the retro-orbital or intraperitoneal route into lethally irradiated B6 (CD45.2) adult or neonatal recipients respectively. The expression of CD45 by flow cytometry was used to calculate reconstitution with respect to immune compartment and cell type. In reconstituted adult animals 93.2±1.5% of splenic leukocytes expressed the donor CD45.1 antigen thus meeting the standard definition of reconstitution, however only 58.6±13.6% of intestinal lamina propria lymphocytes and 52.4±16.0% of intestinal intraepithelial lymphocytes were of donor origin, confirming splenic reconstitution fails to represent peripheral immune reconstitution. T-cells in the gastrointestinal tract are the most poorly reconstituted, while B-cells appear to be almost universally replaced by donor cells. The inadequate mucosal reconstitution was not corrected by evaluating later time points or by performing the bone marrow transfer during the neonatal period. This demonstration that substantial host T-cells remain in the intestinal mucosa after a "successful" bone marrow transplantation should cause a re-evaluation of data from research bone marrow chimera experiments, as well as the mechanisms for complications after clinical bone marrow transplantation. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Grafting of a Single Donor Myofibre Promotes Hypertrophy in Dystrophic Mouse Muscle

    Science.gov (United States)

    Boldrin, Luisa; Morgan, Jennifer E.

    2013-01-01

    Skeletal muscle has a remarkable capability of regeneration following injury. Satellite cells, the principal muscle stem cells, are responsible for this process. However, this regenerative capacity is reduced in muscular dystrophies or in old age: in both these situations, there is a net loss of muscle fibres. Promoting skeletal muscle muscle hypertrophy could therefore have potential applications for treating muscular dystrophies or sarcopenia. Here, we observed that muscles of dystrophic mdx nude host mice that had been acutely injured by myotoxin and grafted with a single myofibre derived from a normal donor mouse exhibited increased muscle area. Transplantation experiments revealed that the hypertrophic effect is mediated by the grafted fibre and does not require either an imposed injury to the host muscle, or the contribution of donor cells to the host muscle. These results suggest the presence of a crucial cross-talk between the donor fibre and the host muscle environment. PMID:23349935

  18. Biomaterials and host versus graft response: A short review

    Science.gov (United States)

    Velnar, Tomaz; Bunc, Gorazd; Klobucar, Robert; Gradisnik, Lidija

    2016-01-01

    Biomaterials and biotechnology are increasing becoming an important area in modern medicine. The main aim in this area is the development of materials, which are biocompatible to normal tissue. Tissue-implant interactions with molecular, biological and cellular characteristics at the implant-tissue interface are important for the use and development of implants. Implantation may cause an inflammatory and immune response in tissue, foreign body reaction, systemic toxicity and imminent infection. Tissue-implant interactions determine the implant life-period. The aims of the study are to consider the biological response to implants. Biomaterials and host reactions to implants and their mechanisms are also briefly discussed. PMID:26894284

  19. Shift of graft-versus-host-disease target organ tropism by dietary vitamin A.

    Directory of Open Access Journals (Sweden)

    Christian Koenecke

    Full Text Available Gut-homing of donor T cells is causative for the development of intestinal GvHD in recipients of allogeneic hematopoietic stem cell transplantation (HSCT. Expression of the gut-specific homing receptors integrin-α4β7 and chemokine receptor CCR9 on T cells is imprinted in gut-associated lymphoid tissues (GALT under the influence of the vitamin A metabolite retinoic acid. Here we addressed the role of vitamin A deficiency in HSCT-recipients for donor T cell migration in the course of experimental GvHD. Vitamin A-deficient (VAD mice were prepared by feeding them a vitamin A-depleted diet. Experiments were performed in a C57BL/6 into BALB/c model of acute GvHD. We found that expression of integrin-α4β7 and CCR9 in GALT was reduced in VAD recipients after HSCT. Competitive in vivo homing assays showed that allogeneic T cells primed in VAD mice did not home as efficiently to the intestine as T cells primed in mice fed with standard diet (STD. The course of GvHD was ameliorated in VAD HSCT-recipients and, consequently, their survival was prolonged compared to recipients receiving STD. However, VAD-recipients were not protected and died of clinical GvHD. We found reduced numbers of donor T cells in the intestine but increased cell counts and tissue damage in other organs of VAD-recipients. Furthermore, we observed high IFN-γ(+CD4(+ and low FoxP3(+CD4(+ frequencies of total donor CD4(+ T cells in VAD as compared to STD recipients. Taken together, these results indicate that dietary vitamin A deficiency in HSCT-recipients changed target organ tropism in GvHD but also resulted in fatal inflammation after HSCT.

  20. Clinical studies on bone marrow transplantation of acute leukemia and aplastic anemia

    International Nuclear Information System (INIS)

    Morishima, Yasuo

    1979-01-01

    Since 1974, we have done bone marrow transplantation (BMT) in six patients of acute leukemia and two of aplastic anemia. Leukemia patients were premedicated by CY+TBI method; cyclophosphamide (CY) 60 mg/kg/day was administered for two successive days and two days later, total body irradiation (TBI) was done in a dose of 800 - 1000 rad at a rate of 20-28 rad/min by linear accerelator. Patients with aplastic anemia were premedicated by CY method; CY 50 mg/kg/day for four successive days. Bone marrow graft was obtained from donor under general anesthesia. The nucleated bone marrow cells, ranged from 0.7 x 10 10 to 1.4 x 10 10 were transfused into the patient intravenously. Any lethal side effects did not develop in all patient during these procedures. Two died on day 10 and 12 with septicemia. The other 6 patients showed engraftment of bone marrow indicated by rising blood counts, return of marrow cellularity and in one case by blood cytogenetic markers. Relapse of leukemia did not occur in five patients treated with CY + TBI method. Three patients with allogeneic BMT developed moderately severe to severe Graft versus Host Disease. Survival time after BMT were 12, 35, 63, 68, 98, 125 days. 15 months in leukemia, and 10 days, 12 + months in aplastic anemia. (author)

  1. Update: Dura Mater Graft-Associated Creutzfeldt-Jakob Disease - Japan, 1975-2017.

    Science.gov (United States)

    Ae, Ryusuke; Hamaguchi, Tsuyoshi; Nakamura, Yosikazu; Yamada, Masahito; Tsukamoto, Tadashi; Mizusawa, Hidehiro; Belay, Ermias D; Schonberger, Lawrence B

    2018-03-09

    Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder that, according to the most well accepted hypothesis (1), is caused by replicating, transmissible, abnormal forms of a host-encoded prion protein (prions). Most CJD cases occur spontaneously (sporadic CJD) or are inherited (genetic CJD). Iatrogenic CJD can occur after exposure to prion-contaminated instruments or products in medical/surgical settings. Cadaveric dura mater graft-associated CJD (dCJD) accounts for a common form of iatrogenic CJD. This report summarizes the epidemiologic features of 154 cases of dCJD identified in Japan during 1975-2017; these cases account for >60% of dCJD cases reported worldwide (1,2). The unusually high prevalence of dCJD in Japan was first reported in 1997 (3). In 2008, a single brand of graft (Lyodura [B. Braun Melsungen AG, Melsungen, Germany]), frequently used as a patch in neurosurgical procedures, was identified as the probable vehicle of transmission (4). No international recall of the implicated Lyodura occurred, the product had a relatively long shelf life, and the grafts were used frequently in Japanese patients with non-life-threatening conditions (4,5). Since 2008, additional cases have been ascertained, reflecting the identification of previously missed cases and the occurrence of new cases with longer latency periods (interval from exposure to symptom onset) for dCJD (up to 30 years), underscoring the importance of maintaining surveillance for dCJD.

  2. T-cell depleted haploidentical three loci mismatched bone-marrow and peripheral blood stem cell transplantation in acute leukaemia patients

    International Nuclear Information System (INIS)

    Aristei, C.; Aversa, F.; Panizza, B.M.; Perrucci, E.; Barone, V.; Marafioti, L.; Raymondi, C.; Terenzi, A.; Martelli, M.F.; Latini, P.

    1996-01-01

    Objectives: Allogeneic bone-marrow transplantation (BMT) is an established treatment for many haematological malignancies. Unfortunately, most patients lack an HLA geno typically identical sibling and require an alternative donor, such as an HLA-haploidentical mismatched related donor, an HLA phenotypically matched or partially mismatched unrelated donor or an HLA-similar cord blood stem cell donor. However, these types of BMT increase the risk of graft-versus-host disease (GvHD), graft failure, delayed immuno reconstitution and fatal infection that observed after a sibling matched donor. Many centers are exploring the possibility of using donors other than matched sibling. Our approach has been to employ T-cell depleted mismatched haploidentical familial donor BMT to solve the problem of GvHD, a highly immuno- and myelo-suppressive conditioning regimen to reduce the incidence of graft failure and relapse, a graft inoculum plus G-CSF donor mobilized peripheral blood stem cells (PBSC) to overcome the host-versus-graft barrier. Patients and methods: Thirty-six patients (25 male, 11 female; median age 22 years, range 2-51) were treated with an allogeneic T-depleted haploidentical three loci mismatched bone-marrow and G-CSF mobilized PBSC transplantation from a familiar donor (18 siblings, 17 parents and 1 cousin) between March 1993 and June 1995. All had high-risk or advanced stage acute myeloid (12) or acute lymphoid (24) leukaemia; 18 were in haematological complete remission (CR) and 18 in chemo resistant relapse. Patients were conditioned with 8 Gy single dose TBI administered on day -5 at an instantaneous dose-rate of 13.4-31.7 cGy/min/midplane and average of 6.7-12.12 cGy/min/midplane. Shields were used to reduce the lung dose to 7 Gy in the first 23 cases and to 6 Gy in the last 13. 10 mg/Kg thiotepa were administered on day -4, 5 mg/Kg rabbit ATG from day -4 to day -1, 60 or 50 mg/Kg/cyclophosphamide on days -3 and -2. Bone-marrow and PBSC were infused on day

  3. Allogeneic stem cell transplantation benefits for patients ≥ 60 years with acute myeloid leukemia and FLT3 internal tandem duplication: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

    Science.gov (United States)

    Poiré, Xavier; Labopin, Myriam; Polge, Emmanuelle; Passweg, Jakob; Craddock, Charles; Blaise, Didier; Cornelissen, Jan J; Volin, Liisa; Russell, Nigel H; Socié, Gérard; Michallet, Mauricette; Fegueux, Nathalie; Chevallier, Patrice; Brecht, Arne; Hunault-Berger, Mathilde; Mohty, Mohamad; Esteve, Jordi; Nagler, Arnon

    2018-02-01

    Intermediate-risk cytogenetic acute myeloid leukemia with an internal tandem duplication of FLT3 ( FLT3 -ITD) is associated with a high risk of relapse, and is now a standard indication for allogeneic stem cell transplantation. Nevertheless, most studies supporting this strategy have been performed in young patients. To address the benefit of allogeneic transplantation in the elderly, we made a selection from the European Society for Blood and Marrow Transplantation registry of de novo intermediate-risk cytogenetic acute myeloid leukemia harboring FLT3 -ITD in patients aged 60 or over and transplanted from a related or unrelated donor between January 2000 and December 2015. Two hundred and ninety-one patients were identified. Most patients received a reduced-intensity conditioning (82%), while donors consisted of an unrelated donor in 161 (55%) patients. Two hundred and twelve patients received their transplantation in first remission, 37 in second remission and 42 in a more advanced stage of the disease. The 2-year leukemia-free survival rate was 56% in patients in first remission, 22% in those in second remission and 10% in patients with active disease, respectively ( P <0.005). Non-relapse mortality for the entire cohort was 20%. In multivariate analysis, disease status at transplantation was the most powerful predictor of worse leukemia-free survival, graft- versus -host disease and relapse-free survival, and overall survival. In this elderly population, age was not associated with outcome. Based on the current results, allogeneic transplantation translates into a favorable outcome in fit patients ≥ 60 with FLT3 -ITD acute myeloid leukemia in first remission, similarly to current treatment recommendations for younger patients. Copyright© 2018 Ferrata Storti Foundation.

  4. Cost-Effectiveness Evaluation of Heparin Coated Versus Standard Graft for Bypass Surgery in Peripheral Artery Disease Alongside a Randomised Controlled Trial

    DEFF Research Database (Denmark)

    Villemoes, Marie K; Lindholt, Jes S; Houlind, Kim C

    2018-01-01

    as arithmetic means with bootstrapped 95% confidence intervals. Cost-effectiveness acceptability curves were used to illustrate the probability of cost-effectiveness for a range of threshold values of willingness to pay (WTP). RESULTS: No statistically significant differences between the randomisation groups...... were observed for costs or gains of LYs or QALYs. The average cost per QALY was estimated at €10,792. For a WTP threshold of €40,000 per QALY, the overall probability of cost-effectiveness was estimated at 62%, but owing to cost savings in patients with critical ischaemia (cost per QALY ...OBJECTIVE/BACKGROUND: Heparin coating has recently been shown to reduce the risk of graft failure in arterial revascularisation, at least transiently. The aim of this study was to assess the cost-effectiveness of heparin coated versus standard polytetrafluoroethylene grafts for bypass surgery...

  5. Aortic Graft Infection Secondary to Iatrogenic Transcolonic Graft Malposition.

    Science.gov (United States)

    Blank, Jacqueline J; Rothstein, Abby E; Lee, Cheong Jun; Malinowski, Michael J; Lewis, Brian D; Ridolfi, Timothy J; Otterson, Mary F

    2018-01-01

    Aortic graft infections are a rare but devastating complication of aortic revascularization. Often infections occur due to contamination at the time of surgery. Iatrogenic misplacement of the limbs of an aortobifemoral graft is exceedingly rare, and principles of evaluation and treatment are not well defined. We report 2 cases of aortobifemoral bypass graft malposition through the colon. Case 1 is a 54-year-old male who underwent aortobifemoral bypass grafting for acute limb ischemia. He had previously undergone a partial sigmoid colectomy for diverticulitis. Approximately 6 months after vascular surgery, he presented with an occult graft infection. Preoperative imaging and intraoperative findings were consistent with graft placement through the sigmoid colon. Case 2 is a 60-year-old male who underwent aortobifemoral bypass grafting due to a nonhealing wound after toe amputation. His postoperative course was complicated by pneumonia, bacteremia thought to be secondary to the pneumonia, general malaise, and persistent fevers. Approximately 10 weeks after the vascular surgery, he presented with imaging and intraoperative findings of graft malposition through the cecum. Aortic graft infection is usually caused by surgical contamination and presents as an indolent infection. Case 1 presented as such; Case 2 presented more acutely. Both grafts were iatrogenically misplaced through the colon at the index operation. The patients underwent extra-anatomic bypass and graft explantation and subsequently recovered.

  6. Improved survival after transplantation of more donor plasmacytoid dendritic or naïve T cells from unrelated-donor marrow grafts: results from BMTCTN 0201.

    Science.gov (United States)

    Waller, Edmund K; Logan, Brent R; Harris, Wayne A C; Devine, Steven M; Porter, David L; Mineishi, Shin; McCarty, John M; Gonzalez, Corina E; Spitzer, Thomas R; Krijanovski, Oleg I; Linenberger, Michael L; Woolfrey, Ann; Howard, Alan; Wu, Juan; Confer, Dennis L; Anasetti, Claudio

    2014-08-01

    To characterize relationships between specific immune cell subsets in bone marrow (BM) or granulocyte colony-stimulating factor-mobilized peripheral blood (PB) stem cells collected from unrelated donors and clinical outcomes of patients undergoing transplantation in BMTCTN 0201. Fresh aliquots of 161 BM and 147 PB stem-cell allografts from North American donors randomly assigned to donate BM or PB stem cells and numbers of transplanted cells were correlated with overall survival (OS), relapse, and graft-versus-host disease (GvHD). Patients with evaluable grafts were similar to all BMTCTN 0201 patients. The numbers of plasmacytoid dendritic cells (pDCs) and naïve T cells (Tns) in BM allografts were independently associated with OS in multivariable analyses including recipient and donor characteristics, such as human leukocyte antigen mismatch, age, and use of antithymocyte globulin. BM recipients of > median number of pDCs, naïve CD8(+) T cells (CD8Tns), or naïve CD4(+) T cells (CD4Tns) had better 3-year OS (pDCs, 56% v 35%; P = .025; CD8Tns, 56% v 37%; P = .012; CD4Tns, 55% v 37%; P = .009). Transplantation of more BM Tns was associated with less grade 3 to 4 acute GvHD but similar rates of relapse. Transplantation of more BM pDCs was associated with fewer deaths resulting from GvHD or from graft rejection. Analysis of PB grafts did not identify a donor cell subset significantly associated with OS, relapse, or GvHD. Donor immune cells in BM but not PB stem-cell grafts were associated with survival after unrelated-donor allogeneic hematopoietic stem-cell transplantation. The biologic activity of donor immune cells in allogeneic transplantation varied between graft sources. Donor grafts with more BM-derived Tns and pDCs favorably regulated post-transplantation immunity in allogeneic hematopoietic stem-cell transplantation. © 2014 by American Society of Clinical Oncology.

  7. Attempted reconstitution of a foal with primary severe combined immunodeficiency.

    Science.gov (United States)

    Campbell, T M; Studdert, M J; Ellis, W M; Paton, C M

    1983-07-01

    A foal with primary severe combined immunodeficiency, diagnosed within the first two weeks of life, was maintained with its dam in semi-isolation. The foal received continuous prophylactic antibiotic therapy, plasma from a sibling hyperimmunised with equine adenovirus vaccine, and intensive general nursing care. A full sibling female was selected as a bone marrow donor on the basis of red blood cell cross-matching and mixed lymphocyte reactions. Cyclophosphamide was given before two bone marrow transfusions at 35 and 73 days of age. To prevent graft versus host disease graft versus host disease the foal was maintained on methotrexate therapy. Reconstitution was not achieved nor were there signs of graft versus host disease. The foal died suddenly four days after the second bone marrow transfer when 77 days old. It had remained clinically free of any life threatening infectious disease and at necropsy a remarkable degree of freedom from infectious disease was confirmed. The most notable necropsy findings were bilateral nephrosis and myocardial degeneration and fibrosis. The likely cause of death was an electrolyte imbalance, particularly hypokalaemia, which secondarily affected the myocardium. Renal toxicity caused by the cytotoxic drugs, especially cyclophosphamide, may have contributed to the electrolyte imbalance.

  8. CABG Versus PCI: Greater Benefit in Long-Term Outcomes With Multiple Arterial Bypass Grafting.

    Science.gov (United States)

    Habib, Robert H; Dimitrova, Kamellia R; Badour, Sanaa A; Yammine, Maroun B; El-Hage-Sleiman, Abdul-Karim M; Hoffman, Darryl M; Geller, Charles M; Schwann, Thomas A; Tranbaugh, Robert F

    2015-09-29

    Treatment of multivessel coronary artery disease with traditional single-arterial coronary artery bypass graft (SA-CABG) has been associated with superior intermediate-term survival and reintervention compared with percutaneous coronary intervention (PCI) using either bare-metal stents (BMS) or drug-eluting stents (DES). This study sought to investigate longer-term outcomes including the potential added advantage of multiarterial coronary artery bypass graft (MA-CABG). We studied 8,402 single-institution, primary revascularization, multivessel coronary artery disease patients: 2,207 BMS-PCI (age 66.6 ± 11.9 years); 2,381 DES-PCI (age 65.9 ± 11.7 years); 2,289 SA-CABG (age 69.3 ± 9.0 years); and 1,525 MA-CABG (age 58.3 ± 8.7 years). Patients with myocardial infarction within 24 h, shock, or left main stents were excluded. Kaplan-Meier analysis and Cox regression were used to separately compare 9-year all-cause mortality and unplanned reintervention for BMS-PCI and DES-PCI to respective propensity-matched SA-CABG and MA-CABG cohorts. BMS-PCI was associated with worse survival than SA-CABG, especially from 0 to 7 years (p = 0.015) and to a greater extent than MA-CABG was (9-year follow-up: 76.3% vs. 86.9%; p PCI hazard ratios (HR) were as follows: versus SA-CABG, HR: 0.87; and versus MA-CABG, HR: 0.38. DES-PCI showed similar survival to SA-CABG except for a modest 0 to 3 years surgery advantage (HR: 1.06; p = 0.615). Compared with MA-CABG, DES-PCI exhibited worse survival at 5 (86.3% vs. 95.6%) and 9 (82.8% vs. 89.8%) years (HR: 0.45; p PCI for all comparisons (all p PCI or DES-PCI, resulted in substantially enhanced death and reintervention-free survival. Accordingly, MA-CABG represents the optimal therapy for multivessel coronary artery disease and should be enthusiastically adopted by multidisciplinary heart teams as the best evidence-based therapy. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  9. Off-pump versus on-pump coronary artery bypass grafting for ischaemic heart disease

    DEFF Research Database (Denmark)

    Møller, Christian H; Penninga, Luit; Wetterslev, Jørn

    2012-01-01

    Coronary artery bypass grafting (CABG) is performed both without and with cardiopulmonary bypass, referred to as off-pump and on-pump CABG respectively. However, the preferable technique is unclear.......Coronary artery bypass grafting (CABG) is performed both without and with cardiopulmonary bypass, referred to as off-pump and on-pump CABG respectively. However, the preferable technique is unclear....

  10. Dose response of fish oil versus safflower oil on graft arteriosclerosis in rabbit heterotopic cardiac allografts.

    Science.gov (United States)

    Yun, K L; Fann, J I; Sokoloff, M H; Fong, L G; Sarris, G E; Billingham, M E; Miller, D C

    1991-01-01

    With the advent of cyclosporin A, accelerated coronary arteriosclerosis has become the major impediment to the long-term survival of heart transplant recipients. Due to epidemiologic reports suggesting a salutary effect of fish oil, the dose response of fish oil on graft coronary arteriosclerosis in a rabbit heterotopic cardiac allograft model was assessed using safflower oil as a caloric control. Seven groups of New Zealand White rabbits (n = 10/group) received heterotropic heart transplants from Dutch-Belted donors and were immunosuppressed with low-dose cyclosporin A (7.5 mg/kg/day). Group 1 animals were fed a normal diet and served as control. Group 2, 3, and 4 animals received a daily supplement of low- (0.25 mL/kg/day), medium- (0.75 mL/kg/day), and high- (1.5 mL/kg/day) dose fish oil (116 mg n-3 polyunsaturated fatty acid/mL), respectively. Group 5, 6, and 7 animals were supplemented with equivalent dose of safflower oil (i.e., 0.25, 0.75, and 1.5 mL/kg/day). Oil-supplemented rabbits were pretreated for 3 weeks before transplantation and maintained on the same diet for 6 weeks after operation. The extent of graft coronary arteriosclerosis was quantified using computer-assisted, morphometric planimetry. When the animals were killed, cyclosporin A was associated with elevated plasma total cholesterol and triglyceride levels in the control group. While safflower oil prevented the increase in plasma lipids at all dosages, fish oil ameliorated the cyclosporin-induced increase in total cholesterol only with high doses. Compared to control animals, there was a trend for more graft vessel disease with increasing fish oil dose, as assessed by mean luminal occlusion and intimal thickness. A steeper trend was observed for increasing doses of safflower oil; compared to the high-dose safflower oil group, animals supplemented with low-dose safflower oil had less mean luminal occlusion (16.3% +/- 5.9% versus 41.4% +/- 7.6%, p less than 0.017) and intimal thickness (7

  11. Donor Umbilical Cord Blood Transplant in Treating Patients With Hematologic Cancer

    Science.gov (United States)

    2017-11-27

    Chronic Myeloproliferative Disorders; Diamond-blackfan Anemia; Fanconi Anemia; Graft Versus Host Disease; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases

  12. Disease spread across multiple scales in a spatial hierarchy: effect of host spatial structure and of inoculum quantity and distribution.

    Science.gov (United States)

    Gosme, Marie; Lucas, Philippe

    2009-07-01

    Spatial patterns of both the host and the disease influence disease spread and crop losses. Therefore, the manipulation of these patterns might help improve control strategies. Considering disease spread across multiple scales in a spatial hierarchy allows one to capture important features of epidemics developing in space without using explicitly spatialized variables. Thus, if the system under study is composed of roots, plants, and planting hills, the effect of host spatial pattern can be studied by varying the number of plants per planting hill. A simulation model based on hierarchy theory was used to simulate the effects of large versus small planting hills, low versus high level of initial infections, and aggregated versus uniform distribution of initial infections. The results showed that aggregating the initially infected plants always resulted in slower epidemics than spreading out the initial infections uniformly. Simulation results also showed that, in most cases, disease epidemics were slower in the case of large host aggregates (100 plants/hill) than with smaller aggregates (25 plants/hill), except when the initially infected plants were both numerous and spread out uniformly. The optimal strategy for disease control depends on several factors, including initial conditions. More importantly, the model offers a framework to account for the interplay between the spatial characteristics of the system, rates of infection, and aggregation of the disease.

  13. Clinical analysis of amniotic membrane patches and grafts for acute ocular surface burn

    Directory of Open Access Journals (Sweden)

    Lin Li

    2015-01-01

    Full Text Available AIM: To investigate the effect and value of amniotic membrane patches and grafts for acute ocular surface burn at different degrees.METHODS: A retrospective analysis of 28 cases(28 eyesaffected by ocular chemical or thermal burn with different degree were included in our hospital from March 2007 to March 2012. Amniotic membrane patched was undergone in 13 eyes with fresh amnion that the patients corneal burns degree Ⅱ or Ⅲ with partial limbal buns at degree Ⅳ. Amniotic membrane grafts was performed in 15 eyes with fresh amnion that the patients all corneal burns at degree Ⅲ with the whole limbal necrosis without severe eyelid defect. The follow-up time ranged 6~24mo. The postoperative visual acuity, the condition of amniotic membrane transplant, renovation of cornea and complications were observed. RESULTS: Postoperative corrected visual acuity was improved in 20 eyes(71%, it was not changed in 5 eyes(18%, the visual acuity declined in 3 eyes(11%. The amniotic membrane survived in 23 eyes and the survival rate was up to 82%. The cornea of 4 eyes recovered to transparent, nebula emceed in 8 eyes eventually, corneal macula emerged in 10 eyes, 4 eyes ended up with leukoma, 2 eyes developed corneal melting after therapy, then received lamellar keratoplasty. Corneal surface become epithelization after amnion patches or grafts, but any of them have recurrent epithelial erosion, and become stable epithalization after repeat operation.CONCLUSION: Amniotic membrane patches and grafts is an effective method to deal with acute ocular surface burn.

  14. Reduced-intensity conditioning for the treatment of malignant and life-threatening non-malignant disorders.

    Science.gov (United States)

    Slavin, Shimon; Aker, Mehmet; Shapira, Michael Y; Resnick, Igor; Bitan, Menachem; Or, Reuven

    2003-01-01

    Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeutic tool for the treatment of an otherwise incurable broad spectrum of malignant and non-malignant diseases. Until recently, BMT was used primarily to replace a malignant, genetically abnormal or deficient immunohematopoietic compartment and therefore, highly toxic myeloablative regimens were considered mandatory for more effective eradication of all undesirable host-derived hematopoietic cells, including stem cells and their progeny. Our preclinical and ongoing clinical studies indicated that much more effective eradication of host immunohematopoietic system cells can be mediated by donor lymphocytes in the process of adoptive allogeneic cell therapy following BMT. Thus, eradication of all malignant cells, especially in patients with CML and, to a lesser extent, in patients with other hematologic malignancies can be accomplished despite complete resistance of puch tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience suggested that graft-versus-malignancy effects might be used as a tool for eradication of otherwise resistant tumor cells of host origin. We speculated that the therapeutic benefit of BMT may be improved by using safer conditioning for engraftment of donor stem cells induce host-versus-graft unresponsiveness to enable engraftment of donor lymphocytes for subsequent induction of graft-versus-malignancy effects, or even graft-versus-autoimmunity and graft-versus-genetically abnormal cells. In other words, focusing on more selective and smarter rather than stronger modalities. Effective BMT procedures may be accomplished without lethal conditioning of the host, using a new, well-tolerated and user-friendly non-myeloablative regimen, thus eliminating or minimizing immediate and late procedure-related toxicity and mortality. It appears that initial induction of graft tolerance, mediated by engraftment of donor stem cells, leads

  15. Splenectomy versus conservative management for acute sequestration crises in people with sickle cell disease.

    Science.gov (United States)

    Owusu-Ofori, Shirley; Remmington, Tracey

    2015-09-07

    Acute splenic sequestration crises are a complication of sickle cell disease, with high mortality rates and frequent recurrence in survivors of first attacks. Splenectomy and blood transfusion, with their consequences, are the mainstay of long-term management used in different parts of the world. This is a 2015 update of a Cochrane review first published in 2002, and previously updated in 2013. To assess whether splenectomy (total or partial), to prevent acute splenic sequestration crises in people with sickle cell disease, improved survival and decreased morbidity in people with sickle cell disease, as compared with regular blood transfusions. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises of references identified from comprehensive electronic database searches and handsearching relevant journals and abstract books of conference proceedings.Additional trials were sought from the reference lists of the trials and reviews identified by the search strategy.Date of the most recent search: 10 June 2015. All randomized or quasi-randomized controlled trials comparing splenectomy (total or partial) to prevent recurrence of acute splenic sequestration crises with no treatment or blood transfusions in people with sickle cell disease. No trials of splenectomy for acute splenic sequestration were found. No trials of splenectomy for acute splenic sequestration were found. Splenectomy, if full, will prevent further sequestration and if partial, may reduce the recurrence of acute splenic sequestration crises. However, there is a lack of evidence from trials showing that splenectomy improves survival and decreases morbidity in people with sickle cell disease. There is a need for a well-designed, adequately-powered, randomized controlled trial to assess the benefits and risks of splenectomy compared to transfusion programmes, as a means of improving survival and decreasing mortality from acute splenic

  16. Hematopoietic Stem Cell Transplant in Adolescent and Young Adults With Fanconi Anemia Is Feasible With Acceptable Toxicity, With Those Surviving 100 Days Posttransplant Having Excellent Outcomes.

    Science.gov (United States)

    Alhuraiji, Ahmad; Alzahrani, Hazza; Al Mohareb, Fahad; Chaudhri, Naeem; Alsharif, Fahad; Mohamed, Said; Rasheed, Walid; Aldawsari, Ghuzayel; Ahmed, Syed Osman; Aljurf, Mahmoud

    2016-12-01

    Fanconi anemia is a congenital bone marrow failure syndrome that is associated with congenital anomalies and increased risk of cancer. Hematopoietic stem cell transplant is a potentially curative modality for bone marrow failure in Fanconi anemia patients. Here, we report our center's experience regarding adolescent and young adult patients with Fanconi anemia and hematopoietic stem cell transplant. We conducted a retrospective patient record analyses of patients who presented at our center from 1988 to 2014. We included patients greater than 14 years old with confirmed Fanconi anemia based on positive chromosome breakage study and who underwent hematopoietic stem cell transplant at our institution. Our study group comprised 12 patients with Fanconi anemia who underwent hematopoietic stem cell transplant at our institution. The median age was 20 years (range, 14-31 y) with a female predominance of 83%. Low-dose cyclophosphamide (20-80 mg/kg)-based conditioning regimens were used with different combinations that included fludarabine, antithymocyte globulin, or total body irradiation. All patients had HLA-matched sibling grafts. In all patients, stem cell source was the bone marrow. All patients showed engraftment. Four patients (33%) developed acute graft-versus-host disease. Three patients (25%) died early before day 100 after hematopoietic stem cell transplant due to infectious complications, with 1 patient having steroid refractory acute graft-versus-host disease. Overall survival was 75% at a median follow-up of 43 months. All patients who survived are well and remained transfusion independent without evidence of secondary malignancy. Our findings support the feasibility of reduced intensity conditioning allogeneic hematopoietic stem cell transplant in older and more heavily pretreated patients with Fanconi anemia, especially for those who are engrafted.

  17. Acute swelling of the limbs: magnetic resonance pictorial review of fascial and muscle signal changes

    Energy Technology Data Exchange (ETDEWEB)

    Revelon, Geraldine [Department of Radiology, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France); Rahmouni, Alain [Department of Radiology, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France); Jazaerli, Nedal [Department of Radiology, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France); Godeau, Bertrand [Department of Internal Medicine, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France); Chosidow, Olivier [Department of Dermatology, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France); Authier, Jerome [Department of Pathology, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France); Mathieu, Didier [Department of Radiology, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France); Roujeau, Jean-Claude [Department of Dermatology, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France); Vasile, Norbert [Department of Radiology, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France)

    1999-04-01

    Objective: This pictorial review analyzes the magnetic resonance (MR) fascial/muscular changes in 69 patients referred as emergencies with acute swelling of the limbs (ASL) from various causes. Methods and material: A prospective MR imaging (MRI) study of 69 patients referred as emergencies for ASL was performed. Our population consisted of 45 patients with skin and soft-tissue infections (cellulitis and necrotizing fasciitis, and pyomyositis), six patients with soft-tissue inflammatory diseases (dermatomyositis, graft-versus-host disease), 11 patients with acute deep venous thrombosis, three patients with rhabdomyolysis, one patient with acute denervation and three other patients with rare diseases. Hematomas, tumorous or infectious bone involvement and soft-tissue tumors were excluded. All studies included spin echo T1-weighted images and spin echo T2-weighted images. Gadolinium-enhanced spin echo T1-weighted images were obtained when an abscess was suspected on T2-weighted images. Selective fat-saturated T1- and T2-weighted sequences were also used. MRI analysis was performed to obtain a compartmentalized anatomical approach according to the location of signal abnormalities in subcutaneous fat, superficial and deep fascia and muscle. Results: In all patients with ASL, MRI demonstrated soft-tissue abnormalities involving subcutaneous fat, superficial fascia, deep fascia, or muscle. Although MR findings were non-specific, MRI appears sensitive for detecting subtle fascial and muscle signal changes. Conclusions: In skin and soft-tissue infections, MRI can be helpful for therapeutic management by determining the depth of soft-tissue involvement, particularly within fasciae and muscles, which is partly related to the severity of cellulitis with severe systemic manifestations. MRI can also aid the surgeon in diagnosing abscesses. In inflammatory diseases, MRI can determine the best site for biopsy and also monitor therapeutic response.

  18. Immediate Regrafting of the Split Thickness Skin Graft Donor Site Assists Healing.

    Science.gov (United States)

    Bradow, Brian P; Hallock, Geoffrey G; Wilcock, Samuel P

    2017-05-01

    Delayed or even lack of healing of a split-thickness skin graft (STSG) donor site is a potential problem with elderly patients or those with poor wound healing capabilities. A proactive solution that may minimize this risk is to regraft that donor site using otherwise discarded skin graft remnants. A prospective, nonrandomized, consecutive study was designed to compare the time to healing of the commonly used anterior thigh STSG donor site in patients who had routine dressings (n = 113) versus those with comorbidities known to adversely affect wound healing and had planned regrafting (n = 204). Those comorbidities included age (≥65 years), diabetes mellitus, peripheral vascular disease, chronic renal disease, and chronic steroid use. The average number of comorbidities in the regrafted subgroup versus those not regrafted was 1.41 and 0.31, respectively. This was considered to be a significant difference ( P skin graft materials when so indicated and can be a proactive solution to a potentially cumbersome dilemma.

  19. Superior Lower Extremity Vein Graft Bypass Patency among Married Patients with Peripheral Artery Disease.

    Science.gov (United States)

    Lagergren, Emily; Kempe, Kelly; Craven, Timothy E; Kornegay, Susan T; Hurie, Justin B; Garg, Nitin; Velazquez-Ramirez, Gabriela; Edwards, Matthew S; Corriere, Matthew A

    2017-10-01

    Outcome disparities associated with lower extremity bypass (LEB) for peripheral artery disease (PAD) have been identified but are poorly understood. Marital status may affect outcomes through factors related to health risk behaviors, adherence, and access to care but has not been characterized as a predictor of surgical outcomes and is often omitted from administrative data sets. We evaluated associations between marital status and vein graft patency following LEB using multivariable models adjusting for established risk factors. Consecutive patients undergoing autogenous LEB for PAD were identified and analyzed. Survival analysis and Cox proportional hazards models were used to evaluate patency stratified by marital status (married versus single, divorced, or widow[er]) adjusting for demographic, comorbidity, and anatomic factors in multivariable models. Seventy-three participants who underwent 79 autogenous vein LEB had complete data and were analyzed. Forty-three patients (58.9%) were married, and 30 (41.1%) were unmarried. Compared with unmarried patients, married patients were older at the time of their bypass procedure (67.3 ± 10.8 years vs. 62.2 ± 10.6 years; P = 0.05). Married patients also had a lower prevalence of female gender (11.6% vs. 33.3%; P = 0.02). Diabetes, hypertension, hyperlipidemia, and smoking were common among both married and unmarried patients. Minimum great saphenous vein conduit diameters were larger in married versus unmarried patients (2.82 ± 0.57 mm vs. 2.52 ± 0.65 mm; P = 0.04). Twenty-four-month primary patency was 66% for married versus 38% for unmarried patients. In a multivariable proportional hazards model adjusting for proximal and distal graft inflow/outflow, medications, gender, age, race, smoking, diabetes, and minimum vein graft diameter, married status was associated with superior primary patency (hazard ratio [HR] = 0.33; 95% confidence limits [0.11, 0.99]; P = 0.05); other predictive covariates

  20. GVHD (Graft-Versus-Host Disease): A Guide for Patients and Families After Stem Cell Transplant

    Science.gov (United States)

    ... Disease): A guide for patients and families after stem cell transplant The immune system is the body's tool ... and attacking them. When you receive a donor's stem cells (the “graft”), the stem cells recreate the donor's ...

  1. Cartilage grafting in facial reconstruction with special consideration of irradiated grafts

    International Nuclear Information System (INIS)

    Donald, P.J.

    1986-01-01

    The search for the perfect facial implant for reconstruction of the face continues. Cartilage, once thought to be an undesirable graft material because of its propensity for absorption, has regained popularity in the past decade. Various preparation techniques have been employed to ensure graft sterility and diminished absorption. An improved understanding of cartilage structure and physiology has shed considerable light on the host-graft relationship. Gamma irradiation is a time-honored method of preservation. An experiment was undertaken to investigate the physiology of irradiated cartilage grafts following prolonged implantation on the facial skeleton of sheep and dog. Merthiolate preserved grafts were used as controls. Direct observation, histochemical techniques, autoradiography, and transmission electron micrography were used to determine chondrocyte viability and matrix composition. It was surprising to note that following implantation of 16 to 72 months, complete resorption was seen in 87.7% of the irradiated grafts and in 43.8% of the Merthiolate stored controls. Many of the grafts acquired chondrocytes from the host and produced new proteoglycan matrix as well as undergoing some degree of ossification. A comparison to the clinical situation in humans is made. 98 references

  2. Effect of Massive Blood Transfusion on the Therapeutic Efficiency of Homogenic Bone Marrow in Acute Radiation Illness

    Energy Technology Data Exchange (ETDEWEB)

    Seraphimov-Dimitrov, V.; Decheva, Z.; Nedyalkova, M. [Institute of Haematology and Blood Transfusion, Sofia (Bulgaria)

    1969-07-15

    Simultaneously with bone-marrow transplantation, the authors replaced the blood of the lethally irradiated recipient animals with blood from the bone-marrow donor. From experiments on dogs and rabbits it became clear that replacing 86% of the recipient's blood with blood from the bone-marrow donor considerably reduces the therapeutic effect of bone-marrow transplantation. The authors consider that the main cause of the animals' early death in experiments combining bone-marrow transplantation and massive donor blood transfusions is a secondary syndrome resulting from the graft-versus-host reaction. This does not exclude the inverse possibility - that the development of a host-versus-graft reaction is due to the presence of a massive number of antigens of the donor blood in the blood of the recipient. (author)

  3. Acute antibody-mediated rejection of skin grafts without involvement of granulocytes or complement

    International Nuclear Information System (INIS)

    Bogman, M.J.; Cornelissen, I.M.; Koene, R.A.

    1984-01-01

    In immunosuppressed mice that carry rat skin xeno-grafts, acute antibody-mediated graft rejection (AAR) can be induced by intravenous administration of mouse anti-rat globulin. Dependent on the amount of antibody injected and on the complement status of the recipient, an Arthus-like or a Shwartzman-like pattern of vasculitis occurs. The role of polymorphonuclear granulocytes (PMNs) in either type of vasculitis was tested by inducing AAR in recipients depleted of PMNs by total body irradiation. Despite the absence of PMNs in the graft vessels, AAR occurred both in the Arthus-like and in the Shwartzman-like type. Moreover, AAR could be elicited in PMN-depleted recipients that were complement-depleted by cobra venom factor treatment or were congenitally C5-deficient. We conclude that neither the PMN nor complement is an essential mediator the PMN nor complement is an essential mediator in this form of antibody-mediated vasculitis

  4. Bone grafting: An overview

    Directory of Open Access Journals (Sweden)

    D. O. Joshi

    2010-08-01

    Full Text Available Bone grafting is the process by which bone is transferred from a source (donor to site (recipient. Due to trauma from accidents by speedy vehicles, falling down from height or gunshot injury particularly in human being, acquired or developmental diseases like rickets, congenital defects like abnormal bone development, wearing out because of age and overuse; lead to bone loss and to replace the loss we need the bone grafting. Osteogenesis, osteoinduction, osteoconduction, mechanical supports are the four basic mechanisms of bone graft. Bone graft can be harvested from the iliac crest, proximal tibia, proximal humerus, proximal femur, ribs and sternum. An ideal bone graft material is biologically inert, source of osteogenic, act as a mechanical support, readily available, easily adaptable in terms of size, shape, length and replaced by the host bone. Except blood, bone is grafted with greater frequency. Bone graft indicated for variety of orthopedic abnormalities, comminuted fractures, delayed unions, non-unions, arthrodesis and osteomyelitis. Bone graft can be harvested from the iliac crest, proximal tibia, proximal humerus, proximal femur, ribs and sternum. By adopting different procedure of graft preservation its antigenicity can be minimized. The concept of bone banking for obtaining bone grafts and implants is very useful for clinical application. Absolute stability require for successful incorporation. Ideal bone graft must possess osteogenic, osteoinductive and osteocon-ductive properties. Cancellous bone graft is superior to cortical bone graft. Usually autologous cancellous bone graft are used as fresh grafts where as allografts are employed as an alloimplant. None of the available type of bone grafts possesses all these properties therefore, a single type of graft cannot be recomm-ended for all types of orthopedic abnormalities. Bone grafts and implants can be selected as per clinical problems, the equipments available and preference of

  5. Autoimmune Demyelinating Polyneuropathy as a Manifestation of Chronic Graft-versus-Host Disease after Adult Cord Blood Transplantation in a Patient with Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Fredrick Hogan

    2014-01-01

    Full Text Available Immune mediated demyelinating disease after allogeneic stem cell transplantation is a rare entity with unclear etiology. Acute inflammatory demyelinating polyneuropathy (AIDP has been reported after related and adult unrelated allogeneic stem cell transplantation but no such case has been reported after unrelated cord blood transplantation. We hereby present the first case of AIDP after double umbilical cord blood transplantation (DUCBT. A 55-year-old man with chronic lymphocytic leukemia (CLL received a cord blood transplant for relapsed refractory disease with high risk cytogenetics. On day 221, patient presented with skin rash, tingling in both lower extremites, and ascending paralysis that progressed rapidly over the course of 2 days. The workup resulted in a diagnosis of AIDP and administration of intravenous immunoglobulins plus steroids was initiated. Motor and sensory powers were fully recovered and his chronic GVHD was managed for several months with single agent sirolimus.

  6. Hematopoietic stem cell transplantation in children and young adults with secondary myelodysplastic syndrome and acute myelogenous leukemia after aplastic anemia.

    Science.gov (United States)

    Yoshimi, Ayami; Strahm, Brigitte; Baumann, Irith; Furlan, Ingrid; Schwarz, Stephan; Teigler-Schlegel, Andrea; Walther, Joachim-Ulrich; Schlegelberger, Brigitte; Göhring, Gudrun; Nöllke, Peter; Führer, Monika; Niemeyer, Charlotte M

    2014-03-01

    Secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/sAML) are the most serious secondary events occurring after immunosuppressive therapy in patients with aplastic anemia. Here we evaluate the outcome of hematopoietic stem cell transplantation (HSCT) in 17 children and young adults with sMDS/sAML after childhood aplastic anemia. The median interval between the diagnosis of aplastic anemia and the development of sMDS/sAML was 2.9 years (range, 1.2 to 13.0 years). At a median age of 13.1 years (range, 4.4 to 26.7 years), patients underwent HSCT with bone marrow (n = 6) or peripheral blood stem cell (n = 11) grafts from HLA-matched sibling donors (n = 2), mismatched family donors (n = 2), or unrelated donors (n = 13). Monosomy 7 was detected in 13 patients. The preparative regimen consisted of busulfan, cyclophosphamide, and melphalan in 11 patients and other agents in 6 patients. All patients achieved neutrophil engraftment. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and that of chronic GVHD was 70%. Relapse occurred in 1 patient. The major cause of death was transplant-related complication (n = 9). Overall survival and event-free survival at 5 years after HSCT were both 41%. In summary, this study indicates that HSCT is a curative therapy for some patients with sMDS/sAML after aplastic anemia. Future efforts should focus on reducing transplantation-related mortality. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  7. C-Reactive Protein Levels at Diagnosis of Acute Graft-versus-Host Disease Predict Steroid-Refractory Disease, Treatment-Related Mortality, and Overall Survival after Allogeneic Hematopoietic Stem Cell Transplantation

    DEFF Research Database (Denmark)

    Minculescu, Lia; Kornblit, Brian Thomas; Friis, Lone Smidstrups

    2018-01-01

    , and their prognosis is especially poor. There is experimental evidence that coexisting inflammation aggravates aGVHD. Because C-reactive protein (CRP) is a systemic inflammatory marker, we aimed to investigate whether plasma CRP concentrations at the diagnosis of aGVHD can predict the risk of failing first-line...... of aGVHD diagnosis. According to local protocol, patients with failed response to high-dose steroid therapy (2 mg/kg) were treated with the TNF-α inhibitor infliximab and categorized as having steroid-refractory disease. Of 148 patients with grade II-IV aGVHD, 28 (19%) developed steroid......-refractory disease. In these patients, plasma CRP concentration at diagnosis ranged between patients who developed steroid-refractory disease compared with those who responded to high-dose corticosteroid therapy (odds ratio, 1.50; 95% confidence interval, 1...

  8. Endovascular stent graft treatment of acute thoracic aortic transections due to blunt force trauma.

    LENUS (Irish Health Repository)

    Bjurlin, Marc A

    2012-02-01

    Endovascular stent graft treatment of acute thoracic aortic transections is an encouraging minimally invasive alternative to open surgical repair. Between 2006 and 2008, 16 patients with acute thoracic aortic transections underwent evaluation at our institution. Seven patients who were treated with an endovascular stent graft were reviewed. The mean Glasgow Coma Score was 13.0, probability of survival was .89, and median injury severity score was 32. The mean number of intensive care unit days was 7.7, mean number of ventilator support days was 5.4, and hospital length of stay was 10 days. Mean blood loss was 285 mL, and operative time was 143 minutes. Overall mortality was 14%. Procedure complications were a bleeding arteriotomy site and an endoleak. Endovascular treatment of traumatic thoracic aortic transections appears to demonstrate superior results with respect to mortality, blood loss, operative time, paraplegia, and procedure-related complications when compared with open surgical repair literature.

  9. Pre-operative blood donation versus acute normovolemic hemodilution in cardiac surgery

    Directory of Open Access Journals (Sweden)

    Mohammad Rezvan Nobahar

    2014-01-01

    Full Text Available Introduction: Acute normovolemic hemodilution (ANH and preoperative autologous blood donation (PABD have questionable efficacy, viral and bacterial infection risks, intermittent blood shortages as homeostasis problem, electrolyte and hemodynamic disturbances. Materials and Methods: In this cross sectional survey, we studied 70 patients undergoing open heart coronary artery bypass grafts [CABG] and different valvular replacement 1 ml surgery (35 in ANH, 35 in PABD in Shaheed Modares - Hospital. We measured electrolytes and homeostatic factors to evaluate the influence of two transfusion methods on homeostatic function and hemodynamic balance. Results: We compared 70 patients (38 male [54.3%] and 32 female [45.7%] with mean age 54.8 years undergoing open heart surgery (CABG and valvular. In ANH group, significant decrease was detected in Na (28.5% K (2.5%, prothrombin time (PT (88.57%, partial thromboplastin time (PTT (94.28%, creatine phosphokinase (CPK (11.4%, lactic dehydrogenase (LDH (11.43%, albumin (Alb (17.14%, globulin (91.43% and total protein (80%. Mean initial and post-operative hemoglobin was 14.12 ± 1.06 versus 11.97 ± 0.98, hematocrit 42.22 ± 3.45 versus 35.40 ± 2.88, systolic blood pressure 124.1 ± 14.4 versus 110.88 ± 15.6 (reduction 22.86% diastolic blood pressure 76.02 ± 10 versus 69.26 ± 11 (reduction 3% and pulse rate was 75.45 ± 10 versus 84.45 ± 12 (12% in this case difference between two groups was strongly significant (P = 0.001. In PABD group, significant decrease was detected in Na (20%, K (2.5%, PT (91.43% PTT (80%, CPK (8.57%, LDH (5.72%, Alb (57.15%, globulin (71.43% and total-protein (62.85%, the value of hemodynamic changes were in normal range. Conclusion: Though autologous blood transfusion (ANH and PABD was preferable to allogeneic transfusion in cardiac surgical patients; but PABD offers more advantages in homeostasis, hemodynamic stability and electrolyte balance.

  10. GVHD after HLA-matched sibling BMT or PBSCT: Comparison of North American Caucasian and Japanese Populations

    Science.gov (United States)

    Kanda, Junya; Brazauskas, Ruta; Hu, Zhen-Huan; Kuwatsuka, Yachiyo; Nagafuji, Koji; Kanamori, Heiwa; Kanda, Yoshinobu; Miyamura, Koichi; Murata, Makoto; Fukuda, Takahiro; Sakamaki, Hisashi; Kimura, Fumihiko; Seo, Sachiko; Aljurf, Mahmoud; Yoshimi, Ayami; Milone, Giuseppe; Wood, William A; Ustun, Celalettin; Hashimi, Shahrukh; Pasquini, Marcelo; Bonfim, Carmem; Dalal, Jignesh; Hahn, Theresa; Atsuta, Yoshiko; Saber, Wael

    2016-01-01

    The risk of acute graft-versus-host disease (GVHD) after HLA-matched sibling bone marrow (BM) transplantation is lower in Japanese than in Caucasian patients. However, race may have differential effect on GVHD dependent on the graft source. North American Caucasian and Japanese patients receiving their first allogeneic BM or peripheral blood stem cell (PBSC) transplantations from an HLA-matched sibling for leukemia were eligible. BM was used in 13% and 53% of Caucasian and Japanese patients, respectively. In multivariate analysis, the interaction term between race and graft source was not significant in any of the models, indicating that graft source does not affect the impact of race on outcomes. The risk of grades III–IV acute GVHD was significantly lower in Japanese than in Caucasian patients (hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.57–0.96), which resulted in lower risk of non-relapse mortality in Japanese patients (HR 0.69, 95% CI 0.54–0.89). The risk of relapse was also lower in this group. Lower risk of non-relapse mortality and relapse resulted in lower overall mortality rates among Japanese patients. In conclusion, irrespective of graft source, the risk of severe acute GVHD is lower in Japanese patients, which results in lower risk of non-relapse mortality. PMID:26762681

  11. Graft-versus-Leukemia Effect Following Hematopoietic Stem Cell Transplantation for Leukemia

    Directory of Open Access Journals (Sweden)

    Anne M. Dickinson

    2017-06-01

    Full Text Available The success of hematopoietic stem cell transplantation (HSCT lies with the ability of the engrafting immune system to remove residual leukemia cells via a graft-versus-leukemia effect (GvL, caused either spontaneously post-HSCT or via donor lymphocyte infusion. GvL effects can also be initiated by allogenic mismatched natural killer cells, antigen-specific T cells, and activated dendritic cells of leukemic origin. The history and further application of this GvL effect and the main mechanisms will be discussed and reviewed in this chapter.

  12. Serial soluble CD30 measurements as a predictor of kidney graft outcome.

    Science.gov (United States)

    Halim, M A; Al-Otaibi, T; Al-Muzairai, I; Mansour, M; Tawab, K A; Awadain, W H; Balaha, M A; Said, T; Nair, P; Nampoory, M R N

    2010-04-01

    High levels of soluble CD30 (sCD30), a marker for T-helper 2-type cytokine-producing T cells, pre or post-renal transplantation serves as a useful predictor of acute rejection episodes. Over the course of 1-year, we evaluated the accuracy of serial sCD30 tests to predict acute rejection episodes versus other pathologies that affect graft outcomes. Fifty renal transplant recipients were randomly selected to examine sCD30 on days 0, 3, 5, 7, 14, and 21 followed by 1, 3, 6, and 12 months. The results were analyzed for development of an acute rejection episode, acute tubular necrosis (ATN), or other pathology as well as the graft outcome at 1 year. Compared with pretransplantation sCD30, there was a significant reduction in the average sCD30 immediately posttransplantation from day 3 onward (Pacute rejection episodes (18%); (3) ATN (16%); and (4) other diagnoses (10%). There was a significant reduction in sCD30 immediately posttransplantation for groups 1, 2, and 3 (Pacute rejection episode after 1 month showed higher pretransplantation sCD30 values than these who displayed rejection before 1 month (P=.019). All groups experienced significant improvement in graft function over 1-year follow-up without any significant differences. Though a significant drop of sCD30 posttransplantation was recorded, serial measurements of sCD30 did not show a difference among subjects who displayed acute rejection episodes, ATN, or other diagnoses. Copyright (c) 2010 Elsevier Inc. All rights reserved.

  13. Intermediate-Term Outcomes of Dual Adult versus Single-Kidney Transplantation: Evolution of a Surgical Technique.

    Science.gov (United States)

    Islam, Ana K; Knight, Richard J; Mayer, Wesley A; Hollander, Adam B; Patel, Samir; Teeter, Larry D; Graviss, Edward A; Saharia, Ashish; Podder, Hemangshu; Asham, Emad H; Gaber, A Osama

    2016-01-01

    Background. Acceptance of dual kidney transplantation (DKT) has proven difficult, due to surgical complexity and concerns regarding long-term outcomes. We herein present a standard technique for ipsilateral DKT and compare outcomes to single-kidney transplant (SKT) recipients. Methods. A retrospective single-center comparison of DKT and SKT performed between February 2007 and July 2013. Results. Of 516 deceased donor kidney transplants, 29 were DKT and 487 were SKT. Mean follow-up was 43 ± 67 months. DKT recipients were older and more likely than SKT recipients to receive an extended criteria graft (p DKT versus SKT, the rates of delayed graft function (10.3 versus 9.2%) and acute rejection (20.7 versus 22.4%) were equivalent (p = ns). A higher than expected urologic complication rate in the DKT cohort (14 versus 2%, p DKT and SKT groups (p = ns) with actuarial 3-year DKT patient and graft survivals of 100% and 93%. At 3 years, the groups had similar renal function (p = ns). Conclusions. By utilizing extended criteria donor organs as DKT, the donor pool was enlarged while providing excellent patient and graft survival. The DKT urologic complication rate was reduced by modification of the ureteral anastomosis.

  14. The significance of parenchymal changes of acute cellular rejection in predicting chronic liver graft rejection

    NARCIS (Netherlands)

    Gouw, ASH; van den Heuvel, MC; van den Berg, AP; Slooff, NJH; de Jong, KP; Poppema, S

    2002-01-01

    Background. Chronic rejection (CR) in liver allografts shows a rapid onset and progressive course, leading to graft failure within the first year after transplantation. Most cases are preceded by episodes of acute cellular rejection (AR), but histological features predictive for the transition

  15. Cost-Utility Analysis: Sartorius Flap versus Negative Pressure Therapy for Infected Vascular Groin Graft Managment.

    Science.gov (United States)

    Chatterjee, Abhishek; Macarios, David; Griffin, Leah; Kosowski, Tomasz; Pyfer, Bryan J; Offodile, Anaeze C; Driscoll, Daniel; Maddali, Sirish; Attwood, John

    2015-11-01

    Sartorius flap coverage and adjunctive negative pressure wound therapy (NPWT) have been described in managing infected vascular groin grafts with varying cost and clinical success. We performed a cost-utility analysis comparing sartorius flap with NPWT in managing an infected vascular groin graft. A literature review compiling outcomes for sartorius flap and NPWT interventions was conducted from peer-reviewed journals in MEDLINE (PubMed) and EMBASE. Utility scores were derived from expert opinion and used to estimate quality-adjusted life years (QALYs). Medicare current procedure terminology and diagnosis-related groups codes were used to assess the costs for successful graft salvage with the associated complications. Incremental cost-effectiveness was assessed at $50,000/QALY, and both univariate and probabilistic sensitivity analyses were conducted to assess robustness of the conclusions. Thirty-two studies were used pooling 384 patients (234 sartorius flaps and 150 NPWT). NPWT had better clinical outcomes (86.7% success rate, 0.9% minor complication rate, and 13.3% major complication rate) than sartorius flap (81.6% success rate, 8.0% minor complication rate, and 18.4% major complication rate). NPWT was less costly ($12,366 versus $23,516) and slightly more effective (12.06 QALY versus 12.05 QALY) compared with sartorius flap. Sensitivity analyses confirmed the robustness of the base case findings; NPWT was either cost-effective at $50,000/QALY or dominated sartorius flap in 81.6% of all probabilistic sensitivity analyses. In our cost-utility analysis, use of adjunctive NPWT, along with debridement and antibiotic treatment, for managing infected vascular groin graft wounds was found to be a more cost-effective option when compared with sartorius flaps.

  16. MAGIC biomarkers predict long term outcomes for steroid-resistant acute GVHD.

    Science.gov (United States)

    Major-Monfried, Hannah; Renteria, Anne S; Pawarode, Attaphol; Reddy, Pavan; Ayuk, Francis; Holler, Ernst; Efebera, Yvonne A; Hogan, William J; Wölfl, Matthias; Qayed, Muna; Hexner, Elizabeth O; Wudhikarn, Kitsada; Ordemann, Rainer; Young, Rachel; Shah, Jay; Hartwell, Matthew J; Chaudhry, Mohammed; Aziz, Mina; Etra, Aaron; Yanik, Gregory A; Kröger, Nicolaus; Weber, Daniela; Chen, Yi-Bin; Nakamura, Ryotaro; Rösler, Wolf; Kitko, Carrie L; Harris, Andrew C; Pulsipher, Michael; Reshef, Ran; Kowalyk, Steven; Morales, George; Torres, Ivan; Özbek, Umut; Ferrara, James L M; Levine, John E

    2018-03-15

    Acute graft versus host disease (GVHD) is treated with systemic corticosteroid immunosuppression. Clinical response after one week of therapy often guides further treatment decisions, but long term outcomes vary widely between centers and more accurate predictive tests are urgently needed. We analyzed clinical data and blood samples taken after one week of systemic treatment for GVHD from 507 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC), dividing them into test (n=236) and two validation cohorts separated in time (n = 142 and 129, respectively). Initial response to systemic steroids correlated with response at four weeks, one-year non-relapse mortality (NRM) and overall survival (OS). A previously validated algorithm of two MAGIC biomarkers (ST2 and REG3α) consistently separated steroid resistant patients into two groups with dramatically different NRM and OS (p<0.001 for all three cohorts). High biomarker probability, resistance to steroids and GVHD severity (Minnesota risk) were all significant predictors of NRM in multivariate analysis. A direct comparison of receiver operating curves showed the area under the curve for biomarker probability (0.82) was significantly greater than that for steroid response (0.68, p=0.004) and for Minnesota risk (0.72, p=0.005). In conclusion, MAGIC biomarker probabilities generated after one week of systemic treatment for GVHD predict long term outcomes in steroid resistant GVHD better than clinical criteria and should prove useful in developing better treatment strategies. Copyright © 2018 American Society of Hematology.

  17. Molecular Mechanisms of Foot-and-Mouth Disease Virus Targeting the Host Antiviral Response.

    Science.gov (United States)

    Rodríguez Pulido, Miguel; Sáiz, Margarita

    2017-01-01

    Foot-and-mouth disease virus (FMDV) is the causative agent of an acute vesicular disease affecting pigs, cattle and other domestic, and wild animals worldwide. The aim of the host interferon (IFN) response is to limit viral replication and spread. Detection of the viral genome and products by specialized cellular sensors initiates a signaling cascade that leads to a rapid antiviral response involving the secretion of type I- and type III-IFNs and other antiviral cytokines with antiproliferative and immunomodulatory functions. During co-evolution with their hosts, viruses have acquired strategies to actively counteract host antiviral responses and the balance between innate response and viral antagonism may determine the outcome of disease and pathogenesis. FMDV proteases Lpro and 3C have been found to antagonize the host IFN response by a repertoire of mechanisms. Moreover, the putative role of other viral proteins in IFN antagonism is being recently unveiled, uncovering sophisticated immune evasion strategies different to those reported to date for other members of the Picornaviridae family. Here, we review the interplay between antiviral responses induced by FMDV infection and viral countermeasures to block them. Research on strategies used by viruses to modulate immunity will provide insights into the function of host pathways involved in defense against pathogens and will also lead to development of new therapeutic strategies to fight virus infections.

  18. Cellular basis of the immunohematologic defects observed in short-term semiallogeneic B6C3F1→C3H chimeras: evidence for host-versus-graft reaction initiated by radioresistant T cells

    International Nuclear Information System (INIS)

    Aizawa, S.; Sado, T.; Kamisaku, H.; Kubo, E.

    1980-01-01

    Lethally irradiated C3Hf mice reconstituted with a relatively low dose (2 x 10 6 ) of B6C3F 1 bone marrow cells (B6C3F 1 →C3Hf chimeras) frequently manifest immunohematologic deficiencies during the first month following injection of bone marrow cells. They show slow recovery of antibody-forming potential to sheep red blood cells (SRBC) as compared to that observed in syngeneic (C3Hf→C3Hf or B6C3F 1 →B6C3F 1 ) chimeras. They also show a deficiency of B-cell activity as assessed by antibody response to SRBC following further reconstitution with B6C3F 1 -derived thymus cells 1 week after injection of bone marrow cells. A significant fraction of B6C3F 1 →C3Hf chimeras was shown to manifest a sudden loss of cellularity of spleens during the second week following injection of bone marrow cells even though cellularity was restored to the normal level within 1 week. The splenic mononuclear cells recovered from such chimeras almost invariably showed strong cytotoxicity against target cells expressing donor-type specific H-2 antigens (H-2/sup b/) when assesed by 51 Cr-release assay in vitro. The effector cells responsible for the observed anti-donor specific cytotoxicity were shown to be residual host-derived T cells. These results indicate strongly that residual host T cells could develop anti-donor specific cytotoxicity even after exposure to a supralethal dose (1050 R) of radiation and that the immunohematologic disturbances observed in shortterm F 1 to parent bone marrow chimeras (B6C3F 1 →C3Hf) were due to host-versus-graft reaction (HVGR) initiated by residual host T cells. The implication of these findings on the radiobiological nature of the residual T cells and the persistence of potentially anti-donor reactive T-cell clones in long-surviving allogeneic bone marrow chimeras was discussed

  19. Apoptosis of conjunctival epithelial cells before and after the application of autologous serum eye drops in severe dry eye disease.

    Science.gov (United States)

    Rybickova, Ivana; Vesela, Viera; Fales, Ivan; Skalicka, Pavlina; Jirsova, Katerina

    2016-06-01

    To assess the impact of autologous serum eye drops on the level of ocular surface apoptosis in patients with bilateral severe dry eye disease. This prospective study was conducted on 10 patients with severe dry eye due to graft versus host disease (group 1) and 6 patients with severe dry eye due to primary Sjögren's syndrome (group 2). Impression cytology specimens from the bulbar conjunctiva were obtained before and after a three-month treatment with 20% autologous serum eye drops applied a maximum of 12 times a day together with regular therapy with artificial tears. The percentage of apoptotic epithelial cells was evaluated immunochemically using anti-active caspase 3 antibody. In group 1, the mean percentage of apoptotic cells was 3.6% before the treatment. The three-month treatment led to a significant decrease to a mean percentage of 1.8% (P = 0.028). The mean percentage of apoptotic conjunctival cells decreased from 5.4% before the treatment to 3.8% in group 2; however, these results did not reach the level of significance. Three-month autologous serum treatment led to the improvement of ocular surface apoptosis, especially in the group of patients with severe dry eye due to graft versus host disease. This result supports the very positive effect of autologous serum on the ocular surface in patients suffering from severe dry eye.

  20. Revision Vaginoplasty: A Comparison of Surgical Outcomes of Laparoscopic Intestinal versus Perineal Full-Thickness Skin Graft Vaginoplasty

    NARCIS (Netherlands)

    Sluis, W.B. van der; Bouman, M.B.; Buncamper, M.E.; Mullender, M.G.; Meijerink, W.J.H.J.

    2016-01-01

    BACKGROUND: Vaginal (re)construction can greatly improve the quality of life of indicated patients. If primary vaginoplasty fails, multiple surgical approaches exist for revision. The authors compared surgical results of laparoscopic intestinal versus full-thickness skin graft revision vaginoplasty.

  1. Air Pump-Assisted Graft Centration, Graft Edge Unfolding, and Graft Uncreasing in Young Donor Graft Pre-Descemet Endothelial Keratoplasty.

    Science.gov (United States)

    Jacob, Soosan; Narasimhan, Smita; Agarwal, Amar; Agarwal, Athiya; A I, Saijimol

    2017-08-01

    To assess an air pump-assisted technique for graft centration, graft edge unfolding, and graft uncreasing while performing pre-Descemet endothelial keratoplasty (PDEK) using young donor grafts. Continuous pressurized air infusion was used for graft centration, graft edge unfolding, and graft unwrinkling. Ten eyes of 10 patients underwent PDEK with donors aged below 40 years. In all eyes, the donor scrolled into tight scrolls. In all cases, the air pump-assisted technique was effective in positioning and centering the graft accurately and in straightening infolded graft edges and smoothing out graft creases and wrinkles. Endothelial cell loss was 38.6%. Postoperative best-corrected visual acuity at 6 months was 0.66 ± 0.25 in decimal equivalent. Continuous pressurized air infusion acted as a third hand providing a continuous pressure head that supported the graft and prevented graft dislocation as well as anterior chamber collapse during intraocular maneuvering. Adequate maneuvering space was available in all cases, and bleeding, if any, was tamponaded successfully in all cases. Although very young donor grafts may be used for PDEK, they are difficult to center and unroll completely before floating against host stroma. An air pump-assisted technique using continuous pressurized air infusion allows successful final graft positioning even with very young donor corneas. It thus makes surgery easier as several key steps are made easier to handle. It additionally helps in tamponading hemorrhage during peripheral iridectomy, increasing surgical space, preventing fluctuations in the anterior chamber depth, and promoting graft adherence.

  2. [Features of skin graft in pediatric plastic surgery].

    Science.gov (United States)

    Depoortère, C; François, C; Belkhou, A; Duquennoy-Martinot, V; Guerreschi, P

    2016-10-01

    Skin graft is a skin tissue fragment transferred from a donor site to a receiving site with a spontaneous revascularization. Basic process of plastic surgery, skin graft known in children, specific, warnings and refinements. It finds its indication in many pediatric cases: integumental diseases (neavus, hamartoma), acute burns and scars, traumatic loss of substance or surgically induced, congenital malformations of the hands and feet, etc. Specific skin graft techniques in children are developed: donor sites, sampling technique and procedure, early postoperative care. Especially in children, the scalp is a perfect site for split skin graft and technique is actively developed. Refinements and special cases are discussed: use of dermal matrices, allografts, xenografts, negative pressure therapy, prior skin expansion of the donor site. Results of skin graft in children are exposed: taking of graft, growth and shrinkage, pigmentation. Skin graft sometimes allows to stay the complex movement and get the best final benefit, permanent or at least temporary, in a growing being. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  3. Meniscal allograft transplantation. Part 1: systematic review of graft biology, graft shrinkage, graft extrusion, graft sizing, and graft fixation.

    Science.gov (United States)

    Samitier, Gonzalo; Alentorn-Geli, Eduard; Taylor, Dean C; Rill, Brian; Lock, Terrence; Moutzouros, Vasilius; Kolowich, Patricia

    2015-01-01

    To provide a systematic review of the literature regarding five topics in meniscal allograft transplantation: graft biology, shrinkage, extrusion, sizing, and fixation. A systematic literature search was conducted using the PubMed (MEDLINE), ScienceDirect, and EBSCO-CINAHL databases. Articles were classified only in one topic, but information contained could be reported into other topics. Information was classified according to type of study (animal, in vitro human, and in vivo human) and level of evidence (for in vivo human studies). Sixty-two studies were finally included: 30 biology, 3 graft shrinkage, 11 graft extrusion, 17 graft size, and 6 graft fixation (some studies were categorized in more than one topic). These studies corresponded to 22 animal studies, 22 in vitro human studies, and 23 in vivo human studies (7 level II, 10 level III, and 6 level IV). The principal conclusions were as follows: (a) Donor cells decrease after MAT and grafts are repopulated with host cells form synovium; (b) graft preservation alters collagen network (deep freezing) and causes cell apoptosis with loss of viable cells (cryopreservation); (c) graft shrinkage occurs mainly in lyophilized and gamma-irradiated grafts (less with cryopreservation); (d) graft extrusion is common but has no clinical/functional implications; (e) overall, MRI is not superior to plain radiograph for graft sizing; (f) graft width size matching is more important than length size matching; (g) height appears to be the most important factor influencing meniscal size; (h) bone fixation better restores contact mechanics than suture fixation, but there are no differences for pullout strength or functional results; and (i) suture fixation has more risk of graft extrusion compared to bone fixation. Systematic review of level II-IV studies, Level IV.

  4. Coronary Artery Bypass Surgery Versus Drug-Eluting Stent Implantation for Left Main or Multivessel Coronary Artery Disease A Meta-Analysis of Individual Patient Data

    NARCIS (Netherlands)

    Lee, Cheol Whan; Ahn, Jung-Min; Cavalcante, Rafael; Sotomi, Yohei; Onuma, Yoshinobu; Suwannasom, Pannipa; Tenekecioglu, Erhan; Yun, Sung-Cheol; Park, Duk-Woo; Kang, Soo-Jin; Lee, Seung-Whan; Kim, Young-Hak; Park, Seong-Wook; Serruys, Patrick W.; Park, Seung-Jung

    2016-01-01

    OBJECTIVES The authors undertook a patient-level meta-analysis to compare long-term outcomes after coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) with drug-eluting stents (DES) in 3,280 patients with left main or multivessel coronary artery disease (CAD).

  5. Total body irradiation in the bone marrow transplantation in leukemia:an experience

    International Nuclear Information System (INIS)

    Zapatero, A.; Martin de Vidales, C.; Pinar, B.; Marin, A.; Cerezo, L.; Dominguez, P.; Perez, A.

    1996-01-01

    The purpose of this report was to evaluate long-term survival and morbidity of fractioned total body irradiation (TBI) prior to allogeneicbone marrow transplantation (BMT) for leukemia. From June 1985 to May 1992, 94 patients with acute leukemia and chronic myelogenous leukemia (CML), were treated with high dose cyclophosphamide(CY) and fractionated TBI to a total dose of 12 Gy in six fractions prior to allogeneic BMT. The Kaplan-Meier 5-year overall survival and disease-free survival were 53% +-6 and 48%+- respectively for patients with standard risk disease (first remission of acute leukemia and first chronic phase of CML), and 24%+-7 and 21%+-6 for patients with more advanced disease (p=3D0.01). The incidence of interstitial pneumonitis (IP), venoocclusive disease of the liver (VOD) and grade=3D>II acute graft-versus-host disease (GVHD) were respectively 15%, 29% and 51%. Fractionated TBI combined with high dose CY before allogeneic BMT for leukemia is an effective treatment in prolonging relapse-free survival witha low incidence of lung toxicity. (Author) 13 refs

  6. Total body irradiation in the bone marrow transplantation in leukemia: an experience; Irradiacion corporal total fraccionada en el transplante de medula osea ologenica en leucemias: experiencia de un centro

    Energy Technology Data Exchange (ETDEWEB)

    Zapatero, A; Martin de Vidales, C; Pinar, B; Marin, A; Cerezo, L; Dominguez, P; Perez, A [Servicio de Oncologia Radidoterapica Hospital Universitario de la Princesa, Madrid (Spain)

    1996-06-01

    The purpose of this report was to evaluate long-term survival and morbidity of fractioned total body irradiation (TBI) prior to allogeneic bone marrow transplantation (BMT) for leukemia. From June 1985 to May 1992, 94 patients with acute leukemia and chronic myelogenous leukemia (CML), were treated with high dose cyclophosphamide (CY) and fractionated TBI to a total dose of 12 Gy in six fractions prior to allogeneic BMT. The Kaplan-Meier 5-year overall survival and disease-free survival were 53% +-6 and 48%+- respectively for patients with standard risk disease (first remission of acute leukemia and first chronic phase of CML), and 24%+-7 and 21%+-6 for patients with more advanced disease (p=0.01). The incidence of interstitial pneumonitis (IP), venoocclusive disease of the liver (VOD) and grade=>II acute graft-versus-host disease (GVHD) were respectively 15%, 29% and 51%. Fractionated TBI combined with high dose CY before allogeneic BMT for leukemia is an effective treatment in prolonging relapse-free survival with a low incidence of lung toxicity. (Author) 13 refs.

  7. Bone Marrow Transplantation: MedlinePlus Health Topic

    Science.gov (United States)

    ... marrow transplant - discharge (Medical Encyclopedia) Also in Spanish Topic Image MedlinePlus Email Updates Get Bone Marrow Transplantation ... transplant - slideshow Graft-versus-host disease Related Health Topics Bone Marrow Diseases Stem Cells National Institutes of ...

  8. Allogeneic bone marrow transplantation in adults after fractionated body irradiation and high dose cyclophosphamide

    International Nuclear Information System (INIS)

    Brinch, L.; Evensen, S.A.; Albrechtsen, D.; Egeland, T.; Solheim, B.G.; Rollag, H.; Naalsund, A.; Jacobsen, A.B.

    1991-01-01

    The authors present short and long-term results of allogeneic bone marrow transplantation after hyper-fractionated total body irradiation and high dose cyclophosphamide in ten patients treated for leukaemia during th period 1985-89. Three patients died from complications connected to the transplantation, while seven are living free from leukaemia 18 to 59 months after transplantation. Two patients need treatment for chronic graft versus host disease. Allogeneic bone marrow transplantation is expensive and risky. Close cooperation between clinicians and laboratory specialists is essential. The treatment increases long term survival and probably cures certain patients with leukaemia. Some of the patients will need treatment for chronic graft versus host disease and other late sequelae. 19 refs., 2 tabs

  9. Use of Renal Replacement Therapy May Influence Graft Outcomes following Liver Transplantation for Acute Liver Failure: A Propensity-Score Matched Population-Based Retrospective Cohort Study.

    Science.gov (United States)

    Knight, Stephen R; Oniscu, Gabriel C; Devey, Luke; Simpson, Kenneth J; Wigmore, Stephen J; Harrison, Ewen M

    2016-01-01

    Acute kidney injury is associated with a poor prognosis in acute liver failure but little is known of outcomes in patients undergoing transplantation for acute liver failure who require renal replacement therapy. A retrospective analysis of the United Kingdom Transplant Registry was performed (1 January 2001-31 December 2011) with patient and graft survival determined using Kaplan-Meier methods. Cox proportional hazards models were used together with propensity-score based full matching on renal replacement therapy use. Three-year patient and graft survival for patients receiving renal replacement therapy were 77.7% and 72.6% compared with 85.1% and 79.4% for those not requiring renal replacement therapy (Prenal replacement therapy was a predictor of both patient death (hazard ratio (HR) 1.59, 95% CI 1.01-2.50, P = 0.044) but not graft loss (HR 1.39, 95% CI 0.92-2.10, P = 0.114). In groups fully matched on baseline covariates, those not receiving renal replacement therapy with a serum creatinine greater than 175 μmol/L had a significantly worse risk of graft failure than those receiving renal replacement therapy. In patients being transplanted for acute liver failure, use of renal replacement therapy is a strong predictor of patient death and graft loss. Those not receiving renal replacement therapy with an elevated serum creatinine may be at greater risk of early graft failure than those receiving renal replacement therapy. A low threshold for instituting renal replacement therapy may therefore be beneficial.

  10. Intermediate-Term Outcomes of Dual Adult versus Single-Kidney Transplantation: Evolution of a Surgical Technique

    Directory of Open Access Journals (Sweden)

    Ana K. Islam

    2016-01-01

    Full Text Available Background. Acceptance of dual kidney transplantation (DKT has proven difficult, due to surgical complexity and concerns regarding long-term outcomes. We herein present a standard technique for ipsilateral DKT and compare outcomes to single-kidney transplant (SKT recipients. Methods. A retrospective single-center comparison of DKT and SKT performed between February 2007 and July 2013. Results. Of 516 deceased donor kidney transplants, 29 were DKT and 487 were SKT. Mean follow-up was 43 ± 67 months. DKT recipients were older and more likely than SKT recipients to receive an extended criteria graft (p<0.001. For DKT versus SKT, the rates of delayed graft function (10.3 versus 9.2% and acute rejection (20.7 versus 22.4% were equivalent (p = ns. A higher than expected urologic complication rate in the DKT cohort (14 versus 2%, p<0.01 was reduced through modification of the ureteral anastomosis. Graft survival was equivalent between DKT and SKT groups (p = ns with actuarial 3-year DKT patient and graft survivals of 100% and 93%. At 3 years, the groups had similar renal function (p = ns. Conclusions. By utilizing extended criteria donor organs as DKT, the donor pool was enlarged while providing excellent patient and graft survival. The DKT urologic complication rate was reduced by modification of the ureteral anastomosis.

  11. Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD.

    Science.gov (United States)

    Hechinger, Anne-Kathrin; Smith, Benjamin A H; Flynn, Ryan; Hanke, Kathrin; McDonald-Hyman, Cameron; Taylor, Patricia A; Pfeifer, Dietmar; Hackanson, Björn; Leonhardt, Franziska; Prinz, Gabriele; Dierbach, Heide; Schmitt-Graeff, Annette; Kovarik, Jiri; Blazar, Bruce R; Zeiser, Robert

    2015-01-15

    The common γ chain (CD132) is a subunit of the interleukin (IL) receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Because levels of several of these cytokines were shown to be increased in the serum of patients developing acute and chronic graft-versus-host disease (GVHD), we reasoned that inhibition of CD132 could have a profound effect on GVHD. We observed that anti-CD132 monoclonal antibody (mAb) reduced acute GVHD potently with respect to survival, production of tumor necrosis factor, interferon-γ, and IL-6, and GVHD histopathology. Anti-CD132 mAb afforded protection from GVHD partly via inhibition of granzyme B production in CD8 T cells, whereas exposure of CD8 T cells to IL-2, IL-7, IL-15, and IL-21 increased granzyme B production. Also, T cells exposed to anti-CD132 mAb displayed a more naive phenotype in microarray-based analyses and showed reduced Janus kinase 3 (JAK3) phosphorylation upon activation. Consistent with a role of JAK3 in GVHD, Jak3(-/-) T cells caused less severe GVHD. Additionally, anti-CD132 mAb treatment of established chronic GVHD reversed liver and lung fibrosis, and pulmonary dysfunction characteristic of bronchiolitis obliterans. We conclude that acute GVHD and chronic GVHD, caused by T cells activated by common γ-chain cytokines, each represent therapeutic targets for anti-CD132 mAb immunomodulation. © 2015 by The American Society of Hematology.

  12. Clinical characteristics and usage of statins in patients with stable ischemic heart disease referred for angiography or coronary artery bypass grafting

    Directory of Open Access Journals (Sweden)

    I.V. Shklianka

    2017-12-01

    Full Text Available The aim – to compare the clinical characteristics and frequency of statins usage in real clinical practice in patients referred to a specialized clinic for angiography or coronary artery bypass grafting. Materials and methods. In a retrospective slice single-center study data from a primary examination of 155 patients with stable ischemic heart disease, consecutively selected for coronary artery bypass grafting surgery, were analyzed. Depending on the inclusion of statins in the list of medicinal prescriptions, patients were retrospectively divided into two groups: those who had been prescribed statins while they were initially referred to a specialized cardiac surgery center for angiography or revascularization (n = 84 and those who were not prescribed statins (n ​​= 71. Results. The studied patients’ cohort was characterized by earlier coronary events, signs of the peripheral artery atherosclerosis and other absolute indications for treatment with statins in vast majority of cases. At the same time, groups of patients who had been and had not been prescribed statins, did not differ by vast majority of demographic, clinical and instrumental characteristics, concomitant diseases and risk factors. No statin therapy was associated with higher levels of total cholesterol and interleukin-6 compared with the group of patients taking statins (total cholesterol, respectively, 4.8 versus 4.2 mmol/l (p = 0.016 and interleukin-6, respectively, 4.4 versus. 3.1 p/ml (p = 0.022. In general, statins were prescribed in 54,2 % of patients, among them high doses – in 17 patients (20.2 %, moderate – 46 patients (54.8 %, low – 21 patients (25 %. Conclusions. The obtained data show the insufficient level of ambulatory statins usage in patients with ischemic heart disease referred for myocardial revascularization and significant discrepancy between clinical characteristics and real statins usage. Therefore, there is a great need to determine the

  13. Granulocyte Colony-stimulating Factor-primed Bone Marrow: An Excellent Stem-cell Source for Transplantation in Acute Myelocytic Leukemia and Chronic Myelocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Yuhang Li

    2015-01-01

    Full Text Available Background: Steady-state bone marrow (SS-BM and granulocyte colony-stimulating growth factor-primed BM/peripheral blood stem-cell (G-BM/G-PBSC are the main stem-cell sources used in allogeneic hematopoietic stem-cell transplantation. Here, we evaluated the treatment effects of SS-BM and G-BM/G-PBSC in human leucocyte antigen (HLA-identical sibling transplantation. Methods: A total of 226 patients (acute myelogenous leukemia-complete remission 1, chronic myelogenous leukemia-chronic phase 1 received SS-BM, G-BM, or G-PBSC from an HLA-identical sibling. Clinical outcomes (graft-versus-host disease [GVHD], overall survival, transplant-related mortality [TRM], and leukemia-free survival [LFS] were analyzed. Results: When compared to SS-BM, G-BM gave faster recovery time to neutrophil or platelet (P 0.05. Conclusions: G-CSF-primed bone marrow shared the advantages of G-PBSC and SS-BM. We conclude that G-BM is an excellent stem-cell source that may be preferable to G-PBSC or SS-BM in patients receiving HLA-identical sibling hematopoietic stem-cell transplantation.

  14. Sclerodermatous GVHD after Allogeneic Bone Marrow Transplant: a Review

    Directory of Open Access Journals (Sweden)

    Gagan Raju

    2017-05-01

    Full Text Available Chronic graft versus host disease (cGVHD is the leading cause of non-relapse mortality after allogeneic hematopoietic bone marrow transplantation (HCT for blood malignancy in patients who survive for more than two years. cGVHD can significantly affect quality of life and cause decreased mobility amongst other grave consequences such as end-organ damage, contributing to morbidity and mortality rates for recipients of HCT. Unlike acute GVHD (aGVHD, the chronic variant of graft versus host disease (GVHD has complex immunopathology involving both humoral and cell immunity. It typically affects the integumentary system, though is known to also affect myofascial, mucocutaneous tissues as well as cause end organ damage ultimately resulting in death. Sclerodermatous cGVHD is a type of cGVHD characterized by involvement of the skin, subcutaneous tissue and fascia without evidence of disease in the viscera. Manifestations of this disease are often evocative of autoimmune disease, which is a self-directed inflammatory reaction to the innate and adaptive immune system in various tissues or multiple organ systems. This inflammatory reaction gives rise to autoantibodies as well as B-cell and T-cell mediated direct toxicity which can cause chronic inflammatory changes of tissues ultimately resulting in tissue scarring and end organ dysfunction. We aim to review the literature on this grave disease and elucidate aspects of the immunopathology of chronic sclerodermatous GVHD in hopes that it may lead to revelations inspiring novel therapies after its diagnosis or preventative measures before stem cell transplantation for malignancy.

  15. Fibroblast Growth Factor-2 Enhances Expansion of Human Bone Marrow-Derived Mesenchymal Stromal Cells without Diminishing Their Immunosuppressive Potential

    OpenAIRE

    Auletta, Jeffery J.; Zale, Elizabeth A.; Welter, Jean F.; Solchaga, Luis A.

    2011-01-01

    Allogeneic hematopoietic stem cell transplantation is the main curative therapy for many hematologic malignancies. Its potential relies on graft-versus-tumor effects which associate with graft-versus-host disease. Mesenchymal stromal cells (MSCs) possess immunomodulatory properties that make them attractive therapeutic alternatives. We evaluated the in vitro immunosuppressive activity of medium conditioned by human MSCs from 5 donors expanded 13 passages with or without FGF-2. FGF-2 supplemen...

  16. Cell Therapy in Parkinson's Disease: Host Brain Repair Machinery Gets a Boost From Stem Cell Grafts.

    Science.gov (United States)

    Napoli, Eleonora; Borlongan, Cesar V

    2017-06-01

    This commentary highlights the major findings and future research directions arising from the recent publication by Zuo and colleagues in Stem Cells 2017 (in press). Here, we discuss the novel observations that transplanted human neural stem cells can induce endogenous brain repair by specifically stimulating a host of regenerative processes in the neurogenic niche (i.e., subventricular zone [SVZ]) in an animal model of Parkinson's disease. That the identified therapeutic proteomes, neurotrophic factors, and anti-inflammatory cytokines in the SVZ may facilitate brain regeneration and behavioral recovery open a new venue of research for our understanding of the pathology and treatment of Parkinson's disease. Stem Cells 2017;35:1443-1445. © 2017 AlphaMed Press.

  17. Diversity in Betasatellites Associated with Cotton Leaf Curl Disease During Source-To-Sink Movement Through a Resistant Host

    Directory of Open Access Journals (Sweden)

    Iftikhar Ali Khan

    2016-02-01

    Full Text Available Cotton leaf curl is devastating disease of cotton characterized by leaf curling, vein darkening and enations. The disease symptoms are induced by DNA satellite known as Cotton leaf curl Multan betasatellite (CLCuMuB, dominant betasatellite in cotton but another betasatellite known as Chili leaf curl betasatellite (ChLCB is also found associated with the disease. Grafting experiment was performed to determine if host plant resistance is determinant of dominant population of betasatellite in cotton (several distinct strains of CLCuMuB are associated with the disease. Infected scion of Gossypium hirsutum collected from field (the source was grafted on G. arboreum, a diploid cotton species, resistant to the disease. A healthy scion of G. hirsutum (sink was grafted at the top of G. arboreum to determine the movement of virus/betasatellite to upper susceptible scion of G. hirsutum. Symptoms of disease appeared in the upper scion and presence of virus/betasatellite in the upper scion was confirmed via molecular techniques, showing that virus/betasatellite was able to move to upper scion through resistant G. arboreum. However, no symptoms appeared on G. arboreum. Betasatelites were cloned and sequenced from lower scion, upper scion and G. arboreum which show that the lower scion contained both CLCuMuB and ChLCB, however only ChLCB was found in G. arboreum. The upper scion contained CLCuMuB with a deletion of 78 nucleotides (nt in the non-coding region between A-rich sequence and βC1 gene and insertion of 27 nt in the middle of βC1 ORF. This study may help in investigating molecular basis of resistance in G. arboreum.

  18. Alternative donor hematopoietic stem cell transplantation for mature lymphoid malignancies after reduced-intensity conditioning regimen

    DEFF Research Database (Denmark)

    Rodrigues, Celso Arrais; Rocha, Vanderson; Dreger, Peter

    2014-01-01

    We have reported encouraging results of unrelated cord blood transplantation for patients with lymphoid malignancies. Whether those outcomes are comparable to matched unrelated donor transplants remains to be defined. We studied 645 adult patients with mature lymphoid malignancies who received...... an allogeneic unrelated donor transplant using umbilical cord blood (n=104) or mobilized peripheral blood stem cells (n=541) after a reduced-intensity conditioning regimen. Unrelated cord blood recipients had more refractory disease. Median follow-up time was 30 months. Neutrophil engraftment (81% vs. 97......%, respectively; Pblood than after matched unrelated donor, whereas no differences were observed in grade II-IV acute graft-versus-host disease (29% vs. 32%), non-relapse mortality (29% vs. 28...

  19. Disseminated Nocardia cyriacigeorgia causing pancreatitis in a haploidentical stem cell transplant recipient

    Directory of Open Access Journals (Sweden)

    Jason Chen

    2017-01-01

    Full Text Available We report the first published case of acute pancreatitis secondary to disseminated nocardiosis in a hematopoietic stem cell transplant (HSCT recipient on chronic immunosuppression for graft-versus-host disease (GVHD. Nocardiosis in the HSCT population is relatively rare, and has not yet been described in haploidentical HSCT recipients. Our patient is a 28-year-old male with a history of haploidentical HSCT and GVHD of the skin and lung who was admitted to the hospital with acute pancreatitis. The workup for the etiology of his pancreatitis was initially unrevealing. He subsequently developed worsening sepsis and respiratory failure despite broad spectrum antimicrobials. After multiple bronchoscopies and pancreatic fluid sampling, he was found to have disseminated nocardiosis with Nocardia cyriacigeorgia.

  20. Salmonella Typhimurium gastroenteritis leading to chronic prosthetic vascular graft infection.

    Science.gov (United States)

    Cullinan, Milo; Clarke, Michael; Dallman, Tim; Peart, Steven; Wilson, Deborah; Weiand, Daniel

    2017-08-01

    Introduction. It is estimated up to 6 % of prosthetic vascular grafts become infected. Staphylococcus aureus is predominant in early infection and coagulase-negative staphylococci are predominant in late infections. Enterobacteriaceae cause 14-40 % of prosthetic vascular graft infections. This is, to our knowledge the first reported case of Salmonella gastroenteritis causing chronic prosthetic vascular graft infection (PVGI). Case presentation. A 57 years old lady presented with signs and symptoms of prosthetic vascular graft infection. Three years earlier, she had undergone a prosthetic axillo-femoral bypass graft for critical limb ischaemia. The infected prosthetic vascular graft was removed and Salmonella Typhimurium was isolated on culture. In the intervening period, Salmonella Typhimurium was isolated from a faecal specimen, collected during an episode of acute gastroenteritis. Whole-genome sequencing (WGS) showed that the respective Salmonella Typhimurium isolates differed by only a single nucleotide polymorphism (SNP). Salmonella Typhimurium was not isolated on culture of a faecal specimen collected five days following cessation of antimicrobial therapy. Six months after removal of the prosthetic graft, the patient remains under follow-up for her peripheral vascular disease, which currently requires no further surgical intervention. Conclusion. This case has clear implications for the management of chronic PVGI. It is vital to collect high-quality surgical specimens for microbiological analysis and empirical choices of antibiotics are unlikely to cover all potential pathogens. It may also be prudent to enquire about a history of acute gastroenteritis when assessing patients presenting with chronic PVGI.

  1. Derivation of a Predictive Model for Graft Loss Following Acute Kidney Injury in Kidney Transplant Recipients.

    Science.gov (United States)

    Molnar, Amber O; van Walraven, Carl; Fergusson, Dean; Garg, Amit X; Knoll, Greg

    2017-01-01

    Acute kidney injury (AKI) is common in the kidney transplant population. To derive a multivariable survival model that predicts time to graft loss following AKI. Retrospective cohort study using health care administrative and laboratory databases. Southwestern Ontario (1999-2013) and Ottawa, Ontario, Canada (1996-2013). We included first-time kidney only transplant recipients who had a hospitalization with AKI 6 months or greater following transplant. AKI was defined using the Acute Kidney Injury Network criteria (stage 1 or greater). The first episode of AKI was included in the analysis. Graft loss was defined by return to dialysis or repeat kidney transplant. We performed a competing risk survival regression analysis using the Fine and Gray method and modified the model into a simple point system. Graft loss with death as a competing event was the primary outcome of interest. A total of 315 kidney transplant recipients who had a hospitalization with AKI 6 months or greater following transplant were included. The median (interquartile range) follow-up time was 6.7 (3.3-10.3) years. Graft loss occurred in 27.6% of the cohort. The final model included 6 variables associated with an increased risk of graft loss: younger age, increased severity of AKI, failure to recover from AKI, lower baseline estimated glomerular filtration rate, increased time from kidney transplant to AKI admission, and receipt of a kidney from a deceased donor. The risk score had a concordance probability of 0.75 (95% confidence interval [CI], 0.69-0.82). The predicted 5-year risk of graft loss fell within the 95% CI of the observed risk more than 95% of the time. The CIs of the estimates were wide, and model overfitting is possible due to the limited sample size; the risk score requires validation to determine its clinical utility. Our prognostic risk score uses commonly available information to predict the risk of graft loss in kidney transplant patients hospitalized with AKI. If validated

  2. Fluid removal in acute heart failure: diuretics versus devices.

    Science.gov (United States)

    Krishnamoorthy, Arun; Felker, G Michael

    2014-10-01

    Fluid removal and relief of congestion are central to treatment of acute heart failure. Diuretics have been the decongestive mainstay but their known limitations have led to the exploration of alternative strategies. This review compares diuretics with ultrafiltration and examines the recent evidence evaluating their use. Relevant recent studies are the Diuretic Optimization Strategies Evaluation trial (of diuretics) and the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (of ultrafiltration). The Diuretic Optimization Strategies Evaluation study evaluated strategies of loop diuretic use during acute heart failure (continuous infusion versus intermittent bolus and high dose versus low dose). After 72  h, there was no significant difference with either comparison for the coprimary end points. Patients treated with a high-dose strategy tended to have greater diuresis and more decongestion compared with low-dose therapy, at the cost of transient changes in renal function. The Cardiorenal Rescue Study in Acute Decompensated Heart Failure study showed that in acute heart failure patients with persistent congestion and worsening renal function, ultrafiltration, as compared with a medical therapy, was associated with similar weight loss but greater increase in serum creatinine and more adverse events. Decongestion remains a major challenge in acute heart failure. Although recent studies provide useful data to guide practice, the relatively poor outcomes point to the continued need to identify better strategies for safe and effective decongestion.

  3. Similar Outcomes in Diabetes Patients After Coronary Artery Bypass Grafting With Single Internal Thoracic Artery Plus Radial Artery Grafting and Bilateral Internal Thoracic Artery Grafting.

    Science.gov (United States)

    Raza, Sajjad; Blackstone, Eugene H; Houghtaling, Penny L; Koprivanac, Marijan; Ravichandren, Kirthi; Javadikasgari, Hoda; Bakaeen, Faisal G; Svensson, Lars G; Sabik, Joseph F

    2017-12-01

    The purpose of this study was to determine in patients with diabetes mellitus whether single internal thoracic artery (SITA) plus radial artery (RA) grafting yields outcomes similar to those of bilateral internal thoracic artery (BITA) grafting. From January 1994 to January 2011, 1,325 diabetic patients underwent primary isolated coronary artery bypass graft surgery with either (1) SITA plus RA with or without saphenous vein (SV) grafts (n = 965) or (2) BITA with or without SV grafts (n = 360); an internal thoracic artery was used in all patients to graft the left anterior descending coronary artery. Endpoints were in-hospital outcomes and time-related mortality. Median follow-up was 7.4 years, with a total follow-up of 9,162 patient-years. Propensity score matching was performed to identify 282 well-matched pairs for adjusted comparisons. Unadjusted in-hospital mortality was 0.52% for SITA plus RA with or without SV grafts and 0.28% for BITA with or without SV grafts, and prevalence of deep sternal wound infection was 3.2% and 1.7%, respectively. Unadjusted survival at 1, 5, 10, and 14 years was 97%, 88%, 68%, and 51% for SITA plus RA with or without SV grafts, and 97%, 95%, 80%, and 66% for BITA with or without SV grafts, respectively. Among propensity-matched patients, in-hospital mortality (0.35% versus 0.35%) and prevalence of deep sternal wound infection (1.4% versus 1.4%) were similar (p > 0.9) in the two groups, as was 1-, 5-, 10-, and 14-year survival: 97%, 90%, 70%, and 58% for SITA plus RA with or without SV grafting versus 97%, 93%, 79%, and 64% for BITA with or without SV grafting, respectively (early p = 0.8, late p = 0.2). For diabetic patients, SITA plus RA with or without SV grafting and BITA with or without SV grafting yield similar in-hospital outcomes and long-term survival after coronary artery bypass graft surgery. Therefore, both SITA plus RA and BITA plus SV grafting should be considered for these patients. Copyright © 2017 The Society

  4. Gastrointestinal surgical emergencies in patients treated for hemathological malignancies.

    Science.gov (United States)

    Caronna, R; Cardi, M; Arcese, W; Iori, A P; Martelli, M; Catinelli, S; Mangioni, S; Corelli, S; Priore, F; Tarantino, E; Frantellizzi, V; Spera, G; Borrini, F; Chirletti, P

    2005-01-01

    Upper and lower gastrointestinal symptoms are major and serious complications in patients who undergo chemotherapy for hematological malignancies. Their most frequent causes are acute intestinal graft-versus-host disease (GVHD) after bone marrow transplant, infections, toxicity or preexisting gastrointestinal diseases. Mortality can reach 30-60% of cases. We report 15 cases operated on for abdominal emergencies: 3 severe gastrointestinal bleeding and 12 acute abdomen. We performed 10 bowel resections, one cholecystectomy, one splenectomy, two laparotomy with pancreatic debridement and peritoneal lavage, and one suture of perforated peptic ulcer. Operative mortality was 33.3% (5/15). Deaths have been reported only in the group of patients with acute abdomen. In all cases death was correlated to generalized sepsis related to immunosuppression. We believe that an aggressive approach, consisting of close monitoring and early laparotomy combined with vigorous supportive therapy, should be used when dealing with suspected gastrointestinal complications in patients with hematological malignancies.

  5. Stem cell mobilization with G-CSF analogs: a rational approach to separate GVHD and GVL?

    Science.gov (United States)

    Morris, Edward S; MacDonald, Kelli P A; Hill, Geoffrey R

    2006-05-01

    The separation of graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) remains the "holy grail" of allogeneic stem cell transplantation, and improvements are urgently needed to allow more effective therapy of malignant disease. The use of G-CSF-mobilized peripheral blood as a clinical stem cell source is associated with enhanced GVL effects without amplification of significant acute GVHD. Preclinical studies have demonstrated that G-CSF modulates donor T cell function before transplantation, promoting T(H)2 differentiation and regulatory T cell function. In addition, the expansion of immature antigen-presenting cells (APCs) and plasmacytoid dendritic cells (DCs) favors the maintenance of this pattern of T cell differentiation after transplantation. Although these patterns of T cell differentiation attenuate acute GVHD, they do not have an impact on the cytolytic pathways of the CD8(+) T cells that are critical for effective GVL. Recently, it has been demonstrated that modification of G-CSF, either by pegylation of the native cytokine or conjugation to Flt-3L, results in the expansion and activation of donor iNKT cells, which significantly augment CD8(+) T cell-mediated cytotoxicity and GVL effects after transplantation. Given that these cytokines also enhance the expansion of regulatory T cells and APCs, they further separate GVHD and GVL, offering potential clinical advantages for the transplant recipient.

  6. Enrichment of autologous fat grafts with ex-vivo expanded adipose tissue-derived stem cells for graft survival

    DEFF Research Database (Denmark)

    Kølle, Stig-Frederik Trojahn; Fischer-Nielsen, Anne; Mathiasen, Anders Bruun

    2013-01-01

    Autologous fat grafting is increasingly used in reconstructive surgery. However, resorption rates ranging from 25% to 80% have been reported. Therefore, methods to increase graft viability are needed. Here, we report the results of a triple-blind, placebo-controlled trial to compare the survival ...... of fat grafts enriched with autologous adipose-derived stem cells (ASCs) versus non-enriched fat grafts....

  7. Fluoroscopically guided placement of self-expandable metallic stents and stent-grafts in the treatment of acute malignant colorectal obstruction.

    Science.gov (United States)

    Kim, Honsoul; Kim, Seung Hyoung; Choi, Sun Young; Lee, Kwang-Hun; Won, Jong Yoon; Lee, Do Yun; Lee, Jong Tae

    2008-12-01

    To evaluate the technical feasibility and clinical effectiveness of fluoroscopically guided placement of self-expandable metallic stents and stent-grafts for acute malignant colorectal obstruction. Radiologic images and clinical reports of 42 patients (22 men, 20 women; age range, 28-93 years; median age, 65.5 years) who underwent fluoroscopically guided colorectal stent insertion without endoscopic assistance for acute malignant obstruction were reviewed retrospectively. Eighteen patients received bare stents as a bridge to surgery. Twenty-four patients received 27 insertions of either a bare stent (n = 15) or a stent-graft (n = 12) for palliation. The obstruction was located in the rectum (n = 8), sigmoid (n = 17), descending colon (n = 8), splenic flexure (n = 3), and transverse colon (n = 6). Clinical success, defined as more than 50% dilatation of the stent with subsequent symptomatic improvement, was achieved in 41 of the 42 patients (98%). No major procedure-related complications occurred. Minor complications occurred in eight of the 45 procedures (18%). No perioperative mortalities occurred within 1 month after surgery. In the palliative group, the median stent patency was 62 days (range, 0-1,014 days). There was no statistically significant difference in stent patency between the bare stents (range, 0-855 days; median, 68 days) and stent-grafts (range, 1-1,014 days; median, 81 days). Fluoroscopically guided placement of self-expandable metallic stents and stent-grafts for the relief of acute malignant colorectal obstruction was technically feasible without endoscopic assistance-even in lesions proximal to the splenic flexure and transverse colon-and clinically effective in both bridge to surgery and palliative management.

  8. Nuclear DNA as Predictor of Acute Kidney Injury in Patients Undergoing Coronary Artery Bypass Graft: A Pilot Study.

    Science.gov (United States)

    Likhvantsev, Valery V; Landoni, Giovanni; Grebenchikov, Oleg A; Skripkin, Yuri V; Zabelina, Tatiana S; Zinovkina, Liudmila A; Prikhodko, Anastasia S; Lomivorotov, Vladimir V; Zinovkin, Roman A

    2017-12-01

    To measure the release of plasma nuclear deoxyribonucleic acid (DNA) and to assess the relationship between nuclear DNA level and acute kidney injury occurrence in patients undergoing cardiac surgery. Cardiovascular anesthesiology and intensive care unit of a large tertiary-care university hospital. Prospective observational study. Fifty adult patients undergoing cardiac surgery. Nuclear DNA concentration was measured in the plasma. The relationship between the level of nuclear DNA and the incidence of acute kidney injury after coronary artery bypass grafting was investigated. Cardiac surgery leads to significant increase in plasma nuclear DNA with peak levels 12 hours after surgery (median [interquartile range] 7.0 [9.6-22.5] µg/mL). No difference was observed between off-pump and on-pump surgical techniques. Nuclear DNA was the only predictor of acute kidney injury between baseline and early postoperative risk factors. The authors found an increase of nuclear DNA in the plasma of patients who had undergone coronary artery bypass grafting, with a peak after 12 hours and an association of nuclear DNA with postoperative acute kidney injury. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Immunohistochemical study of jejunal graft mucosa cell populations during the initial adaptation phase in the host body in rats.

    Science.gov (United States)

    Tóth, Stefan; Jonecová, Zuzana; Varga, Ján; Staško, Pavel; Kovalčinová, Barbora; Maretta, Milan; Leško, Dušan; Veselá, Jarmila

    2013-10-01

    The character of the changes in cell populations within the jejunal graft mucosa during the initial adaptation phase in the host body was investigated. 24 adult male Wistar rats underwent intestinal heterotopic allotransplantation. Aorto-aortal and porto-caval anastomoses were performed using the end-to-side microsurgery technique. Graft tissues were compared to the intestinal tissues of the recipients. This study demonstrates that: (1) Distinct injury to the graft mucosa 1h after transplantation was accompanied by significant reduction in numbers of epithelial secretory cell populations. The injury was more intense in the mesenteric portion. Six hours after transplantation the graft mucosa was covered by a continuous epithelium, but the number of goblet and Paneth cells was found to be less than 30% of that in the recipient epithelium. (2) In comparison with recipients, myeloperoxidase-positive cell numbers increased significantly in the graft mucosa 1 h after transplantation. In the epithelial layer, denudation and destruction of villi was associated with a significant reduction in intraepithelial lymphocyte numbers. A significant decrease in mucosal mast cell numbers was detected 6 h after transplantation. They attained only 10% of the number found in the recipients. (3) Time-dependent changes in the graft mucosa revealed that CD163-positive cells increased significantly in the graft mucosa during 6 h after transplantation and reached the level found in the recipients. In contrast, the myeloperoxidase-positive cell population significantly decreased in the graft mucosa within the initial 6 h. Copyright © 2013 Elsevier GmbH. All rights reserved.

  10. Infectious Bursal Disease Virus-Host Interactions: Multifunctional Viral Proteins that Perform Multiple and Differing Jobs

    Directory of Open Access Journals (Sweden)

    Yao Qin

    2017-01-01

    Full Text Available Infectious bursal disease (IBD is an acute, highly contagious and immunosuppressive poultry disease caused by IBD virus (IBDV. The consequent immunosuppression increases susceptibility to other infectious diseases and the risk of subsequent vaccination failure as well. Since the genome of IBDV is relatively small, it has a limited number of proteins inhibiting the cellular antiviral responses and acting as destroyers to the host defense system. Thus, these virulence factors must be multifunctional in order to complete the viral replication cycle in a host cell. Insights into the roles of these viral proteins along with their multiple cellular targets in different pathways will give rise to a rational design for safer and effective vaccines. Here we summarize the recent findings that focus on the virus–cell interactions during IBDV infection at the protein level.

  11. Does pretransplant soluble CD30 serum concentration affect deceased-donor kidney graft function 3 years after transplantation?

    Science.gov (United States)

    Kovac, J; Arnol, M; Vidan-Jeras, B; Bren, A F; Kandus, A

    2008-06-01

    Elevated serum concentrations of soluble CD30 molecule (sCD30) have been related to acute cellular rejection and poor graft outcomes in kidney transplantation. This historical cohort study investigated the association of pretransplant sCD30 serum concentrations with kidney graft function expressed as estimated glomerular filtration rate (GFR) at 3 years after transplantation. Pretransplant sera from 176 adult deceased-donor kidney graft recipients were tested for sCD30 content using a commercially available automated enzyme-linked immunosorbent assay. The immunosuppression consisted of induction therapy with monoclonal anti-CD25 antibodies and a maintenance regimen of cyclosporine (CsA)-based therapy. GFR was estimated (eGFR) by the four-variable Modification of Diet in Renal Disease (MDRD) Study equation. According to the distribution of pretransplant sCD30 levels (median 66.7 U/mL; interquartile range, 46.6 to 98.6 U/mL), a concentration of 66 U/mL or higher was defined as high (n = 89) and below 66 U/mL as low (n = 87). Three years after transplantation, eGFR was not significantly different among recipients in high versus low sCD30 groups (69 +/- 23 mL/min/1.73m2 vs 66 +/- 21 mL/min/1.73m2; P = .327) and there was no correlation between eGFR and pretransplant sCD30 levels (r2 = 0.001; P = .73). Upon multivariate regression analysis, donor age, recipient body mass index at transplantation, and acute rejection episodes were independent variables affecting eGFR at 3 years after transplantation. This study showed that pretransplant sCD30 serum concentrations were not associated with deceased-donor kidney graft function at 3 years after transplantation. The immunosuppression with anti-CD25 antibodies and a triple CsA-based maintenance regimen could possibly be decisive for our findings.

  12. Regulatory Immunotherapy in Bone Marrow Transplantation

    Directory of Open Access Journals (Sweden)

    Vanessa Morales-Tirado

    2011-01-01

    Full Text Available Every year individuals receive hematopoietic stem cell transplantation (HSCT to eradicate malignant and nonmalignant disease. The immunobiology of allotransplantation is an area of ongoing discovery, from the recipient's conditioning treatment prior to the transplant to the donor cell populations responsible for engraftment, graft-versus-host disease, and graft-versus-tumor effect. In this review, we focus on donor-type immunoregulatory T cells, namely, natural killer T cells (NKT and regulatory T cells (Treg, and their current and potential roles in tolerance induction after allogeneic HSCT.

  13. A randomized comparison of the Saphenous Vein Versus Right Internal Thoracic Artery as a Y-Composite Graft (SAVE RITA) trial: One-year angiographic results and mid-term clinical outcomes.

    Science.gov (United States)

    Kim, Ki-Bong; Hwang, Ho Young; Hahn, Seokyung; Kim, Jun Sung; Oh, Se Jin

    2014-09-01

    The Saphenous Vein Versus Right Internal Thoracic Artery as a Y-Composite Graft (SAVE RITA) trial was designed to evaluate the noninferiority of the saphenous vein (SV) compared with the right internal thoracic artery ([R]ITA) used as a Y-composite graft. A total of 224 patients who had undergone off-pump revascularization for multivessel coronary artery disease using the SV or RITA as a Y-composite graft based on the in situ left ITA were assigned randomly to the SV Y-composite graft (SV group, n = 112) or free RITA Y-composite graft (RITA group, n = 112). The primary endpoint was the 1-year angiographic patency rate of the second limb conduits (SV or RITA). Postoperative 1-year coronary angiograms were performed in 215 patients (SV group, 108; RITA group, 107). The overall graft patency rate was 97.4% (745 of 765) at 1 year (97.9% in the SV group vs 96.9% in the RITA group, P = .362). The primary endpoint of the study, the 1-year patency rate of the SV composite grafts, was 97.1% (238 of 245) and was noninferior to that of the RITA composite grafts (97.1% [198 of 204]) with a 95% lower confidence limit of -2.6% (P RITA composite grafts in terms of the 1-year angiographic patency rates. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

  14. Pleural subxyphoid drain confers better pulmonary function and clinical outcomes in chronic obstructive pulmonary disease after off-pump coronary artery bypass grafting: a randomized controlled trial.

    Science.gov (United States)

    Guizilini, Solange; Viceconte, Marcela; Esperança, Gabriel Tavares da M; Bolzan, Douglas W; Vidotto, Milena; Moreira, Rita Simone L; Câncio, Andréia Azevedo; Gomes, Walter J

    2014-01-01

    To evaluate the lung function and clinical outcome in severe chronic obstructive pulmonary disease in patients undergoing off-pump coronary artery bypass grafting with left internal thoracic artery graft, comparing the pleural drain insertion in the intercostal versus subxyphoid region. A randomized controlled trial. Chronic obstructive pulmonary disease patients were randomized into two groups according pleural drain site: II group (n=27) - pleural drain in intercostal space; SI group (n=29) - pleural drain in the subxyphoid region. Spirometry values (Forced Vital Capacity - and Forced expiratory volume in 1 second) were obtained on preoperative and 1, 3 and 5 postoperative days. Chest x-ray from preoperative until postoperative day 5 (POD5) was performed for monitoring respiratory events, such as atelectasis and pleural effusion. Pulmonary shunt fraction and pain score was evaluate preoperatively and on postoperative day 1. In both groups there was a significant decrease of the spirometry values (Forced Vital Capacity and Forced expiratory volume in 1 second) until POD5 (Ppleural drainage in severe Chronic obstructive pulmonary disease patients determined better preservation and recovery of pulmonary capacity and volumes with lower pulmonary shunt fraction and better clinical outcomes on early postoperative off-pump coronary artery bypass grafting.

  15. Myeloid Sarcoma after Allogenic Stem Cell Transplantation for Acute Myeloid Leukemia: Successful Consolidation Treatment Approaches in Two Patients

    Directory of Open Access Journals (Sweden)

    Silje Johansen

    2018-01-01

    Full Text Available Myeloid sarcoma is an extramedullary (EM manifestation (i.e., manifestation outside the bone marrow of acute myeloid leukemia (AML; it is assumed to be relatively uncommon and can be the only manifestation of leukemia relapse after allogenic stem cell transplantation (allo-SCT. An EM sarcoma can manifest in any part of the body, although preferentially manifesting in immunological sanctuary sites as a single or multiple tumors. The development of myeloid sarcoma after allo-SCT is associated with certain cytogenetic abnormalities, developing of graft versus host disease (GVHD, and treatment with donor lymphocytes infusion (DLI. It is believed that posttransplant myeloid sarcomas develop because the EM sites evade immune surveillance. We present two patients with EM myeloid sarcoma in the breast and epipharynx, respectively, as the only manifestation of leukemia relapse. Both patients were treated with a combination of local and systemic therapy, with successfully longtime disease-free survival. Based on these two case reports, we give an updated review of the literature and discuss the pathogenesis, diagnosis, and treatment of EM sarcoma as the only manifestation of AML relapse after allo-SCT. There are no standard guidelines for the treatment of myeloid sarcomas in allotransplant recipients. In our opinion, the treatment of these patients needs to be individualized and should include local treatment (i.e., radiotherapy combined with systemic therapy (i.e., chemotherapy, immunotherapy, DLI, or retransplantation. The treatment has to consider both the need for sufficient antileukemic efficiency versus the risk of severe complications due to cumulative toxicity.

  16. Guidelines on the use of extracorporeal photopheresis

    DEFF Research Database (Denmark)

    Knobler, R; Berlin, G; Calzavara-Pinton, P

    2014-01-01

    of other severe and refractory conditions in a multi-disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease. MATERIALS AND METHODS: In order...

  17. Corruption of dendritic cell antigen presentation during acute GVHD leads to regulatory T-cell failure and chronic GVHD.

    Science.gov (United States)

    Leveque-El Mouttie, Lucie; Koyama, Motoko; Le Texier, Laetitia; Markey, Kate A; Cheong, Melody; Kuns, Rachel D; Lineburg, Katie E; Teal, Bianca E; Alexander, Kylie A; Clouston, Andrew D; Blazar, Bruce R; Hill, Geoffrey R; MacDonald, Kelli P A

    2016-08-11

    Chronic graft-versus-host disease (cGVHD) is a major cause of late mortality following allogeneic bone marrow transplantation (BMT) and is characterized by tissue fibrosis manifesting as scleroderma and bronchiolitis obliterans. The development of acute GVHD (aGVHD) is a powerful clinical predictor of subsequent cGVHD, suggesting that aGVHD may invoke the immunologic pathways responsible for cGVHD. In preclinical models in which sclerodermatous cGVHD develops after a preceding period of mild aGVHD, we show that antigen presentation within major histocompatibility complex (MHC) class II of donor dendritic cells (DCs) is markedly impaired early after BMT. This is associated with a failure of regulatory T-cell (Treg) homeostasis and cGVHD. Donor DC-restricted deletion of MHC class II phenocopied this Treg deficiency and cGVHD. Moreover, specific depletion of donor Tregs after BMT also induced cGVHD, whereas adoptive transfer of Tregs ameliorated it. These data demonstrate that the defect in Treg homeostasis seen in cGVHD is a causative lesion and is downstream of defective antigen presentation within MHC class II that is induced by aGVHD. © 2016 by The American Society of Hematology.

  18. Overview of marrow transplantation

    International Nuclear Information System (INIS)

    Thomas, E.D.

    1985-01-01

    Bone marrow transplantation is now an accepted form of therapy for many hematologic disorders including aplastic anemia, genetically determined diseases and malignant diseases, particularly leukemia, and for rescue of patients given intensive chemoradiotherapy for malignant disease. The donor may be a healthy identical twin, a family member or even an unrelated person. Selection is made on the basis of human leukocyte antigen tissue typing. Intensive chemoradiotherapy is used to suppress patients' immune systems to facilitate engraftment and destroy diseased marrow. Transfusion of platelets, erythrocytes and granulocytes (or all of these), antibiotic coverage and protection from infection are necessary during the pancytopenic period. Survival rates vary considerably depending on a patient's disease, clinical state and age. Patients with aplastic anemia transplanted early in the course of their disease have a survival rate of approximately 80%. Patients with acute lymphoblastic leukemia are usually transplanted in a second or subsequent remission and have a survival rate of 25% to 40%. Patients with acute nonlymphoblastic leukemia in remission have survivals ranging from 45% to 70%. More than 200 patients in the chronic phase of chronic granulocytic leukemia have been transplanted with survival ranging from 50% to 70%. Complications of marrow transplantation include marrow graft rejection, graft-versus-host disease, immunologic insufficiency and the possibility of recurrence of the leukemia. 14 references

  19. Outcomes of Prosthetic Hemodialysis Grafts after Deployment of Bare Metal versus Covered Stents at the Venous Anastomosis

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Charles Y., E-mail: charles.kim@duke.edu; Tandberg, Daniel J.; Rosenberg, Michael D.; Miller, Michael J.; Suhocki, Paul V.; Smith, Tony P. [Duke University Medical Center, Division of Vascular and Interventional Radiology (United States)

    2012-08-15

    Purpose: To compare postintervention patency rates after deployment of bare metal versus covered stents across the venous anastomosis of prosthetic arteriovenous (AV) grafts. Methods: Review of our procedural database over a 6 year period revealed 377 procedures involving stent deployment in an AV access circuit. After applying strict inclusion criteria, our study group consisted of 61 stent deployments in 58 patients (median age 58 years, 25 men, 33 women) across the venous anastomosis of an upper extremity AV graft circuit that had never been previously stented. Both patent and thrombosed AV access circuits were retrospectively analyzed. Within the bare metal stent group, 20 of 32 AV grafts were thrombosed at initial presentation compared to 18 of 29 AV grafts in the covered stent group. Results: Thirty-two bare metal stents and 29 covered stents were deployed across the venous anastomosis. The 3, 6, and 12 months primary access patency rates for bare metal stents were not significantly different than for covered stents: 50, 41, and 22 % compared to 59, 52, and 29 %, respectively (p = 0.21). The secondary patency rates were also not significantly different: 78, 78, and 68 % for bare metal stents compared to 76, 69, and 61 % for covered stents, respectively (p = 0.85). However, covered stents demonstrated a higher primary stent patency rate than bare metal stents: 100, 85, and 70 % compared to 75, 67, and 49 % at 3, 6, and 12 months (p < 0.01). Conclusion: The primary and secondary access patency rates after deployment of bare metal versus covered stents at the venous anastomosis were not significantly different. However, bare metal stents developed in-stent stenoses significantly sooner.

  20. Outcomes of Prosthetic Hemodialysis Grafts after Deployment of Bare Metal versus Covered Stents at the Venous Anastomosis

    International Nuclear Information System (INIS)

    Kim, Charles Y.; Tandberg, Daniel J.; Rosenberg, Michael D.; Miller, Michael J.; Suhocki, Paul V.; Smith, Tony P.

    2012-01-01

    Purpose: To compare postintervention patency rates after deployment of bare metal versus covered stents across the venous anastomosis of prosthetic arteriovenous (AV) grafts. Methods: Review of our procedural database over a 6 year period revealed 377 procedures involving stent deployment in an AV access circuit. After applying strict inclusion criteria, our study group consisted of 61 stent deployments in 58 patients (median age 58 years, 25 men, 33 women) across the venous anastomosis of an upper extremity AV graft circuit that had never been previously stented. Both patent and thrombosed AV access circuits were retrospectively analyzed. Within the bare metal stent group, 20 of 32 AV grafts were thrombosed at initial presentation compared to 18 of 29 AV grafts in the covered stent group. Results: Thirty-two bare metal stents and 29 covered stents were deployed across the venous anastomosis. The 3, 6, and 12 months primary access patency rates for bare metal stents were not significantly different than for covered stents: 50, 41, and 22 % compared to 59, 52, and 29 %, respectively (p = 0.21). The secondary patency rates were also not significantly different: 78, 78, and 68 % for bare metal stents compared to 76, 69, and 61 % for covered stents, respectively (p = 0.85). However, covered stents demonstrated a higher primary stent patency rate than bare metal stents: 100, 85, and 70 % compared to 75, 67, and 49 % at 3, 6, and 12 months (p < 0.01). Conclusion: The primary and secondary access patency rates after deployment of bare metal versus covered stents at the venous anastomosis were not significantly different. However, bare metal stents developed in-stent stenoses significantly sooner.

  1. In vivo T-cell depletion using alemtuzumab in family and unrelated donor transplantation for pediatric non-malignant disease achieves engraftment with low incidence of graft vs. host disease.

    Science.gov (United States)

    Saif, M A; Borrill, R; Bigger, B W; Lee, H; Logan, A; Poulton, K; Hughes, S; Turner, A J; Bonney, D K; Wynn, R F

    2015-03-01

    In vivo T-cell depletion, using alemtuzumab therapy prior to SCT, can reduce the incidence of GVHD. This treatment has a potential to delay immune reconstitution resulting in increased morbidity due to viral illnesses. We retrospectively analyzed data on all pediatric patients with non-malignant disorders who received alemtuzumab-based conditioning regimens in our center over the last 10 yr (n = 91). Our data show an OS of 91.2%. The incidence of acute (grade 2-4) GVHD was 18.7% and that of chronic GVHD 5.5%. Viremia due to adenovirus, EBV and CMV was seen in 19.8%, 64.8% and 39.6% patients, respectively, with only two deaths attributed to viral infection (adenovirus). Chimerism level at three month was predictive of graft outcome. Nine patients, who had graft failure after first SCT, were salvaged with a second SCT using RIC and same donor (if available). Based on these results, we conclude that the use of in vivo T-cell depletion is safe, achieves good chimerism and does not lead to increased morbidity and mortality due to viral infections. It is associated with a reduced incidence of chronic GVHD. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Sixteen adult patients with acute leukemia treated by chemotherapy, total body irradiation and allogeneic marrow transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Kodera, Yoshihisa; Morishima, Yasuo; Morishita, Yoshihisa [Nagoya Univ. (Japan). Faculty of Medicine

    1984-12-01

    Since 1976, 16 adult patients with acute leukemia have been treated by chemotherapy, total body irradiation (TBI) and allogeneic bone marrow transplantation (BMT) in the medical school hospital and the satellite hospitals of Nagoya University. The first group of 10 patients were given marrow grafts at the time of leukemic relapse and the second group of six patients were given the grafts in the period of remission of their disease. For the first group (ALL/ANLL 2:8, age (median) 33, M/F 8:2), HLA-identical donor cells (25 x 10/sup 7//kg(median)) were infused after the patients were conditioned with NSC D 245382 (ACNU) or daunorubicin, cyclophosphamide (CY) and a single shot of 1000 rad of TBI. For the second group (ALL/ANLL 4:2, age (median) 20, M/F 5:1), HLA-identical donor cells (22 x 10/sup 7//kg(median)) were infused after the patients were conditioned with CY and fractionated (250 rad x 4) TBI. All the patients were isolated in a laminar air flow room (LAF) after gut and skin decontamination. Engraftment of donor cells was confirmed in 15 out of the 16 patients. Febrile periods in LAF and the days required for platelet transfusion were prolonged in the first group. All the patients in the first group died within 12-214 days after BMT because of interstitial pneumonitis (7 patients) or bacterial infection (3 patients). On the other hand, five out of six patients in the second group are alive 84-540 days after BMT. For the surviving patients, the complications of chronic graft versus host disease, viral infections, tuberculosis, hepatitis, hemorrhagic cystitis and recurrence of leukemia are now the problems. It can be stated that the patient's clinical condition at the time of BMT is one of the most essential factors for the success of BMT although the effects of other variables, such as a change in the conditioning regimens or the supportive care, must also be carefully analyzed.

  3. A comparison of patency and interventions in thigh versus Hemodialysis Reliable Outflow grafts for chronic hemodialysis vascular access.

    Science.gov (United States)

    Brownie, Evan R; Kensinger, Clark D; Feurer, Irene D; Moore, Derek E; Shaffer, David

    2016-11-01

    With improvements in medical management and survival of patients with end-stage renal disease, maintaining durable vascular access is increasingly challenging. This study compared primary, assisted primary, and secondary patency, and procedure-specific complications, and evaluated whether the number of interventions to maintain or restore patency differed between prosthetic femoral-femoral looped inguinal access (thigh) grafts and Hemodialysis Reliable Outflow (HeRO; Hemosphere Inc, Minneapolis, Minn) grafts. A single-center, retrospective, intention-to-treat analysis was conducted of consecutive thigh and HeRO grafts placed between May 2004 and June 2015. Medical history, interventions to maintain or restore patency, and complications were abstracted from the electronic medical record. Data were analyzed using parametric and nonparametric statistical tests, Kaplan-Meier survival methods, and multivariable proportional hazards regression and logistic regression. Seventy-six (43 thigh, 33 HeRO) grafts were placed in 61 patients (54% male; age 53 [standard deviation, 13] years). Median follow-up time in the intention-to-treat analysis was 21.2 months (min, 0.0; max, 85.3 months) for thigh grafts and 6.7 months (min, 0.0; max, 56.3 months) for HeRO grafts (P = .02). The groups were comparable for sex, age, coronary artery disease, diabetes mellitus, peripheral vascular disease, and smoking history (all P ≥ .12). One thigh graft (2%) and five HeRO (15%) grafts failed primarily. In the intention-to-treat analysis, patency durations were significantly longer in the thigh grafts (all log-rank P ≤ .01). Point estimates of primary patency at 6 months, 1 year, and 3 years were 61%, 46%, and 4% for the thigh grafts and 25%, 15%, and 6% for the HeRO grafts. Point estimates of assisted primary patency at 6 months, 1 year, and 3 years were 75%, 66%, and 54% for the thigh grafts and 41%, 30%, and 10% for the HeRO grafts. Point estimates of secondary patency at 6

  4. FEATURES OF PLASMAPHERESIS IN THE TREATMENT OF GRAFT REJECTION AFTER KIDNEY TRANSPLANTATION

    Directory of Open Access Journals (Sweden)

    A. V. Vatazin

    2015-01-01

    Full Text Available Introduction. The development of immunological confl ict in the form of host-versus-graft reaction has always been main problem in transplantation. The worst case is the development of humoral rejection with the presence of circulating immune complexes and antibodies. There are several methods for quick removal of antibodies; among those are traditional plasmapheresis (PA and double fi ltration plasmapheresis (DFPF. In this paper we present our experience with these two methods and give a comparative evaluation of the effectiveness in the treatment of acute humoral rejection in renal allograft. Aim: to compare the effectiveness of traditional and double fi ltration plasmapheresis while processing different volumes of plasma in the treatment of host-versus-graft disease after kidney transplantation.Methods. The study included 58 patients after kidney transplantation. All patients had increased activity of humoral immunity, which was confi rmed by immunofl uorescence with luminescence C4d complement component. In 26 patients we performed DFPF, in 32 patients – traditional PA. We divided the DFPF patients into 4 subgroups depending on the amount of processed plasma: > 50% (5 patients, 50–100% (8 patients, 100–150% (7 patients, 150–200% (6 patients of circulating plasma volume. We also divided PA patients into four subgroups depending on the volume of plasma removed: >50% (8 patients, 50–70% (12 patients, 70–90% (7 patients, 90–110% (5 patients of the volume of circulating plasma. We monitored the immune status with markers of humoral immunity activation IgM, IgG before and after each of the procedures.Results. Each procedure of traditional PA and DFPF was accompanied by a marked decrease in blood concentrations of IgM and IgG antibodies. Their level decreased by an average of 30–55% of the original. However, some patients in both groups showed an increase in the concentration of these immunoglobulins in 1–2 days

  5. Grafted c-kit+/SSEA1- eye-wall progenitor cells delay retinal degeneration in mice by regulating neural plasticity and forming new graft-to-host synapses.

    Science.gov (United States)

    Chen, Xi; Chen, Zehua; Li, Zhengya; Zhao, Chen; Zeng, Yuxiao; Zou, Ting; Fu, Caiyun; Liu, Xiaoli; Xu, Haiwei; Yin, Zheng Qin

    2016-12-30

    Despite diverse pathogenesis, the common pathological change observed in age-related macular degeneration and in most hereditary retinal degeneration (RD) diseases is photoreceptor loss. Photoreceptor replacement by cell transplantation may be a feasible treatment for RD. The major obstacles to clinical translation of stem cell-based cell therapy in RD remain the difficulty of obtaining sufficient quantities of appropriate and safe donor cells and the poor integration of grafted stem cell-derived photoreceptors into the remaining retinal circuitry. Eye-wall c-kit + /stage-specific embryonic antigen 1 (SSEA1) - cells were isolated via fluorescence-activated cell sorting, and their self-renewal and differentiation potential were detected by immunochemistry and flow cytometry in vitro. After labeling with quantum nanocrystal dots and transplantation into the subretinal space of rd1 RD mice, differentiation and synapse formation by daughter cells of the eye-wall c-kit + /SSEA1 - cells were evaluated by immunochemistry and western blotting. Morphological changes of the inner retina of rd1 mice after cell transplantation were demonstrated by immunochemistry. Retinal function of rd1 mice that received cell grafts was tested via flash electroretinograms and the light/dark transition test. Eye-wall c-kit + /SSEA1 - cells were self-renewing and clonogenic, and they retained their proliferative potential through more than 20 passages. Additionally, eye-wall c-kit + /SSEA1 - cells were capable of differentiating into multiple retinal cell types including photoreceptors, bipolar cells, horizontal cells, amacrine cells, Müller cells, and retinal pigment epithelium cells and of transdifferentiating into smooth muscle cells and endothelial cells in vitro. The levels of synaptophysin and postsynaptic density-95 in the retinas of eye-wall c-kit + /SSEA1 - cell-transplanted rd1 mice were significantly increased at 4 weeks post transplantation. The c-kit + /SSEA1 - cells were

  6. Pulmonary Surfactants for Acute and Chronic Lung Diseases (Part II

    Directory of Open Access Journals (Sweden)

    O. A. Rozenberg

    2014-01-01

    Full Text Available Part 2 of the review considers the problem of surfactant therapy for acute respiratory distress syndrome (ARDS in adults and young and old children. It gives information on the results of surfactant therapy and prevention of ARDS in patients with severe concurrent trauma, inhalation injuries, complications due to complex expanded chest surgery, or severe pneumonias, including bilateral pneumonia in the presence of A/H1N1 influenza. There are data on the use of a surfactant in obstetric care and prevention of primary graft dysfunction during lung transplantation. The results of longterm use of surfactant therapy in Russia, suggesting that death rates from ARDS may be substantially reduced (to 20% are discussed. Examples of surfactant therapy for other noncritical lung diseases, such as permanent athelectasis, chronic obstructive pulmonary diseases, and asthma, as well tuberculosis, are also considered.

  7. Inflammatory conditions affect gene expression and function of human adipose tissue-derived mesenchymal stem cells

    NARCIS (Netherlands)

    M.J. Crop (Meindert); C.C. Baan (Carla); S.S. Korevaar (Sander); J.N.M. IJzermans (Jan); M. Pescatori (Mario); A. Stubbs (Andrew); W.F.J. van IJcken (Wilfred); M.H. Dahlke (Marc); E. Eggenhofer (Elke); W. Weimar (Willem); M.J. Hoogduijn (Martin)

    2010-01-01

    textabstractThere is emerging interest in the application of mesenchymal stem cells (MSC) for the prevention and treatment of autoimmune diseases, graft-versus-host disease and allograft rejection. It is, however, unknown how inflammatory conditions affect phenotype and function of MSC. Adipose

  8. Ilizarov bone transport versus fibular graft for reconstruction of tibial bone defects in children.

    Science.gov (United States)

    Abdelkhalek, Mostafa; El-Alfy, Barakat; Ali, Ayman M

    2016-11-01

    The aim of this study was to compare the results of treatment of segmental tibial defects in the pediatric age group using an Ilizarov external fixator versus a nonvascularized fibular bone graft. This study included 24 patients (age range from 5.5 to 15 years) with tibial bone defects: 13 patients were treated with bone transport (BT) and 11 patients were treated with a nonvascularized fibular graft (FG). The outcome parameters were bone results (union, deformity, infection, leg-length discrepancy) and functional results: external fixation index and external fixation time. In group A (BT), one patient developed refracture at the regenerate site, whereas, in group B (FG), after removal of the external fixator, one of the FGs developed a stress fracture. The external fixator time in group A was 10.7 months (range 8-14.5) versus 7.8 months (range 4-11.5 months) in group B (FG). In group A (BT), one patient had a limb-length discrepancy (LLD), whereas, in group B (FG), three patients had LLD. The functional and bone results of the Ilizarov BT technique were excellent in 23.1 and 30.8%, good in 38.5 and 46.2, fair in 30.8 and 15.4, and poor in 7.6 and 7.6%, respectively. The poor functional result was related to the poor bone result because of prolonged external fixator time resulting in significant pain, limited ankle motion, whereas the functional and bone results of fibular grafting were excellent in 9.1 and 18.2%, good in 63.6 and 45.5%, fair in 18.2 and 27.2%, and poor in 9.1 and 9.1%, respectively. Segmental tibial defects can be effectively treated with both methods. The FG method provides satisfactory results, with early removal of the external fixator. However, it had a limitation in patients with severe infection and those with LLD. Also, it requires a long duration of limb bracing until adequate hypertrophy of the graft. The Ilizarov method has the advantages of early weight bearing, treatment of postinfection bone defect in a one-stage surgery, and the

  9. Salvaged allogeneic hematopoietic stem cell transplantation for pediatric chemotherapy refractory acute leukemia.

    Science.gov (United States)

    Wang, Jingbo; Yuan, Lei; Cheng, Haoyu; Fei, Xinhong; Yin, Yumin; Gu, Jiangying; Xue, Song; He, Junbao; Yang, Fan; Wang, Xiaocan; Yang, Yixin; Zhang, Weijie

    2018-01-09

    There is an ongoing debate concerning the performance of salvaged allogeneic hematopoietic stem cell transplantation (allo-HSCT) in pediatric patients with acute refractory leukemia, in whom the prognosis is quite dismal. Few studies have ever been conducted on this subject. This may be partly due to missed opportunities by majority of the patients in such situations. To investigate the feasibility, evaluate the efficiency, and identify the prognostic factors of allo-HSCT in this sub-setting, the authors performed a single institution-based retrospective analysis. A total of 44 patients, of whom 28 had acute myeloid leukemia (AML), 13 had acute lymphocytic leukemia (ALL), and 3 had mixed phenotype leukemia (MPL), were enrolled in this study. With a median follow-up of 19 months, the estimated 2-year overall survival (OS) and progression free survival (PFS) were 34.3% (95% CI, 17.9-51.4%) and 33.6% (95% CI, 18.0-50.1%), respectively. The estimated 2-year incidence rates of relapse and non-relapse mortality (NRM) were 43.8% (95% CI 26.4-60.0%) and 19.6% (95% CI 9.1-32.9%), respectively. The estimated 100-day cumulative incidence of acute graft versus host disease (aGvHD) was 43.6% (95% CI 28.7-57.5%), and the 1-year cumulative incidence of chronic GvHD (cGvHD) was 45.5% (95% CI 30.5-59.3%). Compared with the previous studies, the multivariate analysis in this study additionally identified that female donors and cGvHD were associated with lower relapse and better PFS and OS. Male recipients, age younger than 10 years, a diagnosis of ALL, and the intermediate-adverse cytogenetic risk group were associated with increased relapse. On the contrary, extramedullary disease (EMD) and aGvHD were only linked to worse PFS. These data suggested that although only one-third of the patients would obtain PFS over 2 years, salvaged allo-HSCT is still the most reliable and best therapeutic strategy for refractory pediatric acute leukemia. If probable, choosing a female donor, better

  10. Identification of Heme Oxygenase-1 as a Novel Predictor of Hematopoietic Stem Cell Transplantation Outcomes in Acute Leukemia

    Directory of Open Access Journals (Sweden)

    Yinghao Lu

    2016-09-01

    Full Text Available Objective: The main aim of this study was to determine the correlation between clinical outcome and heme oxygenase-1 (HO-1 expression before and after hematopoietic stem cell transplantation (HSCT in acute leukemia. Methods: HO-1 mRNA levels in 83 patients were measured using qRT-PCR. In a comparative analysis of HO-1 levels in relation to different post-transplant outcomes, the HO-1 threshold, determined via the receiver operating characteristic (ROC curve, was effectively used to predict clinical relapse and acute graft-versus-host disease (aGVHD. The correlations among clinical relapse, aGVHD and HO-1 expression were analyzed based on this threshold. Results: Leukemia risk stratification and relative expression of HO-1 before pretreatment had significant effects on clinical relapse. Leukemia risk stratification, relative expression of HO-1 after HSCT and the interval from diagnosis to transplantation had a significant influence on aGVHD. Both relapse and aGVHD appeared to be associated with relative HO-1 expression. The relative expression rate of HO-1 was 1.131-1.186 before pretreatment, and strongly associated with post-transplantation relapse. The relative expression rate of HO-1 was 1.102-1.144 after transplantation, and closely related to aGVHD. ROC curve analysis revealed high specificity and sensitivity of HO-1 expression in predicting relapse and aGVHD after allo-HSCT. Conclusions: HO-1 expression can be effectively used as a predictor of relapse as well as a diagnostic factor of aGVHD after transplantation for allo-HSCT patients with acute leukemia.

  11. Suppressor cells in transplantation tolerance II. Maturation of suppressor cells in the bone marrow chimera

    International Nuclear Information System (INIS)

    Tutschka, P.J.; Ki, P.F.; Beschorner, W.E.; Hess, A.D.; Santos, G.W.

    1981-01-01

    Histoincompatible bone marrow allografts were established in lethally irradiated rats. At various times after transplantation, the spleen cells were harvested, subjected to mixed lymphocyte cultures, and assayed for suppressor cells in vitro and in vivo by adoptive transfer studies. Alloantigen-nonspecific suppressor cells appeared in the chimera at 40 days after grafting, coinciding with the resolution of graft-versus-host disease (GVHD). At 250 days the nonspecific suppressor cells were replaced by suppressor cells specifically suppressing donor-versus-host alloantigen responses. At 720 days suppressor cells could no longer be identified by in vitro methods but were identified by in vivo adoptive transfer of transplantation tolerance. After injection of host-type antigen into chimeras, the suppressor cells could be again demonstrated by in vitro methods

  12. Suppressor cells in transplantation tolerance. II. maturation of suppressor cells in the bone marrow chimera

    International Nuclear Information System (INIS)

    Tutschka, P.J.; Ki, P.F.; Beschorner, W.E.; Hess, A.D.; Santos, G.W.

    1981-01-01

    Histoincompatible bone marrow allografts were established in lethally irradiated rats. At various times after transplantation, the spleen cells were harvested, subjected to mixed lymphocyte cultures, and assayed for suppressor cells in vitro and in vivo by adoptive transfer studies. Alloantigen-nonspecific suppressor cells appeared in the chimera at 40 days after grafting, coinciding with the resolution of graft-versus-host disease (GVHD). At 250 days the nonspecific suppressor cells were replaced by suppressor cells specifically suppressing donor-versus-host alloantigen responses. At 720 days suppressor cells could no longer be identified by in vitro methods but were identified by in vivo adoptive transfer of transplantation tolerance. After injection of host-type antigen into chimeras, the suppressor cells could be again demonstrated by in vitro methods

  13. Longitudinal Transcriptome Analysis Reveals a Sustained Differential Gene Expression Signature in Patients Treated for Acute Lyme Disease.

    Science.gov (United States)

    Bouquet, Jerome; Soloski, Mark J; Swei, Andrea; Cheadle, Chris; Federman, Scot; Billaud, Jean-Noel; Rebman, Alison W; Kabre, Beniwende; Halpert, Richard; Boorgula, Meher; Aucott, John N; Chiu, Charles Y

    2016-02-12

    Lyme disease is a tick-borne illness caused by the bacterium Borrelia burgdorferi, and approximately 10 to 20% of patients report persistent symptoms lasting months to years despite appropriate treatment with antibiotics. To gain insights into the molecular basis of acute Lyme disease and the ensuing development of post-treatment symptoms, we conducted a longitudinal transcriptome study of 29 Lyme disease patients (and 13 matched controls) enrolled at the time of diagnosis and followed for up to 6 months. The differential gene expression signature of Lyme disease following the acute phase of infection persisted for at least 3 weeks and had fewer than 44% differentially expressed genes (DEGs) in common with other infectious or noninfectious syndromes. Early Lyme disease prior to antibiotic therapy was characterized by marked upregulation of Toll-like receptor signaling but lack of activation of the inflammatory T-cell apoptotic and B-cell developmental pathways seen in other acute infectious syndromes. Six months after completion of therapy, Lyme disease patients were found to have 31 to 60% of their pathways in common with three different immune-mediated chronic diseases. No differential gene expression signature was observed between Lyme disease patients with resolved illness to those with persistent symptoms at 6 months post-treatment. The identification of a sustained differential gene expression signature in Lyme disease suggests that a panel of selected human host-based biomarkers may address the need for sensitive clinical diagnostics during the "window period" of infection prior to the appearance of a detectable antibody response and may also inform the development of new therapeutic targets. Lyme disease is the most common tick-borne infection in the United States, and some patients report lingering symptoms lasting months to years despite antibiotic treatment. To better understand the role of the human host response in acute Lyme disease and the

  14. Small hypoxia-primed mesenchymal stem cells attenuate graft-versus-host disease

    KAUST Repository

    Kim, YongHwan; Jin, Hye Jin; Heo, Jinbeom; Ju, Hyein; Lee, Hye-Yeon; Kim, Sujin; Lee, Seungun; Lim, Jisun; Jeong, Sang Young; Kwon, JiHye; Kim, Miyeon; Choi, Soo Jin; Oh, Wonil; Yang, Yoon Sun; Hwang, Hyun Ho; Yu, Hwan Yeul; Ryu, Chae-Min; Jeon, Hong Bae; Shin, Dong-Myung

    2018-01-01

    mouse model, resulting in significantly improved survival, less weight loss, and reduced histopathologic injuries in GVHD target organs compared with naïve MSC-infused mice. Collectively, our findings suggest that SHC-MSCs can improve the clinical

  15. One-unit versus two-unit cord-blood transplantation for hematologic cancers.

    Science.gov (United States)

    Wagner, John E; Eapen, Mary; Carter, Shelly; Wang, Yanli; Schultz, Kirk R; Wall, Donna A; Bunin, Nancy; Delaney, Colleen; Haut, Paul; Margolis, David; Peres, Edward; Verneris, Michael R; Walters, Mark; Horowitz, Mary M; Kurtzberg, Joanne

    2014-10-30

    Umbilical-cord blood has been used as the source of hematopoietic stem cells in an estimated 30,000 transplants. The limited number of hematopoietic cells in a single cord-blood unit prevents its use in recipients with larger body mass and results in delayed hematopoietic recovery and higher mortality. Therefore, we hypothesized that the greater numbers of hematopoietic cells in two units of cord blood would be associated with improved outcomes after transplantation. Between December 1, 2006, and February 24, 2012, a total of 224 patients 1 to 21 years of age with hematologic cancer were randomly assigned to undergo double-unit (111 patients) or single-unit (113 patients) cord-blood transplantation after a uniform myeloablative conditioning regimen and immunoprophylaxis for graft-versus-host disease (GVHD). The primary end point was 1-year overall survival. Treatment groups were matched for age, sex, self-reported race (white vs. nonwhite), performance status, degree of donor-recipient HLA matching, and disease type and status at transplantation. The 1-year overall survival rate was 65% (95% confidence interval [CI], 56 to 74) and 73% (95% CI, 63 to 80) among recipients of double and single cord-blood units, respectively (P=0.17). Similar outcomes in the two groups were also observed with respect to the rates of disease-free survival, neutrophil recovery, transplantation-related death, relapse, infections, immunologic reconstitution, and grade II-IV acute GVHD. However, improved platelet recovery and lower incidences of grade III and IV acute and extensive chronic GVHD were observed among recipients of a single cord-blood unit. We found that among children and adolescents with hematologic cancer, survival rates were similar after single-unit and double-unit cord-blood transplantation; however, a single-unit cord-blood transplant was associated with better platelet recovery and a lower risk of GVHD. (Funded by the National Heart, Lung, and Blood Institute and the

  16. Peripheral blood hematopoietic stem cells for transplantation of hematological diseases from related, haploidentical donors after reduced-intensity conditioning.

    Science.gov (United States)

    Raj, Kavita; Pagliuca, Antonio; Bradstock, Kenneth; Noriega, Victor; Potter, Victoria; Streetly, Matthew; McLornan, Donal; Kazmi, Majid; Marsh, Judith; Kwan, John; Huang, Gillian; Getzendaner, Lisa; Lee, Stephanie; Guthrie, Katherine A; Mufti, Ghulam J; O'Donnell, Paul

    2014-06-01

    In a multicenter collaboration, we carried out T cell-replete, peripheral blood stem cell (PBSC) transplantations from related, HLA-haploidentical donors with reduced-intensity conditioning (RIC) and post-transplantation cyclophosphamide (Cy) as graft-versus-host disease (GVHD) prophylaxis in 55 patients with high-risk hematologic disorders. Patients received 2 doses of Cy 50 mg/kg i.v. on days 3 and 4 after infusion of PBSC (mean, 6.4 × 10(6)/kg CD34(+) cells; mean, 2.0 × 10(8)/kg CD3(+) cells). The median times to neutrophil (500/μL) and platelet (>20,000/μL) recovery were 17 and 21 days respectively. All but 2 of the patients achieved full engraftment. The 1-year cumulative incidences of grade II and grade III acute GVHD were 53% and 8%, respectively. There were no cases of grade IV GVHD. The 2-year cumulative incidence of chronic GHVD was 18%. With a median follow-up of 509 days, overall survival and event-free survival at 2 years were 48% and 51%, respectively. The 2-year cumulative incidences of nonrelapse mortality and relapse were 23% and 28%, respectively. Our results suggest that PBSC can be substituted safely and effectively for bone marrow as the graft source for haploidentical transplantation after RIC. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  17. Allogeneic bone marrow grafts in genotyped swine

    International Nuclear Information System (INIS)

    Vaiman, M.

    1974-01-01

    The proof of a major histocompatibility complex (MHC) called SL-A enabled to promote bone marrow allografts. A study of the response to that kind of graft in irradiated pig states a number of interesting points. Bone marrow allografting complies with the rule of tissular compatibility with the major histocompatibility complex. The taking of SL-A incompatible bone marrow allografts could not be achieved under the experimental conditions. In spite of the high doses of radiation, 950 to 1050 rads, higher than 1.5 LD 100%, recipients were capable of rejecting their grafts, regularly. SL-A identify ensured 100%, initial achievement. However, animals developed regular fatal disease within a fairly short time. This development could by no means, be ascribed to the sole sequealae of radiation sickness since autografted animals at equal or even higher doses, showed none of the symptome. Assumption of a chronic graft-vs-host reactions, induced by the minor histocompatible systems, was put foreward, but should be confirmed histopathologically [fr

  18. A novel host-proteome signature for distinguishing between acute bacterial and viral infections.

    Directory of Open Access Journals (Sweden)

    Kfir Oved

    Full Text Available Bacterial and viral infections are often clinically indistinguishable, leading to inappropriate patient management and antibiotic misuse. Bacterial-induced host proteins such as procalcitonin, C-reactive protein (CRP, and Interleukin-6, are routinely used to support diagnosis of infection. However, their performance is negatively affected by inter-patient variability, including time from symptom onset, clinical syndrome, and pathogens. Our aim was to identify novel viral-induced host proteins that can complement bacterial-induced proteins to increase diagnostic accuracy. Initially, we conducted a bioinformatic screen to identify putative circulating host immune response proteins. The resulting 600 candidates were then quantitatively screened for diagnostic potential using blood samples from 1002 prospectively recruited patients with suspected acute infectious disease and controls with no apparent infection. For each patient, three independent physicians assigned a diagnosis based on comprehensive clinical and laboratory investigation including PCR for 21 pathogens yielding 319 bacterial, 334 viral, 112 control and 98 indeterminate diagnoses; 139 patients were excluded based on predetermined criteria. The best performing host-protein was TNF-related apoptosis-inducing ligand (TRAIL (area under the curve [AUC] of 0.89; 95% confidence interval [CI], 0.86 to 0.91, which was consistently up-regulated in viral infected patients. We further developed a multi-protein signature using logistic-regression on half of the patients and validated it on the remaining half. The signature with the highest precision included both viral- and bacterial-induced proteins: TRAIL, Interferon gamma-induced protein-10, and CRP (AUC of 0.94; 95% CI, 0.92 to 0.96. The signature was superior to any of the individual proteins (P<0.001, as well as routinely used clinical parameters and their combinations (P<0.001. It remained robust across different physiological systems

  19. Bone marrow transplantation for acute myelogenous leukemia: factors associated with early mortality

    International Nuclear Information System (INIS)

    Bortin, M.M.; Gale, R.P.; Kay, H.E.; Rimm, A.A.

    1983-01-01

    Comprehensive data were reported to the International Bone Marrow Transplant Registry, Milwaukee, regarding 156 patients with acute myelogenous leukemia who were treated with allogeneic bone marrow transplantation between 1978 and 1980. The minimum observation period was 15 months after transplant and most deaths occurred within the first six months. Prognostic factors were evaluated for associations with early mortality or life-threatening complications. Most early deaths were due to infections, interstitial pneumonitis, and graft-v-host disease (GVHD). Multivariate analyses disclosed five factors with significant associations with early death or a major cause of early death: (1) disease status; (2) dose-rate of irradiation; (3) drug used to prevent GVHD; (4) severity of GVHD; and (5) dose of marrow cells.It is emphasized that several of the important prognostic factors are within the control of the referring physician or the transplant team

  20. Dynamics of Cellular Proliferation during 'Acute Homologous Disease' in Mice

    Energy Technology Data Exchange (ETDEWEB)

    Vitale, B.; Silobrcic, V.; Jurin, M.; Matosic, M.; Tomazic, Vesna [Laboratory for Transplantation and Tumour Immunology, Department of Biology, Institute Ruder Boskovic, Zagreb, Yugoslavia (Croatia)

    1968-08-15

    CBA mice, lethally irradiated and injected with 20 x 10{sup 6} bone-marrow cells derived from C57BL donors, develop a chronic form of 'homologous disease' and die between 20 and 40 days after treatment. If 10 x 10{sup 6} lymph node cells are added to the bone-marrow suspension, all recipients develop 'acute' homologous disease and die 6 to 10 days after irradiation. Different parameters of the disease were systematically observed. Among them, changes in spleen weight indicated early cell proliferation, which reached its maximum on day 4 and progressively decreased later on. Chromosomal analysis showed that all dividing cells in the spleen were of donor origin. Their number decreased concomitantly with the shrinkage and devastation of the organ, which started on day 6. The period of devastation of the spleen fully corresponds to the time in which all animals die. The use of cyclophosphamide in the treatment of 'acute' homologous disease transformed the disease into a chronic form with a mortality very similar to that obtained when only bone-marrow cells were injected. Among other effects, treatment with cyclophosphamide prevented early proliferation of donor cells in the spleen, and delayed spleen weight increase for about 10 days. After that period spleen weight increased, reaching its maximum on day 12. At first only donor type cells could be detected, but towards the end of the period in which spleen weight increase was registered host type cells appeared among the cells in mitosis. Their number gradually increased, and in some cases the majority or all of the dividing cells were of the host type. After a transitional decrease in spleen weight, another peak in cellular proliferation consisting of either host or donor or both types of cells was observed about day 30. In spite of the observed irregularities in the origin of dividing cells, all animals died by day 40 after application of cyclophosphamide. The relationship between proliferation of injected lymph node

  1. Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans

    NARCIS (Netherlands)

    Choi, S.W.; Gatza, E.; Hou, G.; Sun, Y; Whitfield, J.; Song, Y.; Oravecz-Wilson, K.; Tawara, I.; Dinarello, C.A.; Reddy, P.

    2015-01-01

    We examined immunological responses in patients receiving histone deacetylase (HDAC) inhibition (vorinostat) for graft-versus-host disease prophylaxis after allogeneic hematopoietic cell transplant. Vorinostat treatment increased histone acetylation in peripheral blood mononuclear cells (PBMCs) from

  2. Acute rejection after kidney transplantation promotes graft fibrosis with elevated adenosine level in rat.

    Directory of Open Access Journals (Sweden)

    Mingliang Li

    Full Text Available Chronic allograft nephropathy is a worldwide issue with the major feature of progressive allograft fibrosis, eventually ending with graft loss. Adenosine has been demonstrated to play an important role in process of fibrosis. Our study aimed to investigate the relationship between adenosine and fibrosis in renal allograft acute rejection in rat.Wistar rats and SD rats were selected as experimental animals. Our study designed two groups. In the allograft transplantation group, kidneys of Wistar rats were orthotopically transplanted into SD rat recipients, the same species but not genetically identical, to induce acute rejection. Kidney transplantations of SD rats to SD rats which were genetically identical were served as the control. We established rat models and detected a series of indicators. All data were analyzed statistically. P<0.05 was considered statistically significant.Compared with the control group, levels of adenosine increased significantly in the allograft transplantation group, in which acute rejection was induced (P<0.05. Progressive allograft fibrosis as well as collagen deposition were observed.These findings suggested that level of adenosine was upregulated in acute rejection after kidney allograft transplantation in rat. Acute rejection may promote renal allograft fibrosis via the adenosine signaling pathways.

  3. Practice Patterns in the Treatment and Monitoring of Acute T Cell-Mediated Kidney Graft Rejection in Canada.

    Science.gov (United States)

    Leblanc, Julie; Subrt, Peter; Paré, Michèle; Hartell, David; Sénécal, Lynne; Blydt-Hansen, Tom; Cardinal, Héloïse

    2018-01-01

    One of the goals of the Canadian National Transplant Research Program (CNTRP) is to develop novel therapies for acute rejection that could positively affect graft outcomes with greater efficacy or less toxicity. To develop innovative management strategies for kidney graft rejection, new modalities need to be compared with current clinical practices. However, there are no standardized practices concerning the management of acute T cell-mediated rejection (TCMR). To describe clinicians' practice patterns in the diagnosis, treatment, and monitoring of acute TCMR in Canada. Survey. Canadian transplant nephrologists and transplant surgeons involved in the management of acute TCMR. We developed an anonymous, web-based survey consisting of questions related to the diagnosis, treatment, and monitoring of TCMR. The survey was disseminated on 3 occasions between June and October 2016 through the Canadian Society of Transplantation (CST) kidney group electronic mailing list. Forty-seven respondents, mostly transplant nephrologists (97%), originating from at least 18 of the 25 Canadian centers offering adult or pediatric kidney transplantation, participated in the study. Surveillance biopsies were used by 28% of respondents to screen for kidney graft rejection. High-dose steroids were used by most of the respondents to treat clinical and subclinical Banff grade 1A and 1B rejections. Nine percent (95% confidence interval [CI]: 1-17) of practitioners used lymphocyte-depleting agents as the first-line approach for the treatment of Banff grade 1B acute rejection. Eighteen percent (95% CI: 7-29) and 36% (95% CI: 8-65) of respondents reported that they would not use high-dose steroids for treating clinical and subclinical borderline rejections, respectively. Seventy percent (95% CI: 54-83) of respondents answered that there was no indication to assess histological response to treatment independent of the change in kidney function. The limitations of this study are its limited sample

  4. Aggressive and acute periodontal diseases.

    Science.gov (United States)

    Albandar, Jasim M

    2014-06-01

    Inflammatory periodontal diseases are highly prevalent, although most of these diseases develop and progress slowly, often unnoticed by the affected individual. However, a subgroup of these diseases include aggressive and acute forms that have a relatively low prevalence but show a rapid-course, high rate of progression leading to severe destruction of the periodontal tissues, or cause systemic symptoms that often require urgent attention from healthcare providers. Aggressive periodontitis is an early-onset, destructive disease that shows a high rate of periodontal progression and distinctive clinical features. A contemporary case definition of this disease is presented. Population studies show that the disease is more prevalent in certain geographic regions and ethnic groups. Aggressive periodontitis is an infectious disease, and recent data show that in affected subjects the subgingival microbiota is composed of a mixed microbial infection, with a wide heterogeneity in the types and proportions of microorganisms recovered. Furthermore, there are significant differences in the microbiota of the disease among different geographic regions and ethnicities. There is also evidence that the Aggregatibacter actinomycetemycomitans-JP2 clone may play an important role in the development of the disease in certain populations. The host response plays an important role in the susceptibility to aggressive periodontitis, where the immune response may be complex and involve multiple mechanisms. Also, genetic factors seem to play an important role in the pathogenesis of this disease, but the mechanisms of increased susceptibility are complex and not yet fully understood. The available data suggest that aggressive periodontitis is caused by mutations either in a few major genes or in multiple small-effect genes, and there is also evidence of gene-gene and gene-environment interaction effects. Diagnostic methods for this disease, based on a specific microbiologic, immunologic or

  5. Exploring genetic and non-genetic risk factors for delayed graft function, acute and subclinical rejection in renal transplant recipients

    NARCIS (Netherlands)

    Moes, Dirk Jan A. R.; Press, Rogier R.; Ackaert, Oliver; Ploeger, Bart A.; Bemelman, Frederike J.; Diack, Cheikh; Wessels, Judith A. M.; van der Straaten, Tahar; Danhof, Meindert; Sanders, Jan-Stephan F.; Homan van der Heide, Jaap J.; Guchelaar, Henk Jan; de Fijter, Johan W.

    2016-01-01

    This study aimed at identifying pharmacological factors such as pharmacogenetics and drug exposure as new predictive biomarkers for delayed graft function (DGF), acute rejection (AR) and/or subclinical rejection (SCR). Adult renal transplant recipients (n = 361) on cyclosporine-based

  6. Comparative genetic diversity of Lyme disease bacteria in Northern Californian ticks and their vertebrate hosts.

    Science.gov (United States)

    Swei, Andrea; Bowie, Verna C; Bowie, Rauri C K

    2015-04-01

    Vector-borne pathogens are transmitted between vertebrate hosts and arthropod vectors, two immensely different environments for the pathogen. There is further differentiation among vertebrate hosts that often have complex, species-specific immunological responses to the pathogen. All this presents a heterogeneous environmental and immunological landscape with possible consequences on the population genetic structure of the pathogen. We evaluated the differential genetic diversity of the Lyme disease pathogen, Borrelia burgdorferi, in its vector, the western black-legged tick (Ixodes pacificus), and in its mammal host community using the 5S-23S rRNA intergenic spacer region. We found differences in haplotype distribution of B. burgdorferi in tick populations from two counties in California as well as between a sympatric tick and vertebrate host community. In addition, we found that three closely related haplotypes consistently occurred in high frequency in all sample types. Lastly, our study found lower species diversity of the B. burgdorferi species complex, known as B. burgdorferi sensu lato, in small mammal hosts versus the tick populations in a sympatric study area. Copyright © 2015 Elsevier GmbH. All rights reserved.

  7. Stem Cell Transplant

    Science.gov (United States)

    ... Graft-versus-host disease: A potential risk when stem cells come from donors If you receive a transplant ... medications and blood products into your body. Collecting stem cells for transplant If a transplant using your own ...

  8. Graft function assessment in mouse models of single- and dual- kidney transplantation.

    Science.gov (United States)

    Wang, Lei; Wang, Ximing; Jiang, Shan; Wei, Jin; Buggs, Jacentha; Fu, Liying; Zhang, Jie; Liu, Ruisheng

    2018-05-23

    Animal models of kidney transplantation (KTX) are widely used in studying immune response of hosts to implanted grafts. Additionally, KTX can be used in generating kidney-specific knockout animal models by transplantation of kidneys from donors with global knockout of a gene to wild type recipients or vise verse. Dual kidney transplantation (DKT) provides a more physiological environment for recipients than single kidney transplantation (SKT). However, DKT in mice is rare due to technical challenges. In this study, we successfully performed DKT in mice and compared the hemodynamic response and graft function with SKT. The surgical time, complications and survival rate of DKT were not significantly different from SKT, where survival rates were above 85%. Mice with DKT showed less injury and quicker recovery with lower plasma creatinine (Pcr) and higher GFR than SKT mice (Pcr = 0.34 and 0.17 mg/dl in DKT vs. 0.50 and 0.36 mg/dl in SKT at 1 and 3 days, respectively; GFR = 215 and 131 µl/min for DKT and SKT, respectively). In addition, the DKT exhibited better renal functional reserve and long-term outcome of renal graft function than SKT based on the response to acute volume expansion. In conclusion, we have successfully generated a mouse DKT model. The hemodynamic responses of DKT better mimic physiological situations with less kidney injury and better recovery than SKT because of reduced confounding factors such as single nephron hyperfiltration. We anticipate DKT in mice will provide an additional tool for evaluation of renal significance in physiology and disease.

  9. Exploring genetic and non-genetic risk factors for delayed graft function, acute and subclinical rejection in renal transplant recipients

    NARCIS (Netherlands)

    Moes, Dirk Jan A. R.; Press, Rogier R.; Ackaert, Oliver; Ploeger, Bart A.; Bemelman, Frederike J.; Diack, Cheikh; Wessels, Judith A. M.; van der Straaten, Tahar; Danhof, Meindert; Sanders, Jan-Stephan F.; van der Heide, Jaap J. Homan; Guchelaar, Henk Jan; de Fijter, Johan W.

    AIMS This study aimed at identifying pharmacological factors such as pharmacogenetics and drug exposure as new predictive biomarkers for delayed graft function (DGF), acute rejection (AR) and/or subclinical rejection (SCR). METHODS Adult renal transplant recipients (n = 361) on cyclosporine-based

  10. Will Post-Transplantation Cell Therapies for Pediatric Patients Become Standard of Care?

    NARCIS (Netherlands)

    Lankester, Arjan C.; Locatelli, Franco; Bader, Peter; Rettinger, Eva; Egeler, Maarten; Katewa, Satyendra; Pulsipher, Michael A.; Nierkens, Stefan; Schultz, Kirk; Handgretinger, Rupert; Grupp, Stephan A.; Boelens, Jaap Jan; Bollard, Catherine M.

    Although allogeneic hematopoietic stem cell transplantation (HSCT) is a curative approach for many pediatric patients with hematologic malignancies and some nonmalignant disorders, some critical obstacles remain to be overcome, including relapse, engraftment failure, graft-versus-host disease

  11. Bone marrow transplantation in patients with storage diseases: a developing country experience

    Directory of Open Access Journals (Sweden)

    Lange Marcos C.

    2006-01-01

    Full Text Available Bone marrow transplantation (BMT is a therapeutic option for patients with genetic storage diseases. Between 1979 and 2002, eight patients, four females and four males (1 to 13 years old were submitted to this procedure in our center. Six patients had mucopolysaccharidosis (MPS I in 3; MPS III in one and MPS VI in 2, one had adrenoleukodystrophy (ALD and one had Gaucher disease. Five patients had related and three unrelated BMT donor. Three patients developed graft versus host disease (two MPS I and one MPS VI and died between 37 and 151 days after transplantation. Five patients survived 4 to 16 years after transplantation. Three patients improved (one MPS I; one MPS VI and the Gaucher disease patient, one patient had no disease progression (ALD and in one patient this procedure did not change the natural course of the disease (MPS III.

  12. Long-Term Outcomes of Catheter-Directed Thrombolysis for Acute Lower Extremity Occlusions of Native Arteries and Prosthetic Bypass Grafts

    NARCIS (Netherlands)

    Schrijver, A. Marjolein; de Vries, Jean Paul P M; van den Heuvel, Daniel A F; Moll, Frans L.

    2016-01-01

    Background Catheter-directed thrombolysis is a well-accepted treatment for acute lower extremity occlusions of native arteries and bypass grafts. Several variables that affect outcomes of thrombolysis have been identified. The hypothesis of this study was that the long-term outcome after

  13. Visceral Leishmaniasis: A Differential Diagnosis to Remember after Bone Marrow Transplantation

    Directory of Open Access Journals (Sweden)

    Margarida Dantas Brito

    2014-01-01

    Full Text Available Leishmania infection in immunocompromised hosts is reported in the literature, mostly concerning human immunodeficiency virus infected patients. It is not well characterized in the context of stem cell transplantation. We report a rare case clinical case of visceral leishmaniasis after allogeneic bone marrow transplantation. A 50-year-old Caucasian male was referred to allogeneic bone marrow transplantation with a high-risk acute lymphoblastic B leukemia in first complete remission. Allogeneic SCT was performed with peripheral blood stem cells from an unrelated Portuguese matched donor. In the following months, patient developed mild fluctuating cytopenias, mostly thrombocytopenia (between 60 and 80∗109/L. The only significant complaint was intermittent tiredness. The common causes for thrombocytopenia in this setting were excluded—no evidence of graft versus host disease, no signs of viral or bacterial infection, and no signs of relapsed disease/dysplastic changes. The bone marrow smear performed 12 months after transplantation revealed an unsuspected diagnosis: a massive bone marrow infiltration with amastigotes.

  14. Radiographic healing and remodelling of cortical and cancellous bone grafts after rigid plate fixation

    International Nuclear Information System (INIS)

    Waris, P.; Karaharju, E.; Slaetis, P.; Paavolainen, P.

    1980-01-01

    Cortical and cancellous interposition grafts, with rigid plate fixation, in the tibiofibular bones of 130 rabbits were followed radiographically for one year. The cancellous grafts healed earlier, but by 12 weeks both graft types had been incorporated, the distal host-graft interface being the last to heal. Progressive cancellous transformation in both the graft and host bone led to an increased over-all bone diameter, a widened medullary canal and a thinned porotic wall. (Auth.)

  15. The impact of Fusarium mycotoxins on human and animal host susceptibility to infectious diseases.

    Science.gov (United States)

    Antonissen, Gunther; Martel, An; Pasmans, Frank; Ducatelle, Richard; Verbrugghe, Elin; Vandenbroucke, Virginie; Li, Shaoji; Haesebrouck, Freddy; Van Immerseel, Filip; Croubels, Siska

    2014-01-28

    Contamination of food and feed with mycotoxins is a worldwide problem. At present, acute mycotoxicosis caused by high doses is rare in humans and animals. Ingestion of low to moderate amounts of Fusarium mycotoxins is common and generally does not result in obvious intoxication. However, these low amounts may impair intestinal health, immune function and/or pathogen fitness, resulting in altered host pathogen interactions and thus a different outcome of infection. This review summarizes the current state of knowledge about the impact of Fusarium mycotoxin exposure on human and animal host susceptibility to infectious diseases. On the one hand, exposure to deoxynivalenol and other Fusarium mycotoxins generally exacerbates infections with parasites, bacteria and viruses across a wide range of animal host species. Well-known examples include coccidiosis in poultry, salmonellosis in pigs and mice, colibacillosis in pigs, necrotic enteritis in poultry, enteric septicemia of catfish, swine respiratory disease, aspergillosis in poultry and rabbits, reovirus infection in mice and Porcine Reproductive and Respiratory Syndrome Virus infection in pigs. However, on the other hand, T-2 toxin has been shown to markedly decrease the colonization capacity of Salmonella in the pig intestine. Although the impact of the exposure of humans to Fusarium toxins on infectious diseases is less well known, extrapolation from animal models suggests possible exacerbation of, for instance, colibacillosis and salmonellosis in humans, as well.

  16. Haematopoietic transplants combining a single unrelated cord blood unit and mobilized haematopoietic stem cells from an adult HLA-mismatched third party donor. Comparable results to transplants from HLA-identical related donors in adults with acute leukaemia and myelodysplastic syndromes.

    Science.gov (United States)

    Sebrango, Ana; Vicuña, Isabel; de Laiglesia, Almudena; Millán, Isabel; Bautista, Guiomar; Martín-Donaire, Trinidad; Regidor, Carmen; Cabrera, Rafael; Fernandez, Manuel N

    2010-06-01

    We describe results of the strategy, developed by our group, of co-infusion of mobilized haematopoietic stem cells as a support for single-unit unrelated cord blood transplant (dual CB/TPD-MHSC transplants) for treatment of haematological malignancies in adults, and a comparative analysis of results obtained using this strategy and transplants performed with mobilized haematopoietic stem cells from related HLA-identical donors (RTD) for treatment of adults with acute leukaemia and myelodysplastic syndromes. Our data show that the dual CB/TPD-MHSC transplant strategy results in periods of post-transplant neutropenia, final rates of full donor chimerism and transplant-related mortality rates comparable to those of the RTD. Final survival outcomes are comparable in adults transplanted because of acute leukaemia, with different incidences of the complications that most influence these: a higher incidence of infections related to late recovery of protective immunity dependent on T cell functions, and a lower incidence of serious acute graft-versus-host disease and relapses. Recent advances in cord blood transplant techniques allow allogeneic haematopoietic stem cell transplantation (HSCT) to be a viable option for almost every patient who may benefit from this therapeutic approach. Development of innovative strategies to improve the post-transplant recovery of T cells function is currently the main challenge to further improving the possibilities of unrelated cord blood transplantation. Copyright © 2010 Elsevier Ltd. All rights reserved.

  17. Comparable Outcomes after HLA-Matched Sibling and Alternative Donor Hematopoietic Cell Transplantation for Children with Fanconi Anemia and Severe Aplastic Anemia.

    Science.gov (United States)

    Ebens, Christen L; DeFor, Todd E; Tryon, Rebecca; Wagner, John E; MacMillan, Margaret L

    2018-04-01

    Fanconi anemia (FA)-associated severe aplastic anemia (SAA) requires allogeneic hematopoietic cell transplantation (HCT) for cure. With the evolution of conditioning regimens over time, outcomes of alternative donor HCT (AD-HCT) have improved dramatically. We compared outcomes of HLA-matched sibling donor HCT (MSD-HCT; n = 17) and AD-HCT (n = 57) performed for FA-associated SAA at a single institution between 2001 and 2016. Overall survival at 5 years was 94% for MSD-HCT versus 86% for AD-HCT, neutrophil engraftment was 100% versus 95%, platelet recovery was 100% versus 89%, grade II-IV acute graft-versus-host disease (GVHD) was 6% versus 12%, grade III-IV acute GVHD was 6% versus 4%, and chronic GVHD was 0 versus 7%, with no statistically significant differences by type of transplant. The use of UCB was associated with decreased rates of neutrophil recovery in AD-HCT and platelet recovery in both MSD-HCT and AD-HCT. A trend toward a higher serious infection density before day +100 post-HCT was observed in AD-HCT compared with MSD-HCT (P = .02). These data demonstrate that AD-HCT should be considered at the same time as MSD-HCT for patients with FA-associated SAA. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  18. The application of closed reduction internal fixation and iliac bone block grafting in the treatment of acute displaced femoral neck fractures.

    Directory of Open Access Journals (Sweden)

    Zhiyong Li

    Full Text Available OBJECTIVE: This study aimed to evaluate the preliminary clinical and radiographic outcomes of acute displaced femoral neck fracture treated by closed reduction and internal fixation (CRIF with free iliac bone block grafting with comparison to a routine protocol of CRIF without bone grafting. METHODS: From December 2008 to February 2010, 220 adult patients with acute displaced femoral neck fractures were enrolled in this study. In study group, there were 124 patients (57 males, 67 females with a mean age of 44.8 years (range, 20-64 years. There were 70 transcervical fractures and 54 subcapital fractures. The patients were treated by CRIF and free iliac bone block grafting. The control group consisted of 96 adult patients (46 males, 50 females with a mean age of 46.3 years (range, 23-64 years. There were 61 transcervical fractures and 35 subcapital fractures. The patients in control group were treated by CRIF without bone grafting. RESULTS: In study group, 112 patients were followed up for an average of 27.4 months (range, 24-34 months. All fractures healed within 5 months. However, 10 patients presented AVN of the femoral heads. The mean Harris score was 88.6 (range, 41-100. In control group, 68 patients were followed up for an average of 31.2 months (range, 24-42 months. The rates of AVN of the femoral head and fracture nonunion in control group were 26.5% (18/68 and 16.2% (11/68, respectively, significantly higher than those in study group (both P<0.05. The mean Harris score in control group was 83.8 (41-100, significantly lower than that in study group (P<0.05. CONCLUSION: Acute displaced femoral neck fractures can be treated by CRIF and free iliac bone block grafting in a minimally invasive manner. This technique can guarantee uneventful fracture healing and significantly reduce the rate of femoral head osteonecrosis.

  19. Allogeneic Stem Cell Transplant for Acute Myeloid Leukemia: Evolution of an Effective Strategy in India

    Directory of Open Access Journals (Sweden)

    Abhijeet Ganapule

    2017-12-01

    Full Text Available Purpose: There are limited data from developing countries on the role and cost-effectiveness of allogeneic stem cell transplantation (allo-SCT for patients with acute myeloid leukemia (AML. Patients and Methods: We undertook a retrospective descriptive study of all patients with AML who underwent allo-SCT from 1994 to 2013 at our center to evaluate the clinical outcomes and cost-effectiveness of this therapeutic modality. Results: Two hundred fifty-four consecutive patients, median age 34 years, who underwent allo-SCT at our center were included in this study. There were 161 males (63.4%. The 5-year overall survival (OS and event-free survival for the entire cohort was 40.1 ± 3.5% and 38.7 ± 3.4%, respectively. The 5-year OS for patients in first (CR1, second, and third complete remission and with disease/refractory AML was 53.1 ± 5.2%, 48.2 ± 8.3%, 31.2 ± 17.8%, and 16.0 ± 4.4%, respectively (P < .001. From 2007, reduced intensity conditioning (RIC with fludarabine and melphalan (Flu/Mel was used in a majority of patients in CR1 (n = 67. Clinical outcomes were compared with historical conventional myeloablative conditioning regimens (n = 38. Use of Flu/Mel was associated with lower treatment-related mortality at 1 year, higher incidence of chronic graft-versus-host-disease, and comparable relapse rates. The 5-year OS and event-free survival for Flu/Mel and myeloablative conditioning group was 67.2 ± 6.6% versus 38.1 ± 8.1% (P = .003 and 63.8 ± 6.4% versus 32.3 ± 7.9% (P = .002, respectively. Preliminary cost analysis suggests that in our medical cost payment system, RIC allo-SCT in CR1 was likely the most cost-effective strategy in the management of AML. Conclusion: In a resource-constrained environment, Flu/Mel RIC allo-SCT for AML CR1 is likely the most efficacious and cost-effective approach in a subset of newly diagnosed young adult patients.

  20. Automation in high-content flow cytometry screening.

    Science.gov (United States)

    Naumann, U; Wand, M P

    2009-09-01

    High-content flow cytometric screening (FC-HCS) is a 21st Century technology that combines robotic fluid handling, flow cytometric instrumentation, and bioinformatics software, so that relatively large numbers of flow cytometric samples can be processed and analysed in a short period of time. We revisit a recent application of FC-HCS to the problem of cellular signature definition for acute graft-versus-host-disease. Our focus is on automation of the data processing steps using recent advances in statistical methodology. We demonstrate that effective results, on par with those obtained via manual processing, can be achieved using our automatic techniques. Such automation of FC-HCS has the potential to drastically improve diagnosis and biomarker identification.

  1. Long-Term Follow-Up After Endovascular Treatment of Acute Aortic Emergencies

    International Nuclear Information System (INIS)

    Pitton, M. B.; Herber, S.; Schmiedt, W.; Neufang, A.; Dorweiler, B.; Dueber, C.

    2008-01-01

    Purpose. To investigate the long-term outcome and efficacy of emergency treatment of acute aortic diseases with endovascular stent-grafts. Methods. From September 1995 to April 2007, 37 patients (21 men, 16 women; age 53.9 ± 19.2 years, range 18-85 years) with acute complications of diseases of the descending thoracic aorta were treated by endovascular stent-grafts: traumatic aortic ruptures (n = 9), aortobronchial fistulas due to penetrating ulcer or hematothorax (n = 6), acute type B dissections with aortic wall hematoma, penetration, or ischemia (n = 13), and symptomatic aneurysm of the thoracic aorta (n = 9) with pain, penetration, or rupture. Diagnosis was confirmed by contrast-enhanced CT. Multiplanar reformations were used for measurement of the landing zones of the stent-grafts. Stent-grafts were inserted via femoral or iliac cut-down. Two procedures required aortofemoral bypass grafting prior to stent-grafting due to extensive arteriosclerotic stenosis of the iliac arteries. In this case the bypass graft was used for introduction of the stent-graft. Results. A total of 46 stent-grafts were implanted: Vanguard/Stentor (n = 4), Talent (n = 31), and Valiant (n = 11). Stent-graft extension was necessary in 7 cases. In 3 cases primary graft extension was done during the initial procedure (in 1 case due to distal migration of the graft during stent release, in 2 cases due to the total length of the aortic aneurysm). In 4 cases secondary graft extensions were performed-for new aortic ulcers at the proximal stent struts (after 5 days) and distal to the graft (after 8 months) and recurrent aortobronchial fistulas 5 months and 9 years after the initial procedure-resulting in a total of 41 endovascular procedures. The 30-day mortality rate was 8% (3 of 37) and the overall follow-up was 29.9 ± 36.6 months (range 0-139 months). All patients with traumatic ruptures demonstrated an immediate sealing of bleeding. Patients with aortobronchial fistulas also demonstrated a

  2. Bone marrow transplantation from genetically HLA-nonidentical donors in children with fatal inherited disorders excluding severe combined immunodeficiencies: use of two monoclonal antibodies to prevent graft rejection.

    Science.gov (United States)

    Jabado, N; Le Deist, F; Cant, A; De Graeff-Meeders, E R; Fasth, A; Morgan, G; Vellodi, A; Hale, G; Bujan, W; Thomas, C; Cavazzana-Calvo, M; Wijdenes, J; Fischer, A

    1996-09-01

    For children with life-threatening inborn errors of metabolism without a matched related bone marrow donor, transplantation from an HLA genetically nonidentical donor is the only therapeutic option. To reduce the high risk of graft rejection in this setting without increasing the conditioning regimen, a protocol based on the infusion of an antiadhesion antibody directed against the CD11a (leukocyte function-associated antigen 1 [LFA-1]) molecule was performed by the European Bone Marrow Transplantation-European Society for Immunodeficiency group with promising results. To optimize engraftment, and thereby survival, further, the additional blockade of a second important leukocyte adhesion and signalization pathway mediated by the CD2 and LFA-3 interaction was attempted in a multicenter protocol conducted by the European Bone Marrow Transplantation-European Society for Immunodeficiency group. Results of this study (ie, engraftment and survival) were compared with a historical control group that received the anti-LFA-1 antibody alone. Factors that may have affected engraftment and survival were also considered in this study. Forty-four children with inborn errors, including inherited immunodeficiencies (excluding severe combined immunodeficiencies), Chédiak-Higashi syndrome, familial hemophagocytic lymphohistiocytosis, and malignant osteopetrosis, received bone marrow from HLA-nonidentical related donors or from HLA-identical unrelated donors at 13 European centers between August 1990 and June 1993. Bone marrow was depleted of T cells by use of either erythrocyte (E) rosetting or monoclonal antibodies (MoAbs) to prevent graft-versus-host disease. The conditioning regimen consisted of busulfan and cyclophosphamide for all patients plus etoposide for patients with osteopetrosis, familial hemophagocytic lymphohistiocytosis, and Chédiak-Higashi syndrome. Infusions of MoAbs specific for the CD11a and the CD2 molecules were started 4 and 3 days, respectively, before and

  3. Hyperfractionated total body irradiation for T-depleted HLA identical bone marrow transplants

    International Nuclear Information System (INIS)

    Latini, P.; Checcaglini, F.; Maranzano, E.; Aristei, C.; Panizza, B.M.; Gobbi, G.; Raymondi, C.; Aversa, F.; Martelli, M.F.

    1988-01-01

    Twenty patients suffering from malignant hemopathies (mean age 31.7 years) were given hyperfractionated total body irradiation (TBI) as conditioning for T-depleted HLA identical allogeneic bone marrow transplantation. At an average of 12 months (range of 4.5-22 months) follow-up there were two cases of early death and two cases (11%) of rejection. There were no cases of acute or chronic graft versus host disease nor cases of interstitial pneumonitis. The average time for durable engraftment was 22 days. Disease-free survival at 12 months was 65%. To improve the results and further reduce the percent of rejection, the authors propose intensifying the immunosuppressive conditioning by increasing the cyclophosphamide dose and that of TBI so that a total dose of 1560 cGy is reached. 35 refs.; 1 figure

  4. Reexamination of the role of Lyt-2-positive T cells in murine skin graft rejection

    International Nuclear Information System (INIS)

    LeFrancois, L.; Bevan, M.J.

    1984-01-01

    The authors have investigated which T cell subclass defined by cytolysis with monoclonal anti-Lyt-1.2 and anti-Lyt-2.2 antibodies is required to adoptively transfer the ability to reject skin grafts. B6.Thy-1.1 spleen cells immune to graft antigens were fractionated with antibody plus C' and transferred to adult thymectomized, irradiated, bone marrow-reconstituted (ATXBM) B6.Thy-1.2 hosts that were simultaneously grafted with BALB.B skin. The authors found that when the ATXBM hosts were used 6 wk after irradiation and marrow reconstitution, both Lyt-1-depleted and Lyt-2-depleted immune spleen cells could transfer the ability to promptly reject skin grafts. However, such ATXBM recipients of Lyt-2-depleted cells that had rejected skin grafts were found to contain graft-specific CTL that were largely of host (B6.Thy-1.2) origin. When ATXBM hosts were used for the experiment 1 wk after irradiation and marrow reconstitution, no host-derived graft-specific CTL could be detected. However, graft rejection occurred in recipients of anti-Lyt-1- or anti-Lyt-2 plus C'-treated immune cells and specific CTL were generated from spleen cells of both groups. Thus, in the absence of a host-derived response, adoptively transferred immune Lyt-2+ cells, either resistant to, or that escaped from, antibody plus C' treatment, are able to expand in response to the antigenic stimulus provided by the graft. A more complete elimination of specific T cell subclasses is therefore needed to assess the relative contribution of a particular subset to the graft rejection process

  5. Arteriovenous shunt graft ulceration with sinus and graft epithelialization

    Directory of Open Access Journals (Sweden)

    Pooja Singhal

    2015-03-01

    Full Text Available Arteriovenous fistula and grafts are used as access sites for patients with chronic kidney disease and are prone for complications. Stent grafts are used to treat access site complications. We report a rare and unusual finding of epithelialization of the sinus tract and the lumen of a polytetrafluoroethylene graft, following ulceration of the overlying skin.

  6. Comparative analysis of unrelated cord blood transplantation and HLA-matched sibling hematopoietic stem cell transplantation in children with high-risk or advanced acute leukemia.

    Science.gov (United States)

    Zheng, Changcheng; Zhu, Xiaoyu; Tang, Baolin; Yao, Wen; Song, Kaidi; Tong, Juan; Geng, Liangquan; Liu, Huilan; Sun, Zimin

    2015-03-01

    The aim of this report was to present a clinical comparison of unrelated cord blood transplantation (CBT) and human leukocyte antigen (HLA)-matched sibling allogeneic peripheral blood stem cell or bone marrow transplantation (allo-PBSCT/BMT) in children with high-risk or advanced acute leukemia. A total of 115 consecutive pediatric patients received unrelated CBT (n = 90) or sibling allo-PBSCT/BMT (n = 25) between 2000 and 2012. Neutrophil and platelet recovery were significantly delayed after CBT compared to allo-PBSCT/BMT. There was no difference in the incidence of acute graft-versus-host disease (GVHD) or chronic GVHD between the two groups. The cumulative incidence of transplant-related mortality (TRM) was higher in the CBT group than in the allo-PBSCT/BMT group (32.5 vs 12.8 %) (p = 0.03). The cumulative incidence of relapse was 13.1 % after CBT, which was significantly lower than that of after allo-PBSCT/BMT (45.3 %) (p = 0.015). The overall survival (OS) and leukemia-free survival (LFS) in the CBT group were similar to those of the allo-PBSCT/BMT group; however, for acute myeloid leukemia (AML) patients, the 5-year LFS in the CBT group was slightly better than the allo-PBSCT/BMT group (55.7 % for CBT and 32.7 % for allo-PBSCT/BMT) (p = 0.08). Our comparisons suggest that for high-risk or advanced childhood acute leukemia, unrelated CBT has a higher TRM and similar long-term survival, but better antileukemia effect than HLA-matched sibling PBSCT/BMT. New strategies and better supportive care are required to decrease the TRM of CBT.

  7. Allogeneic bone marrow transplantation with conditioning regimen to total body irradiation + thiotepa + melphalan for 35 patients with high-risk leukemia

    International Nuclear Information System (INIS)

    Yumura-Yagi, Keiko; Inoue, Masami; Okamura, Takayuki

    1997-01-01

    Thirty-five children with high-risk leukemia received an allogeneic bone marrow transplantation (BMT) following a pre-conditioning regimen consisting of total body irradiation, thiotepa and melphalan. Twenty-one patients had acute lymphocytic leukemia, 6 acute nonlymphocytic leukemia, 2 acute undifferentiated leukemia, 2 acute mixed lineage leukemia, 2 myelodysplastic syndrome and 2 juvenile chronic myeloid leukemia. Sixteen patients received BMT while in complete remission (CR), but 19 were not in CR. Eighteen patients received transplants from HLA-matched related donors, 15 from unrelated donors and 2 from HLA-mismatched related donors. Cyclosporin±methotrexate was used for graft-versus-host disease (GVHD) prophylaxis in the BMTs from related donors and tacrolimus±prednisolone in the BMTs from unrelated donors. Transplant-related death occurred in 12 patients; 5 acute GVHD, 4 infections (3 fungal infections, 1 Cytomegalovirus pneumonia), 1 intracranial haemorrhage and 2 chronic GVHD. Relapses were observed in 6 patients (69, 168, 175, 222, 275 and 609 days post BMT). Event-free survival rate at 2 years is 38.1% in CR patients and 36.9% in nonCR patients. (author)

  8. In vivo outcomes of tissue-engineered osteochondral grafts.

    Science.gov (United States)

    Bal, B Sonny; Rahaman, Mohamed N; Jayabalan, Prakash; Kuroki, Keiichi; Cockrell, Mary K; Yao, Jian Q; Cook, James L

    2010-04-01

    Tissue-engineered osteochondral grafts have been synthesized from a variety of materials, with some success at repairing chondral defects in animal models. We hypothesized that in tissue-engineered osteochondral grafts synthesized by bonding mesenchymal stem cell-loaded hydrogels to a porous material, the choice of the porous scaffold would affect graft healing to host bone, and the quality of cell restoration at the hyaline cartilage surface. Bone marrow-derived allogeneic mesenchymal stem cells were suspended in hydrogels that were attached to cylinders of porous tantalum metal, allograft bone, or a bioactive glass. The tissue-engineered osteochondral grafts, thus created were implanted into experimental defects in rabbit knees. Subchondral bone restoration, defect fill, bone ingrowth-implant integration, and articular tissue quality were compared between the three subchondral materials at 6 and 12 weeks. Bioactive glass and porous tantalum were superior to bone allograft in integrating to adjacent host bone, regenerating hyaline-like tissue at the graft surface, and expressing type II collagen in the articular cartilage.

  9. Free and microvascular bone grafting in the irradiated dog mandible

    International Nuclear Information System (INIS)

    Altobelli, D.E.; Lorente, C.A.; Handren, J.H. Jr.; Young, J.; Donoff, R.B.; May, J.W. Jr.

    1987-01-01

    Microvascular and free rib grafts were placed in 4.5 cm defects in an edentate mandibular body defect 18 to 28 days after completion of 50 Gy of irradiation from a 60 Co source. The animals were sacrificed from two to forty weeks postoperatively and evaluated clinically, radiographically, and histologically. There was a marked difference in the alveolar mucosal viability with the two grafts. Mucosal dehiscence was not observed over any of the microvascular grafts, but was present in seven-eighths of the free grafts. Union of the microvascular bone graft to the host bone occurred within six weeks. In contrast, after six weeks the free graft was sequestered in all the animals. An unexpected finding with both types of graft was the marked subperiosteal bone formation. This bone appeared to be derived from the host bed, stabilizing and bridging the defects bilaterally. The results suggest that radiated periosteum may play an important role in osteogenesis

  10. Association between triglyceride levels and cardiovascular disease in patients with acute pancreatitis.

    Science.gov (United States)

    Copeland, Laurel A; Swendsen, C Scott; Sears, Dawn M; MacCarthy, Andrea A; McNeal, Catherine J

    2018-01-01

    Conventional wisdom supports prescribing "fibrates before statins", that is, prioritizing treatment of hypertriglyceridemia (hTG) to prevent pancreatitis ahead of low-density lipoprotein cholesterol to prevent coronary heart disease. The relationship between hTG and acute pancreatitis, however, may not support this approach to clinical management. This study analyzed administrative data from the Veterans Health Administration for evidence of (1) temporal association between assessed triglycerides level and days to acute pancreatitis admission; (2) association between hTG and outcomes in the year after hospitalization for acute pancreatitis; (3) relative rates of prescription of fibrates vs statins in patients with acute pancreatitis; (4) association of prescription of fibrates alone versus fibrates with statins or statins alone with rates of adverse outcomes after hospitalization for acute pancreatitis. Only modest association was found between above-normal or extremely high triglycerides and time until acute pancreatitis. CHD/MI/stroke occurred in 23% in the year following AP, supporting cardiovascular risk management. Fibrates were prescribed less often than statins, defying conventional wisdom, but the high rates of cardiovascular events in the year following AP support a clinical focus on reducing cardiovascular risk factors.

  11. Kidney graft rejection studies with labeled platelets and lymphocytes

    International Nuclear Information System (INIS)

    Martin-Comin, J.

    1986-01-01

    The usefulness of In-111-labelled platelets and lymphocyte scintigraphy in acute kidney graft rejection is evaluated in 155 patients. Blood cells were labelled with 100-150 uCi of In-111-oxine and reinjected. Subsequently patients were scanned once daily from 2 hours post-reinjection up to a week. The graft/contralateral area activity ratio was calculated in all scans. It is concluded that In-111-labelled platelets scintigraphy is nowadays the method of choice for acute kidney graft rejection diagnosis, especially in patients under cyclosporine immunosuppression. (author)

  12. Comparisons Between Allogeneic Peripheral Blood Stem Cell Transplantation and Allogeneic Bone Marrow Transplantation in Adult Hematologic Disease: A Single Center Experience

    Directory of Open Access Journals (Sweden)

    Yi-Chang Liu

    2003-11-01

    Full Text Available This retrospective study compared the outcomes in 32 adult patients with hematologic diseases (acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, severe aplastic anemia who received allogeneic bone marrow transplantation (BMT, n = 14; median age, 28 years or allogeneic peripheral blood stem cell transplantation (PBSCT, n = 18; median age, 29 years from human leukocyte antigen-identical sibling donors. Median follow-up was 58 months in BMT recipients and 18 months in PBSCT recipients. Neutrophil (median, Day 8 vs Day 13, p < 0.001 and platelet engraftment (median, Day 9 vs Day 17, p < 0.001 was faster in the PBSCT group than in the BMT group. Patients receiving PBSCT required less platelet transfusion than those receiving BMT (median, 54 units vs 144 units, p < 0.001, but there was no significant difference in red cell transfusion. At 100 days, there was no difference in the incidence of acute graft-versus-host disease (GVHD (42.9% vs 33.3%, p = 0.72 or grade II-IV acute GVHD (14.3% vs 5.6%, p = 0.57, and there was no difference in the cumulative incidence of chronic GVHD (20% vs 33.3%, p = 0.67. No chronic GVHD was noted in any relapsed patients (BMT, 5; PBSCT, 3, and no patients with chronic GVHD during follow-up had a relapse. Relapse was the most frequent cause of death in both groups (BMT, 5/9, 55.6%; PBSCT, 3/4, 75%; p = 0.25; all relapses occurred within 1 year after transplantation. Overall survival was significantly better in the PBSCT group (35.7% vs 77.8%, p = 0.029, but this difference was lost if only hematologic malignancies were analyzed (30.8% vs 63.6%, p = 0.20. Our results are similar to those reported previously, with faster neutrophil and platelet engraftment and less severe acute GVHD and extensive chronic GVHD with PBSCT. Allogeneic PBSCT is a feasible and beneficial alternative to allogeneic BMT in adult hematologic disease.

  13. Evaluation of Replacement Grafts and Punch Grafts in the Treatment of Vitiligo

    Directory of Open Access Journals (Sweden)

    Singh Ajit Kumar

    1980-01-01

    Full Text Available Thirtycasesof vitiligo eachwithminimum of two lesions undent replacement graft and multiple punch grafts in one lesion each. Complications observed at the recipient site like infection and raised nigosed surface were significantly more in replacement grafts. Hypopigmentation of the graft was significantly more when the disease was progressive.

  14. Single-Center Experience Using Marginal Liver Grafts in Korea.

    Science.gov (United States)

    Park, P-J; Yu, Y-D; Yoon, Y-I; Kim, S-R; Kim, D-S

    2018-05-01

    Liver transplantation (LT) is an established therapeutic modality for patients with end-stage liver disease. The use of marginal donors has become more common worldwide due to the sharp increase in recipients, with a consequent shortage of suitable organs. We analyzed our single-center experience over the last 8 years in LT to evaluate the outcomes of using so-called "marginal donors." We retrospectively analyzed the database of all LTs performed at our institution from 2009 to 2017. Only patients undergoing deceased-donor LTs were analyzed. Marginal grafts were defined as livers from donors >60 years of age, livers from donors with serum sodium levels >155 mEq, graft steatosis >30%, livers with cold ischemia time ≥12 hours, livers from donors who were hepatitis B or C virus positive, livers recovered from donation after cardiac death, and livers split between 2 recipients. Patients receiving marginal grafts (marginal group) were compared with patients receiving standard grafts (standard group). A total of 106 patients underwent deceased-donor LT. There were 55 patients in the standard group and 51 patients in the marginal group. There were no significant differences in terms of age, sex, Model for End-Stage Liver Disease score, underlying liver disease, presence of hepatocellular carcinoma, and hospital stay between the 2 groups. Although the incidence of acute cellular rejection, cytomegalovirus infection, and postoperative complications was similar between the 2 groups, the incidence of early allograft dysfunction was higher in the marginal group. With a median follow-up of 26 months, the 1-, 3-, and 5-year overall and graft (death-censored) survivals in the marginal group were 85.5%, 75%, and 69.2% and 85.9%, 83.6%, and 77.2%, respectively. Patient overall survival and graft survival (death-censored) were significantly lower in the marginal group (P = .023 and P = .048, respectively). On multivariate analysis, receiving a marginal graft (hazard ratio [HR

  15. alpha-1-Antitrypsin (AAT)-modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics

    NARCIS (Netherlands)

    Marcondes, A.M.; Karoopongse, E.; Lesnikova, M.; Margineantu, D.; Welte, T.; Dinarello, C.A.; Hockenbery, D.; Janciauskiene, S.; Deeg, H.J.

    2014-01-01

    Hematopoietic cell transplantation is curative in many patients. However, graft-versus-host disease (GVHD), triggered by alloreactive donor cells, has remained a major complication. Here, we show an inverse correlation between plasma alpha-1-antitrypsin (AAT) levels in human donors and the

  16. The prevention of oral complications in bone-marrow transplantations by means of oral hygiene and dental intervention

    NARCIS (Netherlands)

    Raber-Durlacher, J. E.; Abraham-Inpijn, L.; van Leeuwen, E. F.; Lustig, K. H.; van Winkelhoff, A. J.

    1989-01-01

    Oral complications cause morbidity and mortality in patients, undergoing allogeneic or autologous bone-marrow transplantation. The clinical features and the pathogenesis of the oral sequelae of bone marrow ablative therapy and graft-versus-host disease are discussed. In addition, a preventive oral

  17. Postoperative radiographic evaluation of vascularized fibular grafts

    International Nuclear Information System (INIS)

    Manaster, B.J.; Coleman, D.A.; Bell, D.A.

    1989-01-01

    This paper reports on thirty-five patients with free vascularized fibular grafts examined postoperatively with plain radiography. Early graft incorporation is seen as a fuzziness of the cortex at the site of its insertion into the host bone. Causes of failure in grafting for bone defects include graft fracture, hardware failure, and infection. A high percentage of complications or at least delayed unions occurred when vascularized fibular grafts were used to fill defects in the lower extremity. Conversely, upper extremity defects bridged by vascularized grafts heal quickly and hypertrophy. Vascularized grafts placed in the femoral head and neck for a vascular necrosis incorporate early on their superior aspect. The osseous tunnel in which they are placed is normally wider than the graft and often becomes sclerotic; this appearance does not represent nonunion

  18. Comparing outcomes of matched related donor and matched unrelated donor hematopoietic cell transplants in adults with B-Cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Segal, Eric; Martens, Michael; Wang, Hai-Lin; Brazauskas, Ruta; Weisdorf, Daniel; Sandmaier, Brenda M; Khoury, H Jean; de Lima, Marcos; Saber, Wael

    2017-09-01

    Allogeneic hematopoietic cell transplantation (HCT) using human leukocyte antigen (HLA)-matched related donors (RDs) and allogeneic HCT using HLA-matched unrelated donors (URDs) produce similar outcomes for patients with acute myelogenous leukemia, whereas the donor source has been reported to be a predictor of outcomes in myelodysplastic syndrome. Post-HCT outcomes for 1458 acute lymphoblastic leukemia patients from 2000 to 2011 were analyzed, and RD and URD transplants were compared. The median age was 37 years (range, 18-69 years). In the multivariate analysis, HLA 8/8 allele-matched URD recipients had similar transplant-related mortality (TRM) and all-cause mortality in comparison with RD recipients (hazard ratios [HRs], 1.16 [95% confidence interval (CI), 0.91-1.48] and 1.01 [95% CI, 0.85-1.19], respectively); 7/8 URD recipients had a greater risk of TRM and all-cause mortality in comparison with RD recipients (HRs, 1.92 [95% CI, 1.47-2.52] and 1.29 [95% CI, 1.05-1.58], respectively). The risk of TRM and all-cause mortality was also greater for 7/8 URD recipients versus 8/8 URD recipients. Compared with RD recipients, both 8/8 and 7/8 URD recipients had a lower risk of relapse (HRs, 0.77 [95% CI, 0.62-0.97] and 0.75 [95% CI, 0.56-1.00], respectively). Both 8/8 and 7/8 URD recipients had a greater risk of acute graft-versus-host disease (GVHD; HRs, 2.18 [95% CI, 1.76-2.70] and 2.65 [95% CI, 2.06-3.42], respectively) and chronic GVHD (HRs, 1.28 [95% CI, 1.06-1.55] and 1.46 [95% CI, 1.14-1.88], respectively) in comparison with RD recipients. In the absence of RD transplantation, 8/8 URD transplantation is a viable alternative with similar survival outcomes, whereas 7/8 URD transplantation is associated with poorer overall survival. Cancer 2017;123:3346-55. © 2017 American Cancer Society. © 2017 American Cancer Society.

  19. Renographic indices for evaluation of changes in graft function

    Energy Technology Data Exchange (ETDEWEB)

    El-Maghraby, T.A.F.; Eck-Smit, B.L.F. van; Pauwels, E.K.J. [Division of Nuclear Medicine, Department of Radiology, Leiden University Medical Centre, Leiden (Netherlands); Fijter, J.W. de [Department of Nephrology, Leiden University Medical Centre, Leiden (Netherlands); Zwinderman, A.H. [Department of Medical Statistics, Leiden University Medical Centre, Leiden (Netherlands); El-Haddad, S.I. [Department of Oncology and Nuclear Medicine, Cairo University (Egypt)

    1998-11-01

    differentiation of the acute tubular necrosis (ATN) group from the acute rejection (AR) group; however, they were of value in monitoring the improvement in the condition of the graft dysfunction in both the AR and ATN groups. As for the parenchymal parameters, both UC{sub 2} and K{sub 3/20} were able to differentiate stable graft function (SGF) versus AR and ATN groups but were unable to separate AR from ATN dysfunction. The ability of these parenchymal parameters to detect improvement in the graft function was poor and statistically non-significant. From the literature data and our own findings it is concluded that radionuclide scintigraphy of renal transplants has assumed an important role, especially if performed serially, in monitoring graft function in the post-transplant period. Many quantitative parameters have been derived from the radionuclide renogram to evaluate changes in perfusion and/or function of the kidney allograft. It appears that these quantitative numerical values are unable to differentiate unequivocally between grafts with ATN and AR cases. The real value of these parameters lies in the follow-up of the dysfunction processes, which helps the clinician to determine the appropriate therapeutic regimen. (orig.) With 5 figs., 2 tabs., 70 refs.

  20. Depression of Complement Regulatory Factors in Rat and Human Renal Grafts Is Associated with the Progress of Acute T-Cell Mediated Rejection.

    Directory of Open Access Journals (Sweden)

    Kazuaki Yamanaka

    Full Text Available The association of complement with the progression of acute T cell mediated rejection (ATCMR is not well understood. We investigated the production of complement components and the expression of complement regulatory proteins (Cregs in acute T-cell mediated rejection using rat and human renal allografts.We prepared rat allograft and syngeneic graft models of renal transplantation. The expression of Complement components and Cregs was assessed in the rat grafts using quantitative real-time PCR (qRT-PCR and immunofluorescent staining. We also administered anti-Crry and anti-CD59 antibodies to the rat allograft model. Further, we assessed the relationship between the expression of membrane cofactor protein (MCP by immunohistochemical staining in human renal grafts and their clinical course.qRT-PCR results showed that the expression of Cregs, CD59 and rodent-specific complement regulator complement receptor 1-related gene/protein-y (Crry, was diminished in the rat allograft model especially on day 5 after transplantation in comparison with the syngeneic model. In contrast, the expression of complement components and receptors: C3, C3a receptor, C5a receptor, Factor B, C9, C1q, was increased, but not the expression of C4 and C5, indicating a possible activation of the alternative pathway. When anti-Crry and anti-CD59 mAbs were administered to the allograft, the survival period for each group was shortened. In the human ATCMR cases, the group with higher MCP expression in the grafts showed improved serum creatinine levels after the ATCMR treatment as well as a better 5-year graft survival rate.We conclude that the expression of Cregs in allografts is connected with ATCMR. Our results suggest that controlling complement activation in renal grafts can be a new strategy for the treatment of ATCMR.