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Sample records for acute graft-versus-host disease

  1. Acute graft versus host disease

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    Vogelsang Georgia B

    2007-09-01

    Full Text Available Abstract Acute graft-versus-host disease (GVHD occurs after allogeneic hematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues. Activated donor T cells damage host epithelial cells after an inflammatory cascade that begins with the preparative regimen. About 35%–50% of hematopoietic stem cell transplant (HSCT recipients will develop acute GVHD. The exact risk is dependent on the stem cell source, age of the patient, conditioning, and GVHD prophylaxis used. Given the number of transplants performed, we can expect about 5500 patients/year to develop acute GVHD. Patients can have involvement of three organs: skin (rash/dermatitis, liver (hepatitis/jaundice, and gastrointestinal tract (abdominal pain/diarrhea. One or more organs may be involved. GVHD is a clinical diagnosis that may be supported with appropriate biopsies. The reason to pursue a tissue biopsy is to help differentiate from other diagnoses which may mimic GVHD, such as viral infection (hepatitis, colitis or drug reaction (causing skin rash. Acute GVHD is staged and graded (grade 0-IV by the number and extent of organ involvement. Patients with grade III/IV acute GVHD tend to have a poor outcome. Generally the patient is treated by optimizing their immunosuppression and adding methylprednisolone. About 50% of patients will have a solid response to methylprednisolone. If patients progress after 3 days or are not improved after 7 days, they will get salvage (second-line immunosuppressive therapy for which there is currently no standard-of-care. Well-organized clinical trials are imperative to better define second-line therapies for this disease. Additional management issues are attention to wound infections in skin GVHD and fluid/nutrition management in gastrointestinal GVHD. About 50% of patients with acute GVHD will eventually have manifestations of chronic GVHD.

  2. Pathogenic mechanisms of Acute Graft versus Host Disease

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    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.

  3. 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.

  4. IMMUNOBIOLOGY OF ACUTE GRAFT-VERSUS-HOST DISEASE

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    G. A. Efimov

    2015-01-01

    significant limitation for clinical applications of stem cell transplantation. Severe immunesuppression or depletion of mature donor T cells from the transplant leads to increased probability of relapse and weakens anti-infectious immunity. Hence, further search for alternative, more specific ways to prevent GVHD is required. This review will focus on the mechanisms of alloreactive T lymphocyte clone development and key pathogenetic stages of acute “graft versus host” disease.

  5. Relative defects in mucosal immunity predict acute graft-versus-host disease.

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    August, Keith J; Chiang, K-Y; Qayed, Muna; Dulson, Ashley; Worthington-White, Diana; Cole, Conrad R; Horan, John T

    2014-07-01

    Impairment of gut mucosal immunity by the transplant process could facilitate translocation of commensal bacteria and thereby augment the graft-versus-host response. To begin to assess the influence of gut mucosal immunity on the development of acute graft-versus-host disease (GVHD), we conducted a prospective study in 24 pediatric allogeneic hematopoietic cell transplant recipients, assessing 4 fecal markers of mucosal immunity: calprotectin, soluble CD8 (sCD8), soluble intracellular adhesion molecule 1, and β-defensin-2. Stool samples were collected prospectively on transplant days 0, +5, +10, and +15 and analyzed by ELISA. Lower levels on day +5 (calprotectin and β-defensin-2) and day +10 (calprotectin, β-defensin-2, and sCD8) were associated with subsequent acute GVHD. The most striking difference was with calprotectin on day +10. Patients with levels below 424 mg/kg had an incidence of 77.8%, whereas those with levels above this threshold had a cumulative incidence of 0% (P = .002). Relative defects in gut mucosal immunity may be important in the pathogenesis of acute GVHD.

  6. 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.

  7. [Research Progress on Notch Signal Pathway in Acute Graft-Versus-Host Disease -Review].

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    Guo, Dong-Mei; Li, Ban-Ban; Li, Chun-Pu; Teng, Qing-Liang

    2017-02-01

    The Notch signaling pathway is a highly conserved cell signaling system that plays an essential role in many biological processes. Notch signaling regulates multiple aspects of hematopoiesis, especially during T cell develop-ment. Recent data suggest that Notch also regulates mature T cell differentiation and function. The latest data show that Notch also plays an essential role in alloreactive T cells mediating acute graft-versus-host disease (aGVHD), the most severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Notch inhibition in donor-derived T cells or blockade of individual Notch ligands and receptors after transplantation can reduce GVHD severity and mortality in mouse models of allo-HSCT, without causing global immunosuppression. These findings indicate Notch in T cells as an attractive therapeutic target to control aGVHD. In this article, the pathophysiology of aGVHD, the Notch signal pathway and aGVHD are reviewed.

  8. Analyses of risk factors for intestinal acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

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    燕法红

    2014-01-01

    Objective To investigate the risk factors of intestinal acute graft-versus-host disease(aGVHD)after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods The clinical data of 534 cases of 533 patients undergoing allo-HSCT during Jan 2004 and Sep 2012were retrospectively analyzed.The effects of donor-recipient HLA

  9. The Role of Purine Metabolites as DAMPs in Acute Graft-versus-Host Disease

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    Apostolova, Petya; Zeiser, Robert

    2016-01-01

    Acute graft-versus-host disease (GvHD) causes high mortality in patients undergoing allogeneic hematopoietic cell transplantation. An early event in the classical pathogenesis of acute GvHD is tissue damage caused by the conditioning treatment or infection that consecutively leads to translocation of bacterial products [pathogen-associated molecular patterns (PAMPs)] into blood or lymphoid tissue, as well as danger-associated molecular patterns (DAMPs), mostly intracellular components that act as pro-inflammatory agents, once they are released into the extracellular space. A subtype of DAMPs is nucleotides, such as adenosine triphosphate released from dying cells that can activate the innate and adaptive immune system by binding to purinergic receptors. Binding to certain purinergic receptors leads to a pro-inflammatory microenvironment and promotes allogeneic T cell priming. After priming, T cells migrate to the acute GvHD target organs, mainly skin, liver, and the gastrointestinal tract and induce cell damage that further amplifies the release of intracellular components. This review summarizes the role of different purinergic receptors in particular P2X7 and P2Y2 as well as nucleotides in the pathogenesis of GvHD.

  10. Improved accuracy of acute graft-versus-host disease staging among multiple centers.

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    Levine, John E; Hogan, William J; Harris, Andrew C; Litzow, Mark R; Efebera, Yvonne A; Devine, Steven M; Reshef, Ran; Ferrara, James L M

    2014-01-01

    The clinical staging of acute graft-versus-host disease (GVHD) varies significantly among bone marrow transplant (BMT) centers, but adherence to long-standing practices poses formidable barriers to standardization among centers. We have analyzed the sources of variability and developed a web-based remote data entry system that can be used by multiple centers simultaneously and that standardizes data collection in key areas. This user-friendly, intuitive interface resembles an online shopping site and eliminates error-prone entry of free text with drop-down menus and pop-up detailed guidance available at the point of data entry. Standardized documentation of symptoms and therapeutic response reduces errors in grade assignment and allows creation of confidence levels regarding the diagnosis. Early review and adjudication of borderline cases improves consistency of grading and further enhances consistency among centers. If this system achieves widespread use it may enhance the quality of data in multicenter trials to prevent and treat acute GVHD.

  11. Assessment of acute intestinal graft versus host disease by abdominal magnetic resonance imaging at 3 Tesla

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    Budjan, Johannes; Michaely, Henrik J.; Attenberger, Ulrike; Haneder, Stefan; Schoenberg, Stefan O. [Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim (Germany); Heidenreich, Daniela; Kreil, Sebastian; Nolte, Florian; Hofmann, Wolf-Karsten; Klein, Stefan A. [University Medical Center Mannheim, Department of Hematology and Oncology, Mannheim (Germany)

    2014-08-15

    After allogeneic stem cell transplantation (SCT), a reliable diagnosis of acute graft versus host disease (aGvHD) is essential for an early and successful treatment. It is the aim of this analysis to assess intestinal aGvHD by magnetic resonance imaging (MRI). Prior to allogeneic SCT, 64 consecutive patients underwent abdominal MRI examination on a 3 T MR system, including axial and coronal T2w sequences and a three-dimensional dynamic T1w, contrast enhanced sequence. After SCT, 20 patients with suspected aGvHD received a second MRI as well as an endoscopic examination. Nine patients suffered from histologically proven intestinal aGvHD. In eleven patients intestinal aGvHD was excluded. In all aGvHD patients typical MRI findings with long-segment bowel wall thickening - always involving the terminal ileum - with profound submucosal oedema, were detected. The bowel wall was significantly thickened in patients with intestinal aGvHD. Bowel contrast enhancement spared the submucosa while demonstrating strong mucosal hyperemia. In intestinal aGvHD, a characteristic MR-appearance can be detected. This MRI pattern might facilitate an early and non-invasive diagnosis of intestinal aGvHD. MRI might thus be used as a sensitive tool to rule out or support the clinical diagnosis of aGvHD. (orig.)

  12. Acute renal graft-versus-host disease in a murine model of allogeneic bone marrow transplantation.

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    Schmid, Peter M; Bouazzaoui, Abdellatif; Schmid, Karin; Birner, Christoph; Schach, Christian; Maier, Lars S; Holler, Ernst; Endemann, Dierk H

    2017-03-23

    Acute kidney injury (AKI) is a very common complication after allogeneic bone marrow transplantation (BMT) and associated with poor prognosis. Generally kidneys are assumed to be no direct target of Graft-versus-Host Disease (GvHD), and renal impairment is often attributed to several other factors occurring in the early phase after BMT. Our study aimed to prove the existence of renal GvHD in a fully MHC-mismatched model of BALB/c mice conditioned and transplanted according to two different intensity protocols. Syngeneically transplanted and untreated animals served as controls. 4 weeks after transplantation, allogeneic animals developed acute GvHD that was more pronounced in the high-intensity protocol (HIP) group than in the low-intensity protocol (LIP) group. Urea and creatinine as classic serum markers of renal function could not verify renal impairment 4 weeks after BMT. Creatinine levels were even reduced as a result of catabolic metabolism and loss of muscle mass due to acute GvHD. Proteinuria, albuminuria, and urinary N-acetyl-beta-Dglucosaminidase (NAG) levels were measured as additional renal markers before and after transplantation. Albuminuria and NAG were only significantly increased after allogeneic transplantation, correlating with disease severity between HIP and LIP animals. Histological investigations of the kidneys showed renal infiltration of T-cells and macrophages with endarteriitis, interstitial nephritis, tubulitis, and glomerulitis. T-cells consisted of CD4+, CD8+, and FoxP3+ cells. Renal expression analysis of allogeneic animals showed increases in indoleamine-2,3 dioxygenase (IDO), different cytokines (TNFα, IFN-γ, IL-1α, IL2, IL-6, and IL-10), and adhesion molecules (ICAM-1 and VCAM-1), resembling findings from other tissues in acute GvHD. In summary, our study supports the entity of renal GvHD with histological features suggestive of cell-mediated renal injury. Albuminuria and urinary NAG levels may serve as early markers of renal

  13. Cutaneous graft-versus-host disease after hematopoietic stem cell transplant - a review*

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    Villarreal, Cesar Daniel Villarreal; Alanis, Julio Cesar Salas; Pérez, Jose Carlos Jaime; Candiani, Jorge Ocampo

    2016-01-01

    Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplants (allo-HSCT) associated with significant morbidity and mortality. The earliest and most common manifestation is cutaneous graft-versus-host disease. This review focuses on the pathophysiology, clinical features, prevention and treatment of cutaneous graft-versus-host disease. We discuss various insights into the disease's mechanisms and the different treatments for acute and chronic skin graft-versus-host disease. PMID:27438202

  14. IL-35 inhibits acute graft-versus-host disease in a mouse model.

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    Zhang, Xiao-Hui; Zhou, Yi; Zhang, Jia-Min; Zhou, Shi-Yuan; Wang, Min; Feng, Ru; Feng, Fer-Er; Wang, Qian-Ming; Zhu, Xiao-Lu; Zhao, Xiao-Su; Lv, Meng; Kong, Yuan; Chang, Ying-Jun; Huang, Xiao-Jun

    2015-12-01

    Acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our previous study found that the novel anti-inflammatory cytokine IL-35 could suppress aGVHD in patients after allo-HSCT. In this study, we used C57BL/6 (B6, H-2b) mice as donors and (B6×DBA/2) F1 (BDF1, H-2b×d) mice as recipients to create a model of aGVHD and explore the relationship between IL-35 and aGVHD. The mice receiving IL-35 survived longer than did the control mice. We observed that treatment with IL-35 and RAPA could reduce the incidence of aGVHD. Additionally, this treatment inhibited intestinal and thymic epithelial cell apoptosis and liver infiltration by the donor T-cells, thereby ameliorating the enteropathy and liver injury caused by aGVHD. We found that IL-35 and RAPA also markedly suppressed TNF-α and IL-17A expression and enhanced IFN-γ expression in the intestine and liver. We measured Tregs in spleen and found that IL-35 and RAPA treatment expanded the number of Tregs in spleen. We found that the phosphorylation of STAT1 and STAT4 were inhibited in mice with aGVHD. In contrast, STAT1 and STAT4 were phosphorylated when the mice were treated with IL-35. IL-35 may have therapeutic potential in the treatment of aGVHD after allo-HSCT.

  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 rela...... 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. Mesenchymal Stem Cell Therapy in the Treatment of Acute and Chronic Graft versus Host Disease

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    Partow eKebriaei

    2011-07-01

    Full Text Available Mesenchymal stem cells (MSC are a cellular component of the supportive microenvironment (stroma found in the bone marrow, umbilical cord, placenta and adipose tissues. In addition to providing cellular and extracellular cues to support the proliferation and differentiation of cells that comprise functional tissues, MSC also contribute to tissue repair and have immunomodulatory properties. Their ability to modulate immunologic reactions while themselves not provoking immunologic responses from alloreactive T-lymphocytes and/or other effector cells, make MSC a potentially ideal therapeutic agent with which to treat graft versus host disease (GvHD following hematopoietic transplantation. Despite in vitro experiments confirming that MSC suppress mixed lymphocyte reactions (MLR and in vivo evidence from mouse models that show evidence that MSC can ameliorate GvHD, clinical trials to date using MSC to treat GvHD have shown mixed results. Whether this is a consequence of suboptimal timing and dose of administered MSC remains to be clarified. It is clear that immunomodulatory potential of MSC as a cellular therapy for GvHD remains to be realized in the clinic.

  17. 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...

  18. Possible implication of bacterial infection in acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

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    Shigeo eFuji

    2014-04-01

    Full Text Available Graft-versus-host disease (GVHD is still one of the major causes of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT. In the pathogenesis of acute GVHD, it has been established that donor-derived T cells activated in the recipient play a major role in GVHD in initiation and maintenance within an inflammatory cascade. To reduce the risk of GVHD, intensification of GVHD prophylaxis like T cell depletion is effective, but it inevitably increases the risk of infectious diseases and abrogates beneficial graft-versus-leukemia effects. Although various cytokines are considered to play an important role in the pathogenesis of GVHD, GVHD initiation is such a complex process that cannot be prevented by means of single inflammatory cytokine inhibition. Thus, efficient methods to control the whole inflammatory milieu both on cellular and humoral view are needed. In this context, infectious diseases can theoretically contribute to an elevation of inflammatory cytokines after allogeneic HSCT and activation of various subtypes of immune effector cells, which might in summary lead to an aggravation of acute GVHD. The appropriate treatments or prophylaxis of bacterial infection during the early phase after allogeneic HSCT might be beneficial to reduce not only infectious-related but also GVHD-related mortality. Here, we aim to review the literature addressing the interactions of bacterial infections and GVHD after allogeneic HSCT.

  19. Possible Implication of Bacterial Infection in Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

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    Fuji, Shigeo; Kapp, Markus; Einsele, Hermann

    2014-01-01

    Graft-versus-host disease (GVHD) is still one of the major causes of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT). In the pathogenesis of acute GVHD, it has been established that donor-derived T-cells activated in the recipient play a major role in GVHD in initiation and maintenance within an inflammatory cascade. To reduce the risk of GVHD, intensification of GVHD prophylaxis like T-cell depletion is effective, but it inevitably increases the risk of infectious diseases and abrogates beneficial graft-versus-leukemia effects. Although various cytokines are considered to play an important role in the pathogenesis of GVHD, GVHD initiation is such a complex process that cannot be prevented by means of single inflammatory cytokine inhibition. Thus, efficient methods to control the whole inflammatory milieu both on cellular and humoral view are needed. In this context, infectious diseases can theoretically contribute to an elevation of inflammatory cytokines after allogeneic HSCT and activation of various subtypes of immune effector cells, which might in summary lead to an aggravation of acute GVHD. The appropriate treatments or prophylaxis of bacterial infection during the early phase after allogeneic HSCT might be beneficial to reduce not only infectious-related but also GVHD-related mortality. Here, we aim to review the literature addressing the interactions of bacterial infections and GVHD after allogeneic HSCT. PMID:24795865

  20. Anti-tumor necrosis factor-a for the treatment of steroid-refractory acute graft-versus-host disease

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    M.C. Nogueira

    2007-12-01

    Full Text Available Allogeneic stem cell transplantation has been increasingly performed for a variety of hematologic diseases. Clinically significant acute graft-versus-host disease (GVHD occurs in 9 to 50% of patients who receive allogeneic grafts, resulting in high morbidity and mortality. There is no standard therapy for patients with acute GVHD who do not respond to steroids. Studies have shown a possible benefit of anti-TNF-a (infliximabfor the treatment of acute GVHD. We report here on the outcomes of 10 recipients of related or unrelated stem cell transplants who received 10 mg/kg infliximab, iv, once weekly for a median of 3.5 doses (range: 1-6 for the treatment of severe acute GVHD and who were not responsive to standard therapy. All patients had acute GVHD grades II to IV (II = 2, III = 3, IV = 5. Overall, 9 patients responded and 1 patient had progressive disease. Among the responders, 3 had complete responses and 6 partial responses. All patients with cutaneous or gastrointestinal involvement responded, while only 2 of 6 patients with liver disease showed any response. None of the 10 patients had any kind of immediate toxicity. Four patients died, all of them with sepsis. Six patients are still alive after a median follow-up time of 544 days (92-600 after transplantation. Considering the severity of the cases and the bad prognosis associated with advanced acute GVHD, we find our results encouraging. Anti-TNF-a seems to be a useful agent for the treatment of acute GVHD.

  1. 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.

  2. Decreased incidence of acute graft-versus-host disease by continuous infusion of cyclosporine with a higher target blood level.

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    Oshima, Kumi; Kanda, Yoshinobu; Nakasone, Hideki; Arai, Shunya; Nishimoto, Nahoko; Sato, Hiroyuki; Watanabe, Takuro; Hosoya, Noriko; Izutsu, Koji; Asai, Takashi; Hangaishi, Akira; Motokura, Toru; Chiba, Shigeru; Kurokawa, Mineo

    2008-03-01

    Cyclosporine A (CsA) is the mainstay of pharmacologic prevention of acute graft-versus-host disease (GVHD). We previously reported that continuous infusion of CsA with a target blood level between 250 and 400 ng/ml significantly increased the incidence of acute GVHD compared to twice-daily infusion with a target trough level between 150 and 300 ng/ml. Thus, we raised the target level of CsA continuous infusion to 450-550 ng/ml. We treated 33 patients with the higher target level (CsA500) and compared the efficacy and toxicity with those in the 33 historical control patients (CsA300 group). Other transplantation procedures were not changed. The patients' characteristics were equivalent. The average CsA concentration was adjusted around 500 ng/ml and the actual daily dose was maintained at the initial dose (CsA 3mg/kg/day). Toxicities were equivalently observed among the two groups. The incidence of grades II-IV acute GVHD was significantly lower in the CsA500 group (27 vs. 52%, P = 0.033). The target level of CsA was identified as an independent significant risk factor for grades II-IV acute GVHD (P = 0.039), adjusted for the presence of HLA mismatch. The incidence of chronic GVHD was also decreased in the CsA500 group (47 vs. 73%, P = 0.016). We conclude that the toxicity of the continuous CsA infusion with a target level of 450-550 ng/ml is acceptable and the efficacy to prevent acute GVHD is significant. A larger comparative study is warranted to confirm these findings.

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

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    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.

  4. 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.

  5. MC1288, a vitamin D analog, prevents acute graft-versus-host disease in rat bone marrow transplantation.

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    Pakkala, I; Taskinen, E; Pakkala, S; Räisänen-Sokolowski, A

    2001-04-01

    The major obstacle to successful bone marrow transplantation (BMT) is graft-versus-host disease (GVHD). Vitamin D analogs have shown their efficacy in solid organ transplantation. The purpose of this study was to investigate the suitability of a novel vitamin D analog, MC1288, in the prevention of acute GVHD in a rat BMT model. Allogeneic BMT were performed from Lewis to BN rats (n = 18). The animals were divided into four groups: an untreated control group, MC1288, cyclosporin A (CsA), and MC1288 + CsA-treated groups. Rats were harvested for histology and immunohistochemistry on day 20 after BMT. Histological changes for GVHD in liver, skin, and spleen were scored. Positivity in immunostaining was quantified as the number of positive cells/high power field. Treatment with MC1288 decreased clinical signs of GVHD compared with untreated or CsA-treated rats. Histological manifestations of GVHD, expressed as mean total increment, were significantly lower (1.4 +/- 0.5) in MC1288 than in untreated (5.0 +/- 1.6) or CsA (3.5 +/- 1.0) groups. Combining MC1288 and CsA further improved histology (1.1 +/- 0.6). The expression of CD4, CD8, MHC class II, interleukin-2 receptor, nitric oxide 2, and NKR-P1A (NK cells) positivity was significantly decreased in the liver and skin of BMT rats by MC1288. MC1288 was effective in preventing clinical and histological signs and symptoms of GVHD. This novel vitamin D analog could be used as an immunomodulating agent in BMT.

  6. Substitution of methotrexate with corticosteroid for acute graft-versus-host disease prevention in transplanted patients who develop methotrexate toxicity.

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    Kim, Sung-Yong; Kim, Ah Ran; Yoon, So Young; Cho, Yo-Han; Lee, Mark Hong

    2016-02-01

    Methotrexate (MTX) toxicity can hamper the administration of all planned doses in acute graft-versus-host disease (GVHD) prophylaxis following allogeneic hematopoietic stem cell transplantation. Reduction or omission of MTX doses results in an increased risk of acute GVHD. In this prospective observational study, we compared the incidence of GVHD and the transplant outcomes between patients who received the full treatment course of MTX (group 1), patients in whom MTX doses were omitted if MTX toxicity developed (group 2), and patients receiving corticosteroid instead of MTX if MTX toxicity developed (group 3). The cumulative incidence of grades II-IV acute GVHD at 100 days post-transplantation was 22.2 % in group 1, 43.6 % in group 2, and 25.0 % in group 3 (P = 0.132). The risk of grades II-IV acute GVHD in group 2 was higher than that in group 1 (hazard ratio (HR) 3.262, P = 0.016), but the risk in group 3 was similar to that in group 1 (HR 0.960, P = 0.890). Group 3 also showed a trend towards a lower risk of chronic GVHD compared to the other groups. The cumulative risk of chronic GVHD at 2 years was 73.9, 71.6, and 33.3 % in groups 1, 2, and 3, respectively (P = 0.084). However, a likely higher relapse incidence and infection-related mortality in group 3 produced a trend towards the lowest relapse-free survival (2-year RFS, 46.3, 49.3, and 25.0 % in groups 1, 2, and 3, respectively; P = 0.329) and overall survival (2-year OS, 45, 52.3, and 25 %, respectively; P = 0.322) in group 3. Although the substitution of MTX with corticosteroid ameliorates the increased risk of GVHD in patients in which it is imperative to omit its dose, its negative impact on relapse and infection risk does not result in favorable transplant outcomes.

  7. Effect and mechanism of acute graft versus host disease on early diffuse murine lung injury following allogeneic stem cell transplantation

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    To explore the effect and pathogenssis of acute graft-versus-host disease (aGVHD) on early diffuse lung injury in allogeneic hematopoietic stem cell transplantation (allo-HSCT), we established an aGVHD model of C57BL/6→BALB/c mice. Chest computed tomography (CT) scans, histopathology and the levels of cytokines including tumor necrosis factor α (TNFα) and Interferon (IFNγ) in lungs were dynamically detected in recipient mice after transplantation. The incidence of aGVHD was respectively 0%, 0% and 100% in simple irradiation group (A), syngeneic transplant group(B) and allogeneic transplant group (C). Chest CT scans of recipient mice were normal in 3 groups on days +3 and +7 after transplantation. CT showed that two of ten mice had bilateral lung diffuse infiltrate on day +12 (on the brink of death) in group A and 6 of 10 mice had bilateral lung diffuse infiltrate on day +14 (3 d after aGVHD occurring) in group C, and were normal on days +12 and +14 in group B after transplantation. Histopathology of lungs in the 3 groups was similar, consisting of minor interstitial pneumonitis on day +3. Group A showed edema, hyperplasia of epithelial cells and widened alveolar interval on day +7, and epithelial cell necrosis, lymphocyte infiltration, hemorrhage, protein leakage, and local consolidation on day +12. The histopathology of group B showed slight edema of epithelial cells on +7 day, which were slighter than that on day +3, and virtually normal on day +14. The histopathology in group C was characterized by the significant expansion and congestion of capillaries, and lymphocyte infiltration on day +7, the acute pneumonitis was present involving tissue edema, lymphocyte and macrophage infiltration, protein leakage and perivascular inflammation on day +14. In group A, the levels of TNFα were lower on day +7 than on day +3. In group B, the levels of TNFα attained a peak on day +3, which decreased on days +7 and +14. In group C, the levels of TNFα were highest on day

  8. Cytokines in lethal graft-versus-host disease

    NARCIS (Netherlands)

    Knulst, A.C.; Bril-Bazuin, C.; Tibbe, G.J.M.; Oudenaren, van A.; Savelkoul, H.F.J.; Benner, R.

    1992-01-01

    Graft-versus-host disease (GVHD) is caused by donor T lymphocytes that recognize foreign antigens on host tissues. This leads to T cell activation, which involves a cascade of events including the transcription of genes for cytokines and their receptors and the production of cytokines. One of the fi

  9. Analysis of T-cell receptor variability in transplanted patients with acute graft-versus-host disease.

    Science.gov (United States)

    Dietrich, P Y; Caignard, A; Diu, A; Genevee, C; Pico, J L; Henry-Amar, M; Bosq, J; Angevin, E; Triebel, F; Hercend, T

    1992-11-01

    T lymphocytes play a pivotal role in graft-versus-host disease (GVHD) and largely contribute to the graft-versus-leukemia (GVL) effect. Most mature T lymphocytes specifically recognize antigens through the alpha/beta T-cell receptor (TCR). Each alpha/beta TCR chain includes a constant region and a variable region, the latter being encoded by V-J alpha or V-D-J beta rearranged gene segments. To better characterize T cells involved in GVHD, V alpha and V beta gene segment usage was analyzed, after cDNA amplification, in peripheral blood mononuclear cells (PBMC) and skin samples from three patients with grade II cutaneous GVHD. At time of GVHD diagnosis (days 11, 22, and 25), when first signs of engraftment were detectable, virtually all V alpha and V beta subfamilies were represented in PBMC RNAs of the three recipients. These results suggest that diversified TCR gene segment expression is observed early after allogenic bone marrow transplantation (alloBMT). Lymphocytes infiltrating GVHD skin also expressed a large series of V alpha and V beta subfamily specificities. However, analysis of the V alpha and V beta amplified products showed substantial differences between PBMC and the skin lymphocyte RNAs. These observations indicate that a large variety of T lymphocytes are present at the disease site, while some of them may be specifically amplified or decreased in response to minor histocompatibility antigens (miHA). Further characterization of the latter T-cell subpopulations should lead to a better understanding of human in vivo responses directed at miHA.

  10. [Chemokine Receptor-5 and Graft-versus-Host Disease].

    Science.gov (United States)

    Yuan, Jing; Liu, Wei; Ren, Han-Yun

    2015-06-01

    Chemokine receptor-5 (CCR5) belongs to a G-protein coupled receptors superfamily. It is mainly expressed on a wide variety of immune cells. CCR5 can bind with its specific ligands, which plays very important roles in inflammatory cell growth, differentiation, activation, adhesion and migration. CCR5 was identified as a co-receptor for human immunodeficiency virus type-1 (HIV-1) to infect CD4+ T cells. In addition, CCR5 not only participates in the pathogenic mechanisms of many inflammation disease such as AIDS, auto-immune disease, and atherosclerosis, but also plays important roles in the development of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Recent studies using murine models have demonstrated the critical role of CCR5 and its ligands which direct T-cell infiltration and recruitment into target tissues during acute GVHD. CCR5 has become the focus of intense interest and discussion, and this review will attempt to describe what is understood about the structure and function, internalization, signal transduction of CCR5, in order to investigate the relationship between CCR5 and acute GVHD.

  11. Increased incidence of acute graft-versus-host disease with the continuous infusion of cyclosporine A compared to twice-daily infusion.

    Science.gov (United States)

    Ogawa, N; Kanda, Y; Matsubara, M; Asano, Y; Nakagawa, M; Sakata-Yanagimoto, M; Kandabashi, K; Izutsu, K; Imai, Y; Hangaishi, A; Kurokawa, M; Tsujino, S; Ogawa, S; Aoki, K; Chiba, S; Motokura, T; Hirai, H

    2004-03-01

    We retrospectively compared the incidence of acute graft-versus-host disease (GVHD) before and after September 1999, when we changed the mode of cyclosporine A (CsA) administration from twice-daily infusions (TD) (n=58) to continuous infusion (CIF) (n=71). The incidence of grade II-IV acute GVHD in the CIF group (56%) was significantly higher than that in the TD group (27%, P=0.00022). Multivariate analysis identified only two independent significant risk factors for the development of grade II-IV acute GVHD; CIF of CsA (relative risk 2.59, 95% CI 1.46-4.60, P=0.0011) and the presence of HLA mismatch (2.01, 95% CI 1.15-3.53, P=0.014). The incidence of relapse was significantly lower in the CIF group when adjusted for disease status before transplantation (0.41, 95% CI 0.18-0.95, P=0.038), which resulted in better disease-free survival in high-risk patients (43 vs 16% at 2 years, P=0.039), but not in standard-risk patients (72 vs 80%, P=0.45). CIF of CsA with a target level of 250-400 ng/ml may not be appropriate for GVHD prophylaxis in standard-risk patients.

  12. A phase 2/3 multicenter randomized clinical trial of ABX-CBL versus ATG as secondary therapy for steroid-resistant acute graft-versus-host disease.

    Science.gov (United States)

    Macmillan, Margaret L; Couriel, Daniel; Weisdorf, Daniel J; Schwab, Gisela; Havrilla, Nancy; Fleming, Thomas R; Huang, Saling; Roskos, Lorin; Slavin, Shimon; Shadduck, Richard K; Dipersio, John; Territo, Mary; Pavletic, Steve; Linker, Charles; Heslop, Helen E; Deeg, H Joachim; Blazar, Bruce R

    2007-03-15

    Treatment for steroid-resistant acute graft-versus-host disease (GVHD) has had limited success. ABX-CBL is a hybridoma-generated murine IgM monoclonal antibody against the CD147 antigen, weakly expressed on human leukocytes and up-regulated on activated lymphocytes. A prospective, multicenter, open-label, randomized clinical trial comparing ABX-CBL to antithymocyte globulin (ATG) for treatment of steroid-resistant acute GVHD was conducted in 95 patients at 21 centers. Forty-eight patients received ABX-CBL daily for 14 consecutive days followed by up to 6 weeks of ABX-CBL twice weekly. Forty-seven patients received equine ATG, 30 mg/kg every other day for a total of 6 doses with additional courses as needed. By day 180, overall improvement was similar in the patients receiving ABX-CBL and in those receiving ATG (56% versus 57%, P = .91). Patient survival at 18 months was less favorable on ABX-CBL than on ATG (35% versus 45%), with the 95% confidence interval ruling out that ABX-CBL provides at least a 10.4% improvement. Data from this trial suggest that ABX-CBL does not offer an improvement over ATG in the treatment of acute steroid-resistant GVHD. This prospective, multicenter, randomized clinical trial for steroid-resistant acute GVHD serves as a model for future evaluation of new agents.

  13. Dermoscopic Follow-Up of the Skin towards Acute Graft-versus-Host-Disease in Patients after Allogeneic Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Grazyna Kaminska-Winciorek

    2016-01-01

    Full Text Available Background. Acute graft-versus-host disease (aGVHD involving skin is one of the most frequent complications of allogeneic hematopoietic stem cell transplantation (alloHSCT, usually diagnosed based on clinical manifestations. So far, skin biopsy with histopathological evaluation is the only method to confirm the diagnosis. Objective. In this prospective study we monitored alloHSCT recipients by dermoscopy in order to assess its utility as an alternative noninvasive tool to early diagnose acute GVHD. Methods. Thirteen consecutive patients who received alloHSCT were examined clinically and dermoscopically towards aGVHD [days 28 (±7, 56 (±7, and 100 (±7], as well as in each patient who developed cutaneous aGVHD diagnosed according to clinical criteria (Glucksberg scale. Results. Six patients (46% developed symptoms of cutaneous acute GVHD (grade 1, n=3; grade 2, n=3. Dermoscopic evaluation revealed pinkish or reddish background and well-visible, multiple thin telangiectasias. Conclusion. To our knowledge, this is the first report on the use of dermoscopy to evaluate skin involvement in the course of acute GVHD suggesting its role as a diagnostic tool in follow-up of GVHD, which can be also used before clinical symptoms occur.

  14. Effect of acute and chronic graft-versus-host disease on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma

    Science.gov (United States)

    Ringdén, Olle; Shrestha, Smriti; da Silva, Gisela Tunes; Zhang, Mei-Jie; Dispenzieri, Angela; Remberger, Mats; Kamble, Rammurti; Freytes, Cesar O.; Gale, Robert Peter; Gibson, John; Gupta, Vikas; Holmberg, Leona; Lazarus, Hillard; McCarthy, Philip; Meehan, Kenneth; Schouten, Harry; Milone, Gustavo A.; Lonial, Sagar; Hari, Parameswaran N

    2011-01-01

    We evaluated the effect of acute and chronic graft-versus-host disease (GVHD) on relapse and survival after allogeneic haematopoietic stem cell transplantation (HSCT) for multiple myeloma (MM) using non-myeloablative conditioning (NMA) and reduced-intensity conditioning (RIC). The outcomes of 177 HLA-identical sibling HSCT recipients between 1997 and 2005 following NMA (n=98) or RIC (n=79) were analyzed. In 105 patients, autografting was followed by planned NMA/RIC allogeneic transplantation. The impact of GVHD was assessed as a time-dependent covariate using Cox models. The incidence of acute GVHD (grades I–IV) was 42% (95% confidence interval (CI) 35 – 49%) and of chronic GVHD at five years was 59% (95% CI 49 – 69%), with 70% developing extensive chronic GVHD. In multivariate analysis, acute GVHD (≥ grade I) was associated with an increased risk of TRM (relative risk (RR)=2.42; p=0.016), whereas limited chronic GVHD significantly decreased the risk of myeloma relapse (RR=0.35, p=0.035) and was associated with superior event-free survival (RR=0.40, p=0.027). Acute GVHD had a detrimental effect on survival, especially in those receiving autologous followed by allogeneic HSCT (RR=3.52; p=0.001). The reduction in relapse risk associated with chronic GVHD is consistent with a beneficial graft-versus-myeloma effect, but this did not translate into a survival advantage. PMID:21946381

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

    OpenAIRE

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

    2015-01-01

    Naturally derived regulatory T cells (nTregs) may prevent graft-versus-host disease (GVHD) while preserving graft-versus-leukemia (GVL) activity. However, clinical application of nTregs has been severely hampered by their scarce availability and non-selectivity. 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 pre-clinical models of bone marrow transplantation (BM...

  16. Post-transplant cyclophosphamide versus anti-thymocyte globulin as graft- versus-host disease prophylaxis in haploidentical transplant

    Science.gov (United States)

    Ruggeri, Annalisa; Sun, Yuqian; Labopin, Myriam; Bacigalupo, Andrea; Lorentino, Francesca; Arcese, William; Santarone, Stella; Gülbas, Zafer; Blaise, Didier; Messina, Giuseppe; Ghavamzadeh, Ardeshi; Malard, Florent; Bruno, Benedetto; Diez-Martin, Jose Luis; Koc, Yener; Ciceri, Fabio; Mohty, Mohamad; Nagler, Arnon

    2017-01-01

    Severe graft-versus-host disease is a major barrier for non-T-cell-depleted haploidentical stem cell transplantation. There is no consensus on the optimal graft-versus-host disease prophylaxis. This study compared the two most commonly used graft-versus-host disease prophylaxis regimens (post-transplant cyclophosphamide-based vs. the anti-thymocyte globulin-based) in adults with acute myeloid leukemia reported to the European Society for Blood and Bone Marrow Transplantation. A total of 308 patients were analyzed; 193 received post-transplant cyclophosphamide-based regimen and 115 anti-thymocyte globulin-based regimen as anti-graft-versus-host disease prophylaxis. The post-transplant cyclophosphamide-based regimen was more likely to be associated to bone marrow as graft source (60% vs. 40%; P=0.01). Patients in the post-transplant cyclophosphamide-based regimen group had significantly less grade 3–4 acute graft-versus-host disease than those in the anti-thymocyte globulin-based group (5% vs. 12%, respectively; P=0.01), comparable to chronic graft-versus-host disease. Multivariate analysis showed that non-relapse mortality was lower in the post-transplant cyclophosphamide-based regimen group [22% vs. 30%, Hazard ratio (HR) 1.77(95%CI: 1.09–2.86); P=0.02] with no difference in relapse incidence. Patients receiving post-transplant cyclophosphamide-based regimen had better graft-versus-host disease-free, relapse-free survival [HR 1.45 (95%CI: 1.04–2.02); P=0.03] and leukemia-free survival [HR 1.48 (95%CI: 1.03–2.12); P=0.03] than those in the anti-thymocyte globulin-based group. In the multivariate analysis, there was also a trend for a higher overall survival [HR 1.43 (95%CI: 0.98–2.09); P=0.06] for post-transplant cyclophosphamide-based regimen versus the anti-thymocyte globulin-based group. Notably, center experience was also associated with non-relapse mortality and graft-versus-host disease-free, relapse-free survival. Haplo-SCT using a post

  17. Chronic graft versus host disease and nephrotic syndrome.

    Science.gov (United States)

    Barbouch, Samia; Gaied, Hanene; Abdelghani, Khaoula Ben; Goucha, Rim; Lakhal, Amel; Torjemen, Lamia; Hamida, Fethi Ben; Abderrahim, Ezzedine; Maiz, Hedi Ben; Adel, Khedher

    2014-09-01

    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 membranous glomerulonephritis associated with a focal segmental glomerulosclerosis. She was started on corticosteroid treatment with good outcome.

  18. 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.

  19. B-Cell-Based and Soluble Biomarkers in Body Liquids for Predicting Acute/Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

    Science.gov (United States)

    Juric, Mateja Kralj; Shevtsov, Maxim; Mozes, Petra; Ogonek, Justyna; Crossland, Rachel E.; Dickinson, Anne M.; Greinix, Hildegard T.; Holler, Ernst; Weissinger, Eva M.; Multhoff, Gabriele

    2017-01-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main curative therapy for hematological malignancy such as leukemias, lymphomas, or multiple myelomas and some other hematological disorders. In this therapy, cure of hematological diseases relies on graft-versus-malignancy effects by allogenic immune cells. However, severe posttransplant treatment-associated complications such as acute graft-versus-host disease (aGvHD) and chronic graft-versus-host disease (cGvHD) limit this approach. Most research into GvHD has concentrated on the aGvHD, while the more complex and multifaceted chronic form has been largely poorly investigated. cGvHD is a multi-organ autoimmune disorder and is the major cause of non-relapse morbidity and mortality following allo-HSCT, occurring in about 50% of patients, or 13,000–15,000 patients per year worldwide. Therefore, there is a high medical need for an early prediction of these therapy-associated toxicities. Biomarkers have gained importance over the last decade in diagnosis, in prognosis, and in prediction of pending diseases or side effects. Biomarkers can be cells, factors isolated from target tissues, or soluble factors that can be detected in body fluids. In this review, we aim to summarize some of the recent developments of biomarkers in the field of allo-HSCT. We will focus on cell-based biomarkers (B-cell subsets) for cGvHD and soluble factors including microRNA (miRNA), which are excreted into serum/plasma and urine. We also discuss the potential role of cytosolic and extracellular 70 kDa heat shock proteins (HSP70) as potential biomarkers for aGvHD and their role in preclinical models. Proteomic biomarkers in the blood have been used as predictors of treatment responses in patients with aGvHD for many years. More recently, miRNAs have been found to serve as a biomarker to diagnose aGvHD in the plasma. Another development relates to urine-based biomarkers that are usually detected by capillary

  20. Recipient CTLA-4*CT60-AA genotype is a prognostic factor for acute graft-versus-host disease in hematopoietic stem cell transplantation for thalassemia

    Science.gov (United States)

    Orrù, Sandro; Orrù, Nicola; Manolakos, Emmanouil; Littera, Roberto; Caocci, Giovanni; Giorgiani, Giovanna; Bertaina, Alice; Pagliara, Daria; Giardini, Claudio; Nesci, Sonia; Locatelli, Franco; Carcassi, Carlo; La Nasa, Giorgio

    2012-01-01

    Polymorphisms of the cytotoxic T-lymphocyte antigen-4 gene (CTLA-4) have been associated with autoimmune diseases and it has recently been reported that donor genotypes correlate with the outcome of allogeneic hematopoietic stem cell transplantation in leukemia patients. With the aim of confirming this finding in thalassemia patients, we investigated the influence of genotype distribution of 3 CTLA-4 gene polymorphisms in 72 thalassemia patients and their unrelated donors. A significant association was observed for recipient CT60-AA genotype and onset of grade II–IV (63.2% vs 24.5%; p = 0.001) and grade III–IV (36.4% vs 7.6%; p = 0.005) acute graft-versus-host disease (aGVHD). The same association was observed for the 88-base-pair allele of the CTLA-4 (AT)n polymorphism, which was determined to be in complete linkage disequilibrium with the CT60 A allele. Multinomial Cox regression demonstrated that this association was independent of CT60 donor genotypes or other risk factors (p = 0.016; hazard ratio = 2.8). Our data confirm that the genetic variability in CTLA-4 is an important prognostic factor for aGVHD and suggest that some of the risk factors for this complication are generated by recipient cells that persist after the myeloablative conditioning regimen. PMID:22245568

  1. Pretransplant β2-Microglobulin Is Associated with the Risk of Acute Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplant.

    Science.gov (United States)

    Costa-Lima, Carolina; Miranda, Eliana Cristina Martins; Colella, Marcos Paulo; Aranha, Francisco Jose Penteado; de Souza, Carmino Antonio; Vigorito, Afonso Celso; De Paula, Erich Vinicius

    2016-07-01

    The risk of acute graft-versus-host disease (aGVHD) can be reliably estimated by the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), which can be further refined by the incorporation of pre-hematopoietic cell transplantation (HCT) serum levels of inflammatory biomarkers such as ferritin and albumin. β2-Microglobulin (β2-m) is a key component of the MHC class I complex, which is independently associated with mortality and frailty in the general population. We took advantage of our institutional protocol that includes measurement of pre-HCT β2-m serum levels in the most patients to investigate whether pre-transplant β2-m levels were associated with the risk of aGVHD. One hundred three consecutive patients submitted to allogeneic HCT, of which 26 developed grades II to IV aGVHD, were included in the analysis. β2-m was significantly associated with age and HCT-CI. Higher levels of β2-m were observed in patients who developed aGVHD (P = .008). In the multivariate Cox regression model, β2-m and HCT-CI remained independently associated with the risk of developing aGVHD. In conclusion, the association between β2-m and the occurrence of aGVHD suggests that the measurement of this protein before HCT might represent an additional element for risk stratification of aGVHD.

  2. Mesenchymal stem cells provide prophylaxis against acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: A meta-analysis of animal models.

    Science.gov (United States)

    Wang, Li; Zhang, Haiyan; Guan, Lixun; Zhao, Shasha; Gu, Zhenyang; Wei, Huaping; Gao, Zhe; Wang, Feiyan; Yang, Nan; Luo, Lan; Li, Yonghui; Wang, Lili; Liu, Daihong; Gao, Chunji

    2016-09-20

    A meta-analysis of animal models was conducted to evaluate the prophylactic effects of mesenchymal stem cells (MSCs) on acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation. A total of 50 studies involving 1848 animals were included. The pooled results showed that MSCs significantly reduced aGVHD-associated mortality (risk ratio = 0.70, 95% confidence interval 0.62 to 0.79, P = 2.73×10-9) and clinical scores (standardized mean difference = -3.60, 95% confidence interval -4.43 to -2.76, P = 3.61×10-17). In addition, MSCs conferred robust favorable prophylactic effects on aGVHD across recipient species, MSC doses, and administration times, but not MSC sources. Our meta-analysis showed that MSCs significantly prevented mortality and alleviated the clinical manifestations of aGVHD in animal models. These data support further clinical trials aimed at evaluating the efficacy of using MSCs to prevent aGVHD.

  3. Risk Factors for Steroid-Refractory Acute Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation from Matched Related or Unrelated Donors.

    Science.gov (United States)

    Calmettes, Claire; Vigouroux, Stéphane; Labopin, Myriam; Tabrizi, Reza; Turlure, Pascal; Lafarge, Xavier; Marit, Gérald; Pigneux, Arnaud; Leguay, Thibaut; Bouabdallah, Krimo; Dilhuydy, Marie-Sarah; Duclos, Cédric; Mohr, Catherine; Lascaux, Axelle; Dumas, Pierre-Yves; Dimicoli-Salazar, Sophie; Saint-Lézer, Arnaud; Milpied, Noël

    2015-05-01

    We performed a retrospective study to identify pretransplantation risk factors for steroid-refractory (SR) acute graft-versus host disease (aGVHD) after allogeneic stem cell transplantation from matched donors in 630 adult patients who underwent transplantation at our center between 2000 and 2012. The cumulative incidence (CI) of SR aGVHD was 11.3% ± 2.3%. The identified independent risk factors were matched unrelated donor (hazard ratio [HR], 2.52; P = .001), female donor for male recipient (HR, 1.84; P = .023) and absence of antithymocyte globulin (HR, 2.02; P = .005). Three risk groups were defined according to the presence of these risk factors. In the whole cohort, the CI of SR aGVHD was 3.5% ± 1.7% in the low-risk group (0 risk factor, n = 115), 9.3% ± 1.6% in the intermediate-risk group (1 risk factor, n = 323), and 19.3% ± 2.9% in the high-risk group (2 or 3 risk factors, n = 192). Our study suggests that pretransplantation characteristics might help identify patients at high risk for SR aGVHD. A risk adapted first-line treatment of aGVHD could be evaluated in those patients.

  4. Reduced IL-35 levels are associated with increased platelet aggregation and activation in patients with acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Zhang, Xiaohui; Zhou, Yi; Xu, Lanping; Han, Wei; Chen, Huan; Chen, Yuhong; Fu, Haixia; Zhou, Shiyuan; Zhao, Jingzhong; Wang, Qianming; Feng, Feier; Zhu, Xiaolu; Liu, Kaiyan; Huang, Xiaojun

    2015-05-01

    Acute graft-versus-host disease (aGVHD) is a major complication associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Interleukin (IL)-35 is a novel anti-inflammatory cytokine that suppresses the immune response. This prospective study explored IL-35 plasma levels in 65 patients after HSCT. The results revealed that the peripheral blood of patients with grades III-IV aGVHD (23.46 ng/ml) had reduced IL-35 compared to transplanted patients with grades I-II aGVHD (40.26 ng/ml, p IL-35 levels with respect to aGVHD. The patients who received lower levels of IL-35 cells in the GBM (28.0 ng/ml, p = 0.551) or lower levels of IL-35 in PBPC (53.46 ng/ml, p = 0.03) exhibited a higher incidence of aGVHD. Patients with aGVHD have increased platelet aggregation. IL-35 was added to patient blood in vitro, and platelet aggregation was inhibited by IL-35 in a dose-dependent manner. The markers of platelet activation (CD62P/PAC-1) can also be inhibited by IL-35. The results indicate that IL-35 may affect the development of aGVHD by inhibiting platelet activation and aggregation. Our data suggests that IL-35 represents a potentially effective therapeutic agent against aGVHD after allo-HSCT.

  5. Narrow-Band Ultraviolet B Phototherapy Ameliorates Acute Graft-Versus-Host Disease of the Intestine by Expansion of Regulatory T Cells.

    Science.gov (United States)

    Hashimoto, Akari; Sato, Tsutomu; Iyama, Satoshi; Yoshida, Masahiro; Ibata, Soushi; Tatekoshi, Ayumi; Kamihara, Yusuke; Horiguchi, Hiroto; Murase, Kazuyuki; Kawano, Yutaka; Takada, Kohichi; Miyanishi, Koji; Kobune, Masayoshi; Ichimiya, Shingo; Kato, Junji

    2016-01-01

    Narrowband ultraviolet B (NB-UVB) has been widely used in dermatological phototherapy. As for the application of NB-UVB phototherapy to graft-versus-host disease (GVHD), we previously reported that it was highly efficacious for cutaneous lesions of acute GVHD (aGVHD) and that expansion of regulatory T (Treg) cells induced by NB-UVB might be one of the mechanisms. In order to examine whether NB-UVB irradiation through expansion of Treg cells is effective for the treatment of not only cutaneous aGVHD but also aGVHD of inner organs such as the intestine or liver, we conducted experiments in which a murine lethal aGVHD model, characterized by severe involvement of the intestine, was irradiated with NB-UVB. We found that NB-UVB irradiation improved the clinical score and survival rate. The pathological score of aGVHD was improved in all affected organs: intestine, liver, and skin. In the serum of mice irradiated with NB-UVB, the levels of Treg cells-associated cytokines such as transforming growth factor beta (TGFβ) and interleukin-10 (IL-10) were elevated. The numbers of infiltrating Treg cells in inflamed tissue of the intestine and those in spleen were increased in mice treated with NB-UVB. This is the first report demonstrating that NB-UVB phototherapy has the ability to ameliorate intestinal aGVHD through the expansion of Treg cells.

  6. High day 28 ST2 levels predict for acute graft-versus-host disease and transplant-related mortality after cord blood transplantation.

    Science.gov (United States)

    Ponce, Doris M; Hilden, Patrick; Mumaw, Christen; Devlin, Sean M; Lubin, Marissa; Giralt, Sergio; Goldberg, Jenna D; Hanash, Alan; Hsu, Katharine; Jenq, Robert; Perales, Miguel-Angel; Sauter, Craig; van den Brink, Marcel R M; Young, James W; Brentjens, Renier; Kernan, Nancy A; Prockop, Susan E; O'Reilly, Richard J; Scaradavou, Andromachi; Paczesny, Sophie; Barker, Juliet N

    2015-01-01

    While cord blood transplantation (CBT) is an effective therapy for hematologic malignancies, acute graft-versus-host disease (aGVHD) is a leading cause of transplant-related mortality (TRM). We investigated if biomarkers could predict aGVHD and TRM after day 28 in CBT recipients. Day 28 samples from 113 CBT patients were analyzed. Suppressor of tumorigenicity 2 (ST2) was the only biomarker associated with grades II-IV and III-IV aGVHD and TRM. Day 180 grade III-IV aGVHD in patients with high ST2 levels was 30% (95% confidence interval [CI], 18-43) vs 13% (95% CI, 5-23) in patients with low levels (P = .024). The adverse effect of elevated ST2 was independent of HLA match. Moreover, high day 28 ST2 levels were associated with increased TRM with day 180 estimates of 23% (95% CI, 13-35) vs 5% (95% CI, 1-13) if levels were low (P = .001). GVHD was the most common cause of death in high ST2 patients. High concentrations of tumor necrosis factor receptor-1, interleukin-8, and regenerating islet-derived protein 3-α were also associated with TRM. Our results are consistent with those of adult donor allografts and warrant further prospective evaluation to facilitate future therapeutic intervention to ameliorate severe aGVHD and further improve survival after CBT.

  7. A genetic variant in the IL-17 promoter is functionally associated with acute graft-versus-host disease after unrelated bone marrow transplantation.

    Directory of Open Access Journals (Sweden)

    J Luis Espinoza

    Full Text Available Interleukin IL-17 is a proinflammatory cytokine that has been implicated in the pathogenesis of various autoimmune diseases. The single nucleotide polymorphism (SNP, rs2275913, in the promoter region of the IL-17 gene is associated with susceptibility to ulcerative colitis. When we examined the impact of rs2275913 in a cohort consisting of 438 pairs of patients and their unrelated donors transplanted through the Japan Marrow Donor Program, the donor IL-17 197A allele was found to be associated with a higher risk of acute graft-versus-host disease (GVHD; hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.00 to 2.13; P = 0.05. Next, we investigated the functional relevance of the rs2275913 SNP. In vitro stimulated T cells from healthy individuals possessing the 197A allele produced significantly more IL-17 than those without the 197A allele. In a gene reporter assay, the 197A allele construct induced higher luciferase activity than the 197G allele, and the difference was higher in the presence of T cell receptor activation and was abrogated by cyclosporine treatment. Moreover, the 197A allele displayed a higher affinity for the nuclear factor activated T cells (NFAT, a critical transcription factor involved in IL-17 regulation. These findings substantiate the functional relevance of the rs2275913 polymorphism and indicate that the higher IL-17 secretion by individuals with the 197A allele likely accounts for their increased risk for acute GVHD and certain autoimmune diseases.

  8. Characterization of acute graft-versus-host disease following reduced-intensity stem-cell transplantation from an HLA-identical related donor.

    Science.gov (United States)

    Murashige, Naoko; Kami, Masahiro; Mori, Shin-ichiro; Katayama, Yuta; Kobayashi, Kazuhiko; Onishi, Yasushi; Hori, Akiko; Kishi, Yukiko; Hamaki, Tamae; Tajima, Kinuko; Kanda, Yoshinobu; Tanosaki, Ryuji; Takaue, Yoichi

    2008-08-01

    To investigate clinical features of acute graft-versus-host disease (GVHD) following reduced intensity stem-cell transplantation (RIST), we retrospectively investigated medical records of 65 patients with hematologic malignancies who underwent RIST from a matched related donor. Preparative regimen comprised fludarabine 30 mg/m(2) (n = 53) or cladribine 0.11 mg/kg (n = 12) for 6 days plus busulfan 4 mg/kg for 2 days. Twelve patients received rabbit antithymocyte globulin 2.5 mg/kg/day for 2-4 consecutive days. Grade II to IV acute GVHD was diagnosed in 36 patients (55%). Its median onset was day 58 (range, 17-109), while it was bimodal, peaking day 15-29 (early-onset GVHD, n = 18) and day 75-89 days (late-onset GVHD, n = 18). Variables that were more common in early-onset GVHD than late-onset GVHD included skin rash (89% vs. 61%) and noninfectious fevers (33% vs. 11%). Desaturation, pulmonary infiltrates and hyperbilirubinemia (>2.0 mg/dL) were more common in late-onset GVHD (6% vs. 22%, 0% vs. 17%, and 6% vs. 33%, respectively). All of the patients with early-onset GVHD given corticosteroid responded to it, while 5 of the 18 patients with late-onset GVHD failed to respond it. Patients with either early-onset or late-onset GVHD tended to have better progression-free survival (PFS) than those without it; however, there was no significant difference in PFS between patients with early-onset GVHD and those with late-onset GVHD. This study suggests that several etiologies might have contributed to the development of acute GVHD following RIST.

  9. Advances in medical decision support systems for diagnosis of acute graft-versus-host disease: molecular and computational intelligence joint approaches

    Institute of Scientific and Technical Information of China (English)

    Maurizio FIASCH(E); Maria CUZZOLA; Giuseppe IRRERA; Pasquale IACOPINO; Francesco Carlo MORABITO

    2011-01-01

    Acute graft-versus-host disease (aGVHD) is a serious systemic complication of allogeneic hematopoietic stem cell transplantation (HSCT) causing considerable morbidity and mortality.Acute GVHD occurs when alloreactive donor-derived T cells recognize host-recipient antigens as foreign.These trigger a complex multiphase process that ultimately results in apoptotic injury in target organs.The early events leading to GVHD seem to occur very soon,presumably within hours from the graft infusion.Therefore,when the first signs of aGVHD clinically manifest,the disease has been ongoing for several days at the cellular level,and the inflammatory cytokine cascade is fully activated.So,it comes as no surprise that progress in treatment based on clinical diagnosis of aGVHD has been limited in the past 30 years.It is likely that a pre-emptive strategy using systemic high-dose corticosteroids as early as possible could improve the outcome of aGVHD.Due to the deleterious effects of such treatment particularly in terms of infection risk posed by systemic steroid administration in a population that is already immune-suppressed,it is critical to identify biomarker signatures for approaching this very complex task.Some research groups have begun addressing this issue through molecular and proteomic analyses,combining these approaches with computational intelligence techniques,with the specific aim of facilitating the identification of diagnostic biomarkers in aGVHD.In this review,we focus on the aGVHD scenario and on the more recent state-of-the-art.We also attempt to give an overview of the classical and novel techniques proposed as medical decision support system for the diagnosis of GVHD.

  10. Impact of Cyclosporine Levels on the Development of Acute Graft versus Host Disease after Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Irene García Cadenas

    2014-01-01

    Full Text Available We analyze the impact of cyclosporine (CsA levels in the development of acute graft-versus-host disease (aGVHD after reduced intensity conditioning allogeneic hematopoietic transplantation (allo-RIC. We retrospectively evaluated 156 consecutive patients who underwent HLA-identical sibling allo-RIC at our institution. CsA median blood levels in the 1st, 2nd, 3rd and 4th weeks after allo-RIC were 134 (range: 10–444, 219 (54–656, 253 (53–910 and 224 (30–699 ng/mL; 60%, 16%, 11% and 17% of the patients had median CsA blood levels below 150 ng/mL during these weeks. 53 patients developed grade 2–4 aGVHD for a cumulative incidence of 45% (95% CI 34–50% at a median of 42 days. Low CsA levels on the 3rd week and sex-mismatch were associated with the development of GVHD. Risk factors for 1-year NRM and OS were advanced disease status (HR: 2.2, P=0.02 and development of grade 2–4 aGVHD (HR: 2.5, P<0.01, while there was a trend for higher NRM in patients with a low median CsA concentration on the 3rd week (P=0.06. These results emphasize the relevance of sustaining adequate levels of blood CsA by close monitoring and dose adjustments, particularly when engraftment becomes evident. CsA adequate management will impact on long-term outcomes in the allo-RIC setting.

  11. High expression of heme oxygenase-1 in target organs may attenuate acute graft-versus-host disease through regulation of immune balance of TH17/Treg.

    Science.gov (United States)

    Yu, Meisheng; Wang, Jishi; Fang, Qin; Liu, Ping; Chen, Shuya; Zhe, Nana; Lin, Xiaojing; Zhang, Yaming; Zhao, Jiangyuan; Zhou, Zhen

    2016-07-01

    The high incidence of acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Grades III and IV aGVHD are the leading causes of death in allo-HSCT recipients. Heme oxygenase-1(HO-1) has anti-inflammatory and immune-regulatory functions. In this study, we evaluated the none GVHD and grade I-IV patients samples which were collected at the first re-examination after successful allo-HSCT, we found that expressions of HO-1 mRNA in the bone marrow and peripheral blood mononuclear cells of allo-HSCT recipients who had subsequent non-GVHD and grade I aGVHD were significantly higher than those in patients with Grade III-IV aGVHD. We then demonstrated that enhanced expression of HO-1 in target organs by infusing HO-1-gene-modified Mesenchymal stem cells (MSCs) alleviated the clinical and histopathological severity of aGVHD in experimental mice. Flow cytometry revealed a higher expression of Treg cells and a lower expression of TH17 cells in splenic and lymph node tissues of mice with enhanced HO-1 expression, as compared to that in the aGVHD mice. This was further substantiated by lower expression levels of ROR-Υt and IL-17A mRNA, and higher levels of Foxp3 mRNA in the splenic tissue of mice with enhanced HO-1 expression. Our results indicate that high expression of HO-1 may reduce the severity of aGVHD by regulation of the TH17/Treg balance.

  12. Treatment of steroid-refractory acute graft-versus-host disease with anti-CD147 monoclonal antibody ABX-CBL.

    Science.gov (United States)

    Deeg, H J; Blazar, B R; Bolwell, B J; Long, G D; Schuening, F; Cunningham, J; Rifkin, R M; Abhyankar, S; Briggs, A D; Burt, R; Lipani, J; Roskos, L K; White, J M; Havrilla, N; Schwab, G; Heslop, H E

    2001-10-01

    ABX-CBL, an immunoglobulin M murine monoclonal antibody, recognizes CD147 and initiates cell killing through complement-mediated lysis. In a dose-finding trial, 27 patients with steroid-refractory acute graft-versus-host disease (GVHD) received ABX-CBL at 0.01 (presumed no effect dose), 0.1, 0.2, or 0.3 mg/kg per day, and an additional 32 patients were given ABX-CBL at 0.2 or 0.15 mg/kg per day. All patients had undergone allogeneic transplantation for malignant or nonmalignant disorders and received GVHD prophylaxis, generally with methotrexate- and cyclosporine-containing regimens. None responded to methylprednisolone, given for a minimum of 3 days. ABX-CBL was started 20 to 236 (median, 47) days after transplantation; it was given for 7 consecutive days and was followed by 2 infusions per week for 2 more weeks. Among 51 patients evaluable for efficacy, 26 (51%) responded, including 13 with complete responses (CR) and 13 with partial responses (PR). CR lasting 14 days or longer or PR lasting 7 days or longer occurred in 21 (41%; 8 CR, 13 PR) patients, including 19 of 43 (44%) patients who received 0.1 to 0.3 mg/kg ABX-CBL and 2 of 8 (25%) patients given 0.01 mg/kg per day. Myalgias at doses 0.2 mg/kg or greater were dose limiting and resolved without sequelae. Causes of death included organ failure, progressive GVHD, and infection. No death was attributed to ABX-CBL. At 6 months after the initiation of ABX-CBL therapy, 26 (44%) patients were surviving. These results are encouraging. Further studies on the use of ABX-CBL in the management of GVHD are warranted.

  13. Lithium Carbonate in Treating Patients With Acute Intestinal Graft-Versus-Host-Disease (GVHD) After Donor Stem Cell Transplant

    Science.gov (United States)

    2017-01-24

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, Breakpoint Cluster Region-abl Translocation (BCR-ABL) Negative; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Gastrointestinal Complications; Juvenile Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Poor Prognosis Metastatic Gestational Trophoblastic Tumor; Previously Treated Childhood Rhabdomyosarcoma; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia

  14. 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....

  15. The impact of histopathologic examination of graft-versus-host disease in the era of reduced-intensity conditioning regimen: a study from the Gruppo Italiano Trapianto di Midollo Osseo.

    Science.gov (United States)

    Massi, Daniela; Fondi, Cristina; Nozzoli, Chiara; Benemei, Silvia; Lapi, Francesco; Albarello, Luca; Avellini, Claudio; Bonoldi, Emanuela; Casini, Marco; Cesinaro, Anna Maria; Ciceri, Fabio; Colombetti, Vito; Comin, Camilla Eva; Donelli, Amedea; Fortunato, Mirella; Fratoni, Stefano; Guidi, Stefano; Messerini, Luca; Milone, Giuseppe; Rapezzi, Davide; Negri, Giovanni; Patriarca, Francesca; Peccatori, Fedro Alessandro; Ponzoni, Maurilio; Rafaniello, Paola; Raimondi, Roberto; Salomone, Edvige; Tendas, Andrea; Villari, Loredana; Santucci, Marco; Bosi, Alberto

    2011-02-01

    Reduced-intensity conditioning regimens have reshaped the clinical presentation of graft-versus-host disease after hematopoietic stem cell transplants. However, histopathologic features of graft-versus-host disease following reduced-intensity conditioning regimens have not been fully characterized. In a series of 112 biopsies (skin, n = 60; gastrointestinal [GI] tract, n = 44; liver, n = 8), we described the morphologic profile of graft-versus-host disease following reduced-intensity conditioning and investigated whether histopathologic changes of graft-versus-host disease following reduced-intensity conditioning have a diagnostic and/or prognostic value. Forty-four patients (49.5%) experienced acute graft-versus-host disease, 2 (2.2%) late-onset acute graft-versus-host disease (grade I, n = 13; grade II-IV, n = 33), 24 (27.0%) chronic graft-versus-host disease (de novo n = 12, progressive n = 12) and 19 (21.3%) overlap syndrome. In the skin, we observed: (i) phase-nonspecific changes, such as acute graft-versus-host disease features in chronic graft-versus-host disease patients (n = 4/24; 16.6%), (ii) subtle alterations such as superficial fibrosis in widened dermal papillae (n = 8), in acute graft-versus-host disease/late-onset graft-versus-host disease (n = 6/46; 13.0%) or chronic graft-versus-host disease (n = 2/24, 8.3%) patients, and (iii) features of chronic and acute graft-versus-host disease coexisting in the same specimen in overlap syndrome (n = 3/19; 15.7%). In the GI tract, we did not demonstrate peculiar features differing from those commonly observed in the myeloablative setting. By univariate analysis, a reduced overall survival was associated with graft-versus-host disease type (chronic graft-versus-host disease P = .006, acute graft-versus-host disease P = .03), older age (P = .04), and histopathologic diagnosis of "consistent with" + definite graft-versus-host disease (P = .02). Histopathologic diagnosis retained an independent prognostic value

  16. Immunosuppression for 6-8 weeks after modified donor lymphocyte infusion reduced acute graft-versus-host disease without influencing graft-versus-leukemia effect in haploidentical transplant

    Institute of Scientific and Technical Information of China (English)

    Yan Chenhua; Xu Lanping; Liu Daihong; Chen Huan; Wang Yu; Liu Kaiyan; Huang Xiaojun

    2014-01-01

    Background In haploidentical hematopoietic stem cell transplantation (HSCT),the duration of graft-versus-host disease (GVHD) prophylaxis after modified donor lymphocyte infusion (DLI) was the only risk factor of DLI-associated grades 3-4 acute GVHD.However,the successful application of modified DLI depended not only on the reduction of severe GVHD,but also on the preservation of graft-versus-leukemia (GVL) effect.Therefore,this study was performed to compare the impact of prophylaxis for 6-8 weeks and prophylaxis for <6 weeks on GVL effect after modified DLI in haploidentical HSCT.Methods A total of 103 consecutive patients developing hematological relapse or minimal residual disease (MRD)-positive status after haploidentical HSCT and receiving modified DLI were investigated retrospectively.Fifty-two patients received prophylaxis for 6-8 weeks after modified DLI; the remaining 51 patients received prophylaxis for <6 weeks.Results First,compared with prophylaxis for <6 weeks,prophylaxis for 6-8 weeks reduced incidence of relapse in total patients (26.6% vs.69.0%,P <0.001).Besides,prophylaxis for 6-8 weeks also reduced incidence of relapse in 54 patients developing hematological relapse post-transplant (P=0.018) and in 49 patients developing MRD-positive status post-transplant (P <0.001).Second,prophylaxis for 6-8 weeks reduced incidence of acute GVHD (P <0.05),reduced the therapeutic application of immunosuppressive agents (P=0.019),but increased the incidence of chronic GVHD (P<0.05).Third,prophylaxis for 6-8 weeks improved overall survival and disease-free survival in total patients,as well as in patients developing hematological relapse post-transplant and in patients developing MRD-positive status post-transplant (P <0.05).Conclusions In haploidentical HSCT,prophylaxis for 6-8 weeks after modified DLI does not reduce GVL effect,but reduces the incidence of DLI-associated acute GVHD compared with prophylaxis for <6 weeks.This strategy will

  17. Novel regulatory therapies for prevention of Graft-versus-host disease

    Directory of Open Access Journals (Sweden)

    Leventhal Joseph

    2012-05-01

    Full Text Available Abstract Graft-versus-host disease is one of the major transplant-related complications in allogeneic hematopoietic stem cell transplantation. Continued efforts have been made to prevent the occurrence of severe graft-versus-host disease by eliminating or suppressing donor-derived effector T cells. Conventional immunosuppression does not adequately prevent graft-versus-host disease, especially in mismatched transplants. Unfortunately, elimination of donor-derived T cells impairs stem cell engraftment, and delays immunologic reconstitution, rendering the recipient susceptible to post-transplant infections and disease relapse, with potentially lethal consequences. In this review, we discuss the role of dynamic immune regulation in controlling graft-versus-host disease, and how cell-based therapies are being developed using regulatory T cells and other tolerogenic cells for the prevention and treatment of graft-versus-host disease. In addition, advances in the design of cytoreductive conditioning regimens to selectively target graft-versus-host disease-inducing donor-derived T cells that have improved the safety of allogeneic stem cell transplantation are reviewed. Finally, we discuss advances in our understanding of the tolerogenic facilitating cell population, a phenotypically and functionally distinct population of bone marrow-derived cells which promote hematopoietic stem cell engraftment while reducing the risk of graft-versus-host disease.

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

    Directory of Open Access Journals (Sweden)

    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

  19. Pericardial effusion and cardiac tamponade: clinical manifestation of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Ferreira, David Cavalcanti; de Oliveira, José Salvador Rodrigues; Parísio, Katya; Ramalho, Fernanda Maria Morselli

    2014-03-01

    The authors report a case with pericardial effusion and cardiac tamponade as a rare clinical manifestation of chronic graft-versus-host disease in a young man with acute myelogenous leukemia submitted to an allogeneic hematopoietic stem cell transplantation from a related donor.

  20. Effects of lupeol on acute graft-versus-host disease%羽扇豆醇对急性移植物抗宿主病的作用

    Institute of Scientific and Technical Information of China (English)

    梁勇; 马守宝; 胡命宝

    2013-01-01

    目的 探讨羽扇豆醇对小鼠异基因骨髓移植(allo-BMT)后急性移植物抗宿主病(aGVHD)的预防作用.方法 25只小鼠随机均分为羽扇豆醇1mg/只高剂量组(A1组)、羽扇豆醇0.5mg/只中剂量组(A2组)、羽扇豆醇0.25 mg/只低剂量组(A3组)、模型对照组(B组)和正常对照组(C组).采用减弱强度的预处理方式建立aGVHD动物模型,HE染色观察aGVHD小鼠的病理改变,ELISA法检测血清炎性细胞因子的水平变化.结果 A1组小鼠中位生存期明显长于B组(27 d vs.17 d)(P<0.05);与B组相比,A1组aGVHD病理改变减轻,炎性细胞因子水平降低(P<0.05),而A2、A3组各观察指标差异无统计学意义.结论 高剂量羽扇豆醇可显著延长aGVHD小鼠生存时间,有效减轻aGVHD病理损害程度.%Objective To investigate the preventive effect of lupeol on the mice with acute graft-versus-host disease(aGVHD) in an allogeneic bone marrow transplantation(allo-BMT) model. Methods Twenty-five mice were equally randomized into five groups of A1 (treated with lupeol 1 mg/mouse), A2 (treated with lupeol 0.5 mg/mouse), A3 (treated with lupeol 0.25 mg/mouse), B(model controls) and C(normal controls). The aGVHD model was established by intensity-reducing preconditioning. The pathological changes of mice with aGVHD were observed by HE staining, and the levels of inflammatory cytokines in blood supernatant were detected by ELISA. Results The mean survival time in group A1 was longer than that in group B(27 d vs. 17 d)(P<0. 05). Compared with group B, the pathological changes of mice with aGVHD and the levels of inflammatory cytokines were decreased in group A1 (P<0. 05), which were not significantly changed in groups of A2 and A3. Conclusion Lupoel in high concentration can obviously prolong the survival time of mice with aGVHD and effectively relieve the degree of pathological lesion.

  1. A Canine Model of Chronic Graft-versus-Host Disease.

    Science.gov (United States)

    Graves, Scott S; Rezvani, Andrew; Sale, George; Stone, Diane; Parker, Maura; Rosinski, Steven; Spector, Michele; Swearingen, Bruce; Kean, Leslie; Storb, Rainer

    2017-03-01

    In long-term survivors of allogeneic hematopoietic cell transplantation (HCT), chronic graft-versus-host disease (GVHD) is the major cause of morbidity and mortality and a major determinant of quality of life. Chronic GVHD responds poorly to current immunosuppressive drugs, and while T cell depletion may be preventive, this gain is offset by increased relapse rates. A significant impediment to progress in treating chronic GVHD has been the limitations of existing animal models. The goal of this study was to develop a reproducible comprehensive model of chronic GVHD in the dog. Ten recipient dogs received 920 cGy total body irradiation, infusion of marrow, and an infusion of buffy coat cells from a dog leukocyte antigen (DLA)-mismatched unrelated donor. Postgrafting immunosuppression consisted of methotrexate (days 1, 3, 6, 11) and cyclosporine. The duration of cyclosporine administration was limited to 80 days instead of the clinically used 180 days. This was done to contain costs, as chronic GVHD was expected to develop at earlier time points. All recipients were given ursodiol for liver protection. One dog had graft failure and 9 dogs showed stable engraftment. Eight of the 9 developed de novo chronic GVHD. Dogs progressed with clinical signs of chronic GVHD over a period of 43 to 164 (median, 88) days after discontinuation of cyclosporine. Target organs showed the spectrum of chronic GVHD manifestations that are typically seen clinically. These included lichenoid changes of the skin, fasciitis, ocular involvement (xerophthalmia), conjunctivitis, bronchiolitis obliterans, salivary gland involvement, gingivitis, esophageal involvement, and hepatic involvement. Peripheral blood lymphocyte surface antigen expression of CD28 and inducible costimulator was elevated in dogs with GHVD compared with those in normal dogs, but not significantly so. Serum levels of IL-8 and monocyte chemotactic protein-1 in GVHD-affected dogs at time of euthanasia were elevated, whereas

  2. Danger Signals and Graft-versus-host Disease: Current Understanding and Future Perspectives

    Science.gov (United States)

    Toubai, Tomomi; Mathewson, Nathan D.; Magenau, John; Reddy, Pavan

    2016-01-01

    Graft-versus-host response after allogeneic hematopoietic stem cell transplantation (allo-HCT) represents one of the most intense inflammatory responses observed in humans. Host conditioning facilitates engraftment of donor cells, but the tissue injury caused from it primes the critical first steps in the development of acute graft-versus-host disease (GVHD). Tissue injuries release pro-inflammatory cytokines (such as TNF-α, IL-1β, and IL-6) through widespread stimulation of pattern recognition receptors (PRRs) by the release of danger stimuli, such as damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). DAMPs and PAMPs function as potent stimulators for host and donor-derived antigen presenting cells (APCs) that in turn activate and amplify the responses of alloreactive donor T cells. Emerging data also point towards a role for suppression of DAMP induced inflammation by the APCs and donor T cells in mitigating GVHD severity. In this review, we summarize the current understanding on the role of danger stimuli, such as the DAMPs and PAMPs, in GVHD. PMID:27965667

  3. ORAL CHRONIC GRAFT VERSUS HOST DISEASE IN AN IMMUNOCOMPETENT PATIENT: A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Redwin Dhas Manchi

    2014-06-01

    Full Text Available Graft-versus-host disease (GVHD is a complication which occurs in an individual who has received allogenic transplant. This was first noticed in individuals who had undergone bone marrow transplantation. Since then it has been described in solid organ transplantation and even transfusion of blood and blood products. Transfusion-associated GVHD (TA-GVHD is acute or chronic in nature. Acute TA-GVHD is rare and usually runs a fulminant and fatal course. In its chronic form, oral cavity is frequently affected with wide variety of signs and symptoms resulting in significant short and long-term complications ranging from mucosal sensitivity and limited oral in take to secondary malignancy and early death. Herewith we report a case of oral cGVHD in an immuno competent patient who underwent transfusion of platelets from an unrelated donor

  4. Does minor histocompatibility antigen HA-1 disparity affect the occurrence of graft-versus-host disease in tunisian recipients of hematopoietic stem cells?

    Directory of Open Access Journals (Sweden)

    Mohamed Hichem Sellami

    2010-01-01

    Full Text Available INTRODUCTION: Minor histocompatibility antigen HA-1 (MiHAg-HA-1 disparity between a patient and his or her human leukocyte antigen (HLA genoidentical donor has been widely associated with an increased risk of graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. OBJECTIVE: To examine the effect of HA-1 disparity on the incidence of both acute and chronic graft-versus-host disease in Tunisian recipients of hematopoietic stem cells. METHODS: A total of 60 patients and their 60 respective sibling hematopoietic stem cell donors were enrolled in this study. All patients prophylactically received cyclosporine A and/or methotrexate for graft-versus-host disease. An HA-1 genotyping assay was performed with the SSP-PCR method, and HLA-A*0201- and/or HLA-A*0206-positive samples were identified using the Luminex HLA typing method. RESULTS: The Luminex HLA typing assay showed that 54 patients were positive for either the HLA-A*0201 or HLA-A*0206 alleles. Among these cases, six pairs were mismatched for MiHAg-HA-1. Both acute and chronic graft-versus-host disease occurred in four mismatched patients (Fisher's p-values were 0.044 and 0.170, respectively. A univariate logistic regression model analysis showed that only acute graft-versus-host disease may be affected by recipient MiHAg-HA-1 disparity (p: 0.041, OR: 6.727, while chronic graft-versus-host disease correlates with both age and recipient/donor sex mismatch (p: 0.014, OR: 8.556 and p: 0.033, OR: 8.664, respectively. CONCLUSION: Our findings support previously reported data suggesting a significant association between HA-1 disparity and the risk of acute graft-versus-host disease following hematopoietic stem cell transplantation.

  5. Liver Graft versus Host Disease after Allogeneic Peripheral Stem Cell Transplantation: Update on Etiopathogenesis and Diagnosis.

    Science.gov (United States)

    Mihăilă, R-G

    2016-01-01

    Graft versus host disease (GVHD) is the main complication of allogeneic hematopoietic cell transplantation and is more frequent after peripheral stem cell transplants. Graft versus leukemia or lymphoma component of them is beneficial to eradicate residual tumor mass after previous treatment and conditioning regimen. A severe GVHD may endanger the patient's life. The most important liver manifestations of GVHD are increased serum alkaline phosphatase and bilirubin values. The last allows to estimate the GVHD severity. Sometimes, an increase of aminotransferases can mimic an acute hepatitis. Donor-derived hematopoietic cells appeared to turn in mesenchymal liver cells. Activated CD4(+) T cells, humoral and complement activation, a large number of cytokines and cytokine receptors are involved in GVHD development. Correct and early recognition of GVHD and its differentiation from the other liver diseases are essential for the medical practice.

  6. Successful treatment for graft-versus-host disease after pancreas transplantation.

    Science.gov (United States)

    Chang, Jei wen; Sageshima, Junichiro; Ciancio, Gaetano; Mattiazzi, Adela; Chen, Linda; Tsai, Hsin-Lin; Ruiz, Phillip; Burke, George W

    2014-02-01

    Graft-versus-host disease (GVHD) after pancreas transplantation is a rare but serious complication: All previously reported cases were fatal. We herein report three cases of GVHD after pancreas transplantation with favorable outcomes. Patients with a history of kidney (and pancreas) transplantation subsequently received a pancreas (and kidney) transplantation (i.e., pancreas retransplantation or pancreas after kidney transplantation) and developed acute GVHD. All of them responded to increased immunosuppression (e.g., steroid bolus, antithymocyte globulin) and retained normal graft function. Because the clinical manifestations are non-specific, vigilance is necessary to make an accurate diagnosis. We underscored the importance of a biopsy of involved organs and the clinicopathologic correlation in the early diagnosis of GVHD. Augmented immunosuppression to prevent progression from a self-limited disease to life-threatening pancytopenia or sepsis may be most critical to improve outcome.

  7. Lymphadenectomy prior to rat hind limb allotransplantation prevents graft-versus-host disease in chimeric hosts

    NARCIS (Netherlands)

    Brouha, PCR; Perez-Abadia, G; Francois, CG; Laurentin-Perez, LA; Gorantla, [No Value; Vossen, M; Tai, C; Pidwell, D; Anderson, GL; Stadelmann, WK; Hewitt, CW; Kon, M; Barker, JH; Maldonado, C

    2004-01-01

    In previous rat studies, the use of mixed allogeneic chimerism (MAC) to induce host tolerance to hind limb allografts has resulted in severe graft-versus-host disease (GVHD). The purpose of this study was to determine if immunocompetent cells in bone marrow (BM) and/or lymph nodes (LNs) of transplan

  8. Emerging pathogen in immunocompromised hosts: Exophiala dermatitidis mycosis in graft-versus-host disease.

    Science.gov (United States)

    Chalkias, S; Alonso, C D; Levine, J D; Wong, M T

    2014-08-01

    Infection with the dematiaceous environmental fungus Exophiala, an emerging pathogen in immunocompromised individuals, poses a diagnostic and therapeutic challenge. Herein, we report the first Exophiala dermatitidis fungemia case, to our knowledge, in an allogeneic hematopoietic stem cell transplant patient with graft-versus-host disease, expanding the clinical setting where Exophiala species mycosis should be suspected.

  9. Minimal change disease in graft versus host disease: a podocyte response to the graft?

    Science.gov (United States)

    Huskey, Janna; Rivard, Chris; Myint, Han; Lucia, Scott; Smith, Maxwell; Shimada, Michiko; Ishimoto, Takuji; Araya, Carlos; Garin, Eduardo H; Johnson, Richard J

    2013-12-01

    Nephrotic syndrome is a rare complication of hematopoietic cell transplantation. It has been suggested that nephrotic syndrome may represent a limited form of graft-versus-host disease although the pathological link between these two entities remains unclear. In this paper, we report a case of a 61-year-old female who underwent nonmyeloablative allogenic stem cell transplantation for T-cell prolymphocytic leukemia and subsequently developed biopsy proven minimal change disease shortly after cessation of her immunosuppression therapy. Urinary CD80 was markedly elevated during active disease and disappeared following corticosteroid-induced remission. We hypothesize that alloreactive donor T cells target the kidney and induce podocyte expression of CD80 that results in proteinuria from limited 'graft versus host' disease.

  10. Role of acute graft-versus-host disease in the risk of bacteremia and invasive fungal disease after allogeneic hemopoietic stem cell transplantation in children. Results from a single-center observational study.

    Science.gov (United States)

    Castagnola, Elio; Bagnasco, Francesca; Bandettini, Roberto; Caviglia, Ilaria; Morreale, Giuseppe; Lanino, Edoardo; Giardino, Stefano; Moroni, Cristina; Haupt, Riccardo; Faraci, Maura

    2014-07-01

    Data on epidemiology of severe infectious complications, ie, bacteremia or invasive fungal disease (IFD), in children with acute graft-versus-host disease (aGVHD) after allogeneic hemopoietic stem cell transplantation (HSCT) are scarce. In a retrospective, single-center study, we analyzed the risk (hazard ratio [HR]) and the rate (episodes/1000 patients days at risk) of bacteremias and IFD in children receiving allogeneic HSCT, according to the type of donor (matched related [MRD] or alternative [AD]) and presence and grade of aGVHD. From 2000 to 2009, 198 children receiving 217 allogeneic HSCT developed 134 severe infectious episodes (103 bacteremias and 31 IFD). The type of donor (AD versus MRD) was the most important risk factor for the severe infections (P = .0052). In separate multivariable analysis for bacteremia and IFD, children receiving an AD HSCT had increased HR and rate of bacteremia compared with those receiving a MRD transplantation (P = .0171 and P = .0001, respectively), whereas the HR and the rate of IFD were significantly influenced by the grade of aGVHD (P = .0002 and P design management strategies of infections in pediatric allogeneic HSCT.

  11. 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.

  12. Skin and kidney histological changes in graft-versus-host disease (GVHD) after kidney transplantation.

    Science.gov (United States)

    Pintar, Tadeja; Alessiani, Mario; Pleskovič, Alojz; Pleskovič, Aleš; Zorc-Pleskovič, Ruda; Milutinović, Aleksandra

    2011-05-01

    Kidney transplantation (Ktx) is generally performed during end stage renal disease due to a loss of the kidneys' ability to filter wastes from the circulatory system. Acute graft-versus-host disease (GVHD) after Ktx is a life-threatening complication that progresses to organ failure, systemic complications, and death. The current study evaluated the significance of histologic findings of GVHD as obtained from skin biopsies following Ktx in swine. A swine model of Ktx with tacrolimus-based immunosuppression was used to assess possible correlations between acute-graft-cellular rejection and skin histological findings for prediction of GVHD. Animals were divided into a Ktx treatment group or a control group with no Ktx and skin and kidney biopsies were histologically assessed at postoperative days 0, 15, 30, 45 and 60. Skin samples were analyzed and classified from grade 1 to 4 of skin GVHD and the major histopathological changes of kidney acute cellular rejection were described using Banff's score system. We observed a significant linear correlation between the histological grading values of skin biopsy changes and the histological grading values of kidney biopsies (Kendall's tau_b=0.993) in the Ktx experimental group. No histological changes were observed in controls. Our findings demonstrate the diagnostic value of staging skin GVHD after Ktx and suggest it's future utility for monitoring long term Ktx-induced changes.

  13. Regulatory T-Cell Therapy for Graft-versus-host Disease

    OpenAIRE

    Heinrichs, Jessica; Bastian, David; Veerapathran, Anandharaman; Anasetti, Claudio; Betts, Brain; Yu, Xue-Zhong

    2016-01-01

    Graft-versus-host disease (GVHD) is a significant cause of non-relapse mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Existing strategies to prevent and treat GVHD are incomplete, where a significant portion of allo-HCT recipients developed this complication. Despite this, one such therapy has emerged involving the use of regulatory T cells (Tregs) to control GVHD. The use of natural Tregs (nTregs) yielded positive pre-clinical results and are actively under investi...

  14. Voriconazole-Induced Periostitis Mimicking Chronic Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation.

    Science.gov (United States)

    Sweiss, Karen; Oh, Annie; Rondelli, Damiano; Patel, Pritesh

    2016-01-01

    Voriconazole is an established first-line agent for treatment of invasive fungal infections in patients undergoing allogeneic stem cell transplantation (ASCT). It is associated with the uncommon complication of periostitis. We report this complication in a 58-year-old female undergoing HSCT. She was treated with corticosteroids with minimal improvement. The symptoms related to periostitis can mimic chronic graft-versus-host disease in patients undergoing HSCT and clinicians should differentiate this from other diagnoses and promptly discontinue therapy.

  15. Management of oral Graft versus Host Disease with topical agents: A systematic review

    OpenAIRE

    Albuquerque, Rui; Khan, Zahid; Poveda, Ana; Higham, Jonathan; Richards, Andrea; Monteiro,Luís Silva; Jane Salas, Enric; López López, José, 1958-; Warnakulasuriya, Saman

    2015-01-01

    Background Oral Graft-versus-Host Disease (oGvHD) is a common complication of haematopoietic stem cell transplantation. Choosing the right topical application to be used intra orally can be a challenge. Consequently, the aim of this work is to review the effectiveness and safety of topical agents currently used in the management of the inflammatory mucosal lesions encountered in oGVHD. Material and Methods We carried out electronic searches of publications up to May 2015 of the databases Pubm...

  16. Methotrexate Reduces the Incidence of Severe Acute Graft-versus-Host Disease without Increasing the Risk of Relapse after Reduced-Intensity Allogeneic Stem Cell Transplantation from Unrelated Donors.

    Science.gov (United States)

    Vigouroux, Stéphane; Tabrizi, Reza; Melot, Cyril; Coiffard, Joelle; Lafarge, Xavier; Marit, Gérald; Bouabdallah, Krimo; Pigneux, Arnaud; Leguay, Thibaut; Dilhuydy, Marie-Sarah; Schmitt, Anna; Boiron, Jean-Michel; Milpied, Noël

    2011-01-01

    Optimized prophylaxis against graft-versus-host disease (GVHD) after unrelated reduced-intensity allogeneic transplantation when preceded by a conditioning regimen utilizing antithymocyte globulin (ATG) is poorly defined. To investigate the effects of methotrexate (MTX) in this treatment setting, we conducted a retrospective analysis. Sixty-three patients were selected based on the administration of a total dose of 5 mg/kg of ATG in the conditioning regimen and then separated into either group M+ (n = 39), which received MTX or group M- (n = 24), which did not. All patients received cyclosporine. In the M- and M+ groups, cumulative incidences (CI) of grade III-IV acute GVHD (aGVHD) were 43% and 10%, respectively (P = .002). Multivariate analysis indicated that grade III-IV aGVHD was favored by both the absence of MTX and the provision of a female donor for a male recipient. At 2 years, the M+ and M- groups exhibited, respectively: overall survival of 69% and 40% (P = .06), disease-free survival of 57% and 43% (P = .2), nonrelapse mortality of 20% and 44% (P = .1), and incidence of relapse of 27% and 35% (P = .6). These data suggest that MTX reduces the incidence of severe aGVHD without increasing the risk of relapse but with an accompanying trend toward improved survival after unrelated reduced-intensity transplantation with ATG in the conditioning regimen.

  17. IL-22 promoted CD3+ T cell infiltration by IL-22R induced STAT3 phosphorylation in murine acute graft versus host disease target organs after allogeneic bone marrow transplantation.

    Science.gov (United States)

    Zhao, Kai; Ruan, Suhong; Tian, Yu; Zhao, Dongmei; Chen, Chong; Pan, Bin; Yan, Zhiling; Yin, Lingling; Zhu, Shengyun; Xu, Kailin

    2016-10-01

    Graft versus host disease (GVHD) is a life threatening complication of bone marrow stem cell transplantation, in which considerable numbers of proinflammatory cytokines secreted by allo-reactive donor T cells are involved. We and other previous studies have found that interleukin-22 (IL-22) was able to aggravate the target organs damage of GVHD. However, the mechanism and the signal pathway of IL-22 in murine acute GVHD was not clear. Here, we observed that compared with GVHD group, more serious pathological damage and more CD3(+) T cells infiltrated in GVHD target organs were detected in the mice injected with IL-22. Meanwhile, transcription factor T-bet, RORγt and AhR respectively associated with Th1, Th17 and Th22 cells changed in varying degrees in different GVHD target organs. Furthermore, the increased expression of IL-22R and its downstream protein P-STAT3 were detected in GVHD mice with IL-22 treated. These results suggested that the pathological role of IL-22 in GVHD target organs contribute to exogenous injected IL-22 as well as secreted IL-22 from the infiltrated allo-reactive effector T cells. In addition, the IL-22R-STAT3 pathway may play important role in GVHD tissue injury and target this way may yield new approaches for reduction of GVHD.

  18. Graft monocytic myeloid-derived suppressor cell content predicts the risk of acute graft-versus-host disease after allogeneic transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood stem cells.

    Science.gov (United States)

    Vendramin, Antonio; Gimondi, Silvia; Bermema, Anisa; Longoni, Paolo; Rizzitano, Sara; Corradini, Paolo; Carniti, Cristiana

    2014-12-01

    Myeloid-derived suppressor cells (MDSCs) are powerful immunomodulatory cells that in mice play a role in infectious and inflammatory disorders, including acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. Their relevance in clinical acute GVHD is poorly known. We analyzed whether granulocyte colony-stimulating factor (G-CSF) administration, used to mobilize hematopoietic stem cells, affected the frequency of MDSCs in the peripheral blood stem cell grafts of 60 unrelated donors. In addition, we evaluated whether the MDSC content in the peripheral blood stem cell grafts affected the occurrence of acute GVHD in patients undergoing unrelated donor allogeneic stem cell transplantation. Systemic treatment with G-CSF induces an expansion of myeloid cells displaying the phenotype of monocytic MDSCs (Lin(low/neg)HLA-DR(-)CD11b(+)CD33(+)CD14(+)) with the ability to suppress alloreactive T cells in vitro, therefore meeting the definition of MDSCs. Monocytic MDSC dose was the only graft parameter to predict acute GVHD. The cumulative incidence of acute GVHD at 180 days after transplantation for recipients receiving monocytic MDSC doses below and above the median was 63% and 22%, respectively (P = .02). The number of monocytic MDSCs infused did not impact the relapse rate or the transplant-related mortality rate (P > .05). Although further prospective studies involving larger sample size are needed to validate the exact monocytic MDSC graft dose that protects from acute GVHD, our results strongly suggest the modulation of G-CSF might be used to affect monocytic MDSCs graft cell doses for prevention of acute GVHD.

  19. 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.

  20. [A case of asymmetric demyelinating neuropathy in a patient with chronic graft-versus-host disease].

    Science.gov (United States)

    Matsumoto, Hideyuki; Seki, Naoko; Yamamoto, Tomotaka; Oshima, Kumi; Asai, Takashi; Motokura, Toru; Ugawa, Yoshikazu; Goto, Jun; Tsuji, Shoji

    2005-10-01

    A 47-year-old man, who suffered from acute lymphocytic leukemia at 45 years old and was treated with hematopoietic stem cell transplantation at 46 years old after the induction of complete remission by the standard chemotherapy, developed the symptoms of chronic graft-versus-host disease (cGVHD) such as dry eyes, dry mouth, skin thickening, skin scaling, skin pigmentation and impaired liver function. He was admitted to our hospital because of the acute development of diplopia and weakness of his left upper extremity accompanying with the exacerbation of other symptoms of cGVHD. Neurological examinations revealed the right abducens nerve palsy and asymmetric muscular weakness of the extremities; the proximal part of the left upper extremity and the distal part of the right upper extremity were markedly involved. Neurophysiological studies including magnetic motor root stimulation revealed demyelinating neuropathy specifically involving the motor nerves. On the basis of these findings, a diagnosis of peripheral neuropathy associated with cGVHD was made. Nighteen reports are available on peripheral neuropathy in cGVHD patients, but to date little is known about the pathophysiology of this condition. Most of those patients have been diagnosed as having symmetric demyelinating polyneuropathy, such as Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy. In this study, contrary to previous reports, the asymmetric involvement of motor nerves is noteworthy. Accumulation and further analyses of the cases like the present case are necessary to elucidate the pathogenesis of peripheral neuropathy in cGVHD.

  1. TGF-β-induced CD4+Foxp3+ T cells attenuate acute graft-versus-host disease via suppressing expansion and killing of effector CD8+ cells

    OpenAIRE

    Gu, Jian; Lu, Ling; Chen, Maogen; Xu, Lili; Lan, Qin; Li, Qiang; Liu, Zhongmin; Chen, Guihua; Wang, Ping; Wang, Xuehao; Brand, David; Olsen, Nancy; Zheng, Song Guo

    2014-01-01

    TGF-β-induced CD4+Foxp3+ T cells (iTregs) have been identified as important prevention and treatment strategies for cell therapy in autoimmune diseases and other disorders. However, the potential use of iTregs as a treatment modality for acute graft-verse-host disease (GVHD) has not been realized because iTregs may be unstable and less suppressive in this disease. Here we restudied the ability of iTregs to prevent and treat acute GVHD in two different mouse models. Our results showed that so ...

  2. Intestinal Blautia Is Associated with Reduced Death from Graft-versus-Host Disease.

    Science.gov (United States)

    Jenq, Robert R; Taur, Ying; Devlin, Sean M; Ponce, Doris M; Goldberg, Jenna D; Ahr, Katya F; Littmann, Eric R; Ling, Lilan; Gobourne, Asia C; Miller, Liza C; Docampo, Melissa D; Peled, Jonathan U; Arpaia, Nicholas; Cross, Justin R; Peets, Tatanisha K; Lumish, Melissa A; Shono, Yusuke; Dudakov, Jarrod A; Poeck, Hendrik; Hanash, Alan M; Barker, Juliet N; Perales, Miguel-Angel; Giralt, Sergio A; Pamer, Eric G; van den Brink, Marcel R M

    2015-08-01

    The relationship between intestinal microbiota composition and acute graft-versus-host disease (GVHD) after allogeneic blood/marrow transplantation (allo-BMT) is not well understood. Intestinal bacteria have long been thought to contribute to GVHD pathophysiology, but recent animal studies in nontransplant settings have found that anti-inflammatory effects are mediated by certain subpopulations of intestinal commensals. Hypothesizing that a more nuanced relationship may exist between the intestinal bacteria and GVHD, we evaluated the fecal bacterial composition of 64 patients 12 days after BMT. We found that increased bacterial diversity was associated with reduced GVHD-related mortality. Furthermore, harboring increased amounts of bacteria belonging to the genus Blautia was associated with reduced GVHD lethality in this cohort and was confirmed in another independent cohort of 51 patients from the same institution. Blautia abundance was also associated with improved overall survival. We evaluated the abundance of Blautia with respect to clinical factors and found that loss of Blautia was associated with treatment with antibiotics that inhibit anaerobic bacteria and receiving total parenteral nutrition for longer durations. We conclude that increased abundance of commensal bacteria belonging to the Blautia genus is associated with reduced lethal GVHD and improved overall survival.

  3. Methotrexate for the Treatment of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Amr Nassar

    2014-01-01

    Full Text Available Glucocorticoids have been the primary treatment of graft-versus-host disease (GVHD over the past decade. Complete responses to steroid therapy are usually expected in almost one-third of aGVHD cases and partial response is anticipated in another one-third of patients. However, for those patients not responding to corticosteroid treatment, there is no standard second-line therapy for acute or chronic GVHD. Methotrexate (MTX for treatment of steroid refractory GVHD has been evaluated in a number of studies. Results from peer-reviewed original articles were identified and the pooled data analyzed. Despite several limitations in data collection and analysis, weekly administration of methotrexate at a median dose of 7.5 mg/m2 seems to be safe with minimal toxicities in the context of both aGVHD and cGVHD treatments. The observed overall response (OR in patients with aGVHD to MTX treatment in the published studies was 69.9%, with complete response (CR in 59.2% and PR in 10.6%. In cGVHD the OR was 77.6%, with CR reported in 49.6% and PR in 28% of patients. Predictors of better responses were lower grade GVHD, cutaneous involvement, and isolated organ involvement. MTX as a steroid sparing agent might reduce long-term complications and improve the quality of life of GVHD affected individuals.

  4. Third-party tolerogenic dendritic cells reduce allo-reactivity in vitro and ameliorate the severity of acute graft-versus-host disease in allo-bone marrow transplantation.

    Science.gov (United States)

    Yang, J; Li, R; Ren, Y; Yang, Y; Xie, R; Fan, H

    2013-12-01

    Tolerogenic dendritic cells (tDCs) potently induce and maintain tolerance based on their distinct characteristics compared with conventional DCs. Recent reports show that donor or host tDCs promote allograft survival in mice. In this study, the efficacy of third-party tDCs in the prevention of acute graft-versus-host disease (aGVHD) was evaluated. In vitro, tDCs derived from the bone marrow (BM) of D1 mice were induced by GM-CSF, IL-10 and TGF-β1. The phenotypes, expression of cytokines and suppression of tDCs were analysed. In vivo, the effects of adoptive transfer of third-party-tDCs were evaluated in an MHC-mismatched aGVHD mouse model. Survival, body weight, GVHD scoring, histopathological specimens and serum cytokines were analysed in tDC-treated mice and untreated controls. Tolerogenic DCs had low expression of MHC and co-stimulatory molecules, expressed high levels of 'immunosuppressive' cytokines and suppressed allo-CD4(+) T cell proliferation. In the B6→D2 mouse model, all aGVHD mice died within 18 days. Fortunately, third-party tDCs transferred at low doses (10(4)) effectively prolonged survival after allo-BMT. Furthermore, in the mice treated with 10(4) tDCs, serum levels of IL-10/TGF-β were significantly higher and the percentage of Foxp3(+) cells continually increased compared with the mice treated with other doses of tDCs. Third-party tDCs play a crucial role in reducing the severity of aGVHD by modulating the secretion of various cytokines and expanding Foxp3(+) regulatory T cells, which suggests the possibility of using third-party tDCs for therapeutic applications. Furthermore, special attention should be paid to the optimal range of tDCs for preventing allograft rejection.

  5. Voriconazole-Induced Periostitis Mimicking Chronic Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Karen Sweiss

    2016-01-01

    Full Text Available Voriconazole is an established first-line agent for treatment of invasive fungal infections in patients undergoing allogeneic stem cell transplantation (ASCT. It is associated with the uncommon complication of periostitis. We report this complication in a 58-year-old female undergoing HSCT. She was treated with corticosteroids with minimal improvement. The symptoms related to periostitis can mimic chronic graft-versus-host disease in patients undergoing HSCT and clinicians should differentiate this from other diagnoses and promptly discontinue therapy.

  6. Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

    Science.gov (United States)

    O’Connor, Roddy S.; Thangavelu, Govindarajan; Lovitch, Scott B.; Dandamudi, Durga Bhavani; Vincent, Benjamin G.; Tkachev, Victor; Pawlicki, Jan M.; Furlan, Scott N.; Kean, Leslie S.; Aoyama, Kazutoshi; Taylor, Patricia A.; Panoskaltsis-Mortari, Angela; Foncea, Rocio; Ranganathan, Parvathi; Devine, Steven M.; Burrill, Joel S.; Guo, Lili; Sacristan, Catarina; Snyder, Nathaniel W.; Blair, Ian A.; Milone, Michael C.; Dustin, Michael L.; Riley, James L.; Bernlohr, David A.; Murphy, William J.; Fife, Brian T.; Munn, David H.; Miller, Jeffrey S.; Serody, Jonathan S.; Freeman, Gordon J.; Sharpe, Arlene H.; Turka, Laurence A.

    2016-01-01

    Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1–/– donors. PD-L1–deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1–/– donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell–mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD. PMID:27294527

  7. Clinical Application of Mesenchymal Stem Cells in the Treatment and Prevention of Graft-versus-Host Disease

    Directory of Open Access Journals (Sweden)

    Yi Lin

    2011-01-01

    Full Text Available Mesenchymal stem cells (MSCs represent a heterogeneous population of stromal cells with pluripotent mesenchymal differentiation potential. They have been found to have immunosuppressive properties and the ability to modulate angiogenesis and endogenous tissue repair by in vitro and animal studies. Clinical trials have examined the utility of these cells in autoimmune and inflammatory conditions. In particular, in allogeneic hematopoietic stem cell transplant (HSCT, multiple studies have been conducted to explore the use of MSC to treat acute and chronic graft-versus-host disease (GVHD and for cotransplantation with HSCT to promote HSC engraftment and prevent GVHD. We review here the results of these studies and discuss some challenges of this treatment modality in this disease setting.

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

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    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.

  9. Graft-versus-Host Disease-Associated Vulvovaginal Symptoms after Bone Marrow Transplantation.

    Science.gov (United States)

    Chung, Christopher P; Sargent, Rachel E; Chung, Nadia T; Lacey, James V; Wakabayashi, Mark T

    2016-02-01

    We conducted a retrospective review to assess the prevalence of graft-versus-host disease (GVHD)-associated gynecologic conditions among bone marrow transplantation (BMT) patients at City of Hope Medical Center. We calculated the associations among the estimated risks of various gynecologic complications, including vaginal stenosis, by performing chi-square tests and t-test statistics. Between 2010 and 2014, 180 patients were referred to the gynecologic clinic after their BMT. One hundred twenty-four patients (69%) had GVHD; among these patients, 51 (41%) experienced dyspareunia and 43 (35%) had vaginal stenosis. GVHD patients were significantly more likely to have vaginal stenosis (P vulvovaginal symptoms, such as dyspareunia and pelvic pain. Patients with GVHD are at high risk for vaginal stenosis requiring the use of a vaginal dilator. However, they are at low risk for developing UI and POP.

  10. 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.

  11. Enlargement of the human spleen in graft-versus-host disease.

    Science.gov (United States)

    Dilly, S A; Sloane, J P

    1988-04-01

    The spleens of 49 patients who had undergone allogeneic bone marrow transplantation for leukemia were compared at autopsy to determine the pathological changes associated with graft-versus-host disease (GVHD). The only significant finding was an increase in weight of about 1.7 times that of spleens from patients without GVHD. This was not explained by differences in the patients' sex, length of survival after transplantation, presence of infection, or liver pathology. On histological examination, there was no detectable increase in congestion, siderosis, or numbers of lymphocytes, macrophages, antigen-presenting cells, blast cells, pyknotic cells, plasma cells, or hemopoietic cells to explain the increase in spleen weight. On the contrary, there was actually a reduction in CD8+ T lymphocytes. No proliferative phase of GVHD could be identified, possibly due to a lack of specimens examined less than 8 days after transplantation and to prophylactic measures undertaken to minimize GVHD. The pathogenesis of splenomegaly in human GVHD is unclear.

  12. Management of oral Graft versus Host Disease with topical agents: A systematic review

    Science.gov (United States)

    Khan, Zahid; Poveda, Ana; Higham, Jonathan; Richards, Andrea; Monteiro, Luis; Jané-Salas, Enric; Lopez-Lopez, José; Warnakulasuriya, Saman

    2016-01-01

    Background Oral Graft-versus-Host Disease (oGvHD) is a common complication of haematopoietic stem cell transplantation. Choosing the right topical application to be used intra orally can be a challenge. Consequently, the aim of this work is to review the effectiveness and safety of topical agents currently used in the management of the inflammatory mucosal lesions encountered in oGVHD. Material and Methods We carried out electronic searches of publications up to May 2015 of the databases Pubmed, National Library of Medicine’s Medline, Embase and the Cochrane Central Register of Controlled Clinical trials to identify potentially relevant studies (keywords: “oral”, “graft”, “versus”, “host”, “disease” and “treatment”). The main inclusion criterion was the reported use of a topical agent which was not intentionally swallowed when used for the treatment of oGVHD. A 3-point grading system, described by the Swedish Council on Technology Assessment in Health Care and the Centre for Reviews and Dissemination, University of York, was used to rate the methodological quality of the papers. Results From the 902 entries identified in the search, 7 studies qualifying for inclusion were analysed. Overall, there is limited evidence with regards to the effectiveness of topical steroids for oGVHD. However, the studies showed some effect of Budesonide alone and when combined with dexamethasone. Topical tacrolimus also appears to have some effect and clobetasol propionate mouthwash had a significantly better clinical response than dexamethasone mouthwash in treating oGVHD. Conclusions As the number of clinical trials conducted is limited, there is little evidence to support the use of topical therapies to treat the inflammatory mucosal lesions found in oGVHD. High quality randomised control trials are needed in order to measure the effectiveness of any topical application for the treatment of the inflammatory mucosal lesions found in oGVHD. Key words

  13. 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 ra

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

    NARCIS (Netherlands)

    Jansen, Jeroen P.; O'Sullivan, Amy K.; Lugtenburg, Elly; Span, Lambert F. R.; Janssen, Jeroen J. W. M.; Stam, Wiro B.

    2010-01-01

    The 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 randomized tri

  15. Expression profiling of major histocompatibility and natural killer complex genes reveals candidates for controlling risk of graft versus host disease.

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    Peter Novota

    Full Text Available BACKGROUND: The major histocompatibility complex (MHC is the most important genomic region that contributes to the risk of graft versus host disease (GVHD after haematopoietic stem cell transplantation. Matching of MHC class I and II genes is essential for the success of transplantation. However, the MHC contains additional genes that also contribute to the risk of developing acute GVHD. It is difficult to identify these genes by genetic association studies alone due to linkage disequilibrium in this region. Therefore, we aimed to identify MHC genes and other genes involved in the pathophysiology of GVHD by mRNA expression profiling. METHODOLOGY/PRINCIPAL FINDINGS: To reduce the complexity of the task, we used genetically well-defined rat inbred strains and a rat skin explant assay, an in-vitro-model of the graft versus host reaction (GVHR, to analyze the expression of MHC, natural killer complex (NKC, and other genes in cutaneous GVHR. We observed a statistically significant and strong up or down regulation of 11 MHC, 6 NKC, and 168 genes encoded in other genomic regions, i.e. 4.9%, 14.0%, and 2.6% of the tested genes respectively. The regulation of 7 selected MHC and 3 NKC genes was confirmed by quantitative real-time PCR and in independent skin explant assays. In addition, similar regulations of most of the selected genes were observed in GVHD-affected skin lesions of transplanted rats and in human skin explant assays. CONCLUSIONS/SIGNIFICANCE: We identified rat and human MHC and NKC genes that are regulated during GVHR in skin explant assays and could therefore serve as biomarkers for GVHD. Several of the respective human genes, including HLA-DMB, C2, AIF1, SPR1, UBD, and OLR1, are polymorphic. These candidates may therefore contribute to the genetic risk of GVHD in patients.

  16. 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.

  17. Therapeutics for Graft-versus-Host Disease: From Conventional Therapies to Novel Virotherapeutic Strategies

    Directory of Open Access Journals (Sweden)

    Nancy Y. Villa

    2016-03-01

    Full Text Available Allogeneic hematopoietic stem cell transplantation (allo-HSCT has a curative potential for many hematologic malignancies and blood diseases. However, the success of allo-HSCT is limited by graft-versus-host disease (GVHD, an immunological syndrome that involves inflammation and tissue damage mediated by donor lymphocytes. Despite immune suppression, GVHD is highly incident even after allo-HSCT using human leukocyte antigen (HLA-matched donors. Therefore, alternative and more effective therapies are needed to prevent or control GVHD while preserving the beneficial graft-versus-cancer (GVC effects against residual disease. Among novel therapeutics for GVHD, oncolytic viruses such as myxoma virus (MYXV are receiving increased attention due to their dual role in controlling GVHD while preserving or augmenting GVC. This review focuses on the molecular basis of GVHD, as well as state-of-the-art advances in developing novel therapies to prevent or control GVHD while minimizing impact on GVC. Recent literature regarding conventional and the emerging therapies are summarized, with special emphasis on virotherapy to prevent GVHD. Recent advances using preclinical models with oncolytic viruses such as MYXV to ameliorate the deleterious consequences of GVHD, while maintaining or improving the anti-cancer benefits of GVC will be reviewed.

  18. Therapeutics for Graft-versus-Host Disease: From Conventional Therapies to Novel Virotherapeutic Strategies.

    Science.gov (United States)

    Villa, Nancy Y; Rahman, Masmudur M; McFadden, Grant; Cogle, Christopher R

    2016-03-22

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has a curative potential for many hematologic malignancies and blood diseases. However, the success of allo-HSCT is limited by graft-versus-host disease (GVHD), an immunological syndrome that involves inflammation and tissue damage mediated by donor lymphocytes. Despite immune suppression, GVHD is highly incident even after allo-HSCT using human leukocyte antigen (HLA)-matched donors. Therefore, alternative and more effective therapies are needed to prevent or control GVHD while preserving the beneficial graft-versus-cancer (GVC) effects against residual disease. Among novel therapeutics for GVHD, oncolytic viruses such as myxoma virus (MYXV) are receiving increased attention due to their dual role in controlling GVHD while preserving or augmenting GVC. This review focuses on the molecular basis of GVHD, as well as state-of-the-art advances in developing novel therapies to prevent or control GVHD while minimizing impact on GVC. Recent literature regarding conventional and the emerging therapies are summarized, with special emphasis on virotherapy to prevent GVHD. Recent advances using preclinical models with oncolytic viruses such as MYXV to ameliorate the deleterious consequences of GVHD, while maintaining or improving the anti-cancer benefits of GVC will be reviewed.

  19. Tirosin Kinase Inhibitors in Chronic Graft versus Host Disease: From Bench to Bedside

    Directory of Open Access Journals (Sweden)

    Jacopo Olivieri

    2011-01-01

    Full Text Available Chronic Graft Versus Host Disease (cGVHD is a major complication of allogeneic stem-cell transplantation (SCT. In many inflammatory fibrotic diseases, such as Systemic Scleroderma (SSc and cGVHD with fibrotic features, an abnormal activation of transforming growth factor (TGFβ and platelet-derived growth factor receptor (PDGF-R pathways have been observed. Tyrosin Kinase Inhibitors (TKIs, which are currently used for treatment of patients with Chronic Myeloid Leukemia (CML, share potent antifibrotic and antiinflammatory properties, being powerful dual inhibitors of both PDGF-R and TGFβ pathways. Moreover accumulating in vitro data confirm that TKIs, interacting with the TCR and other signalling molecules, carry potent immunomodulatory effects, being involved in both T-cell and B-cell response. Translation to the clinical setting revealed that treatment with Imatinib can achieve encouraging responses in patients with autoimmune diseases and steroid-refractory cGVHD, showing a favourable toxicity profile. While the exact mechanisms leading to such efficacy are still under investigation, use of TKIs in the context of clinical trials should be promoted, aiming to evaluate the biological changes induced in vivo by TKIs and to assess the long term outcome of these patients. Second-generation TKIs, with more favourable toxicity profile are under evaluation in the same setting.

  20. Alloantigen presentation and graft-versus-host disease: fuel for the fire.

    Science.gov (United States)

    Koyama, Motoko; Hill, Geoffrey R

    2016-06-16

    Allogeneic stem cell transplantation (SCT) is a unique procedure, primarily in patients with hematopoietic malignancies, involving chemoradiotherapy followed by the introduction of donor hematopoietic and immune cells into an inflamed and lymphopenic environment. Interruption of the process by which recipient alloantigen is presented to donor T cells to generate graft-versus-host disease (GVHD) represents an attractive therapeutic strategy to prevent morbidity and mortality after SCT and has been increasingly studied in the last 15 years. However, the immune activation resulting in GVHD has no physiological equivalent in nature; alloantigen is ubiquitous, persists indefinitely, and can be presented by multiple cell types at numerous sites, often on incompatible major histocompatibility complex, and occurs in the context of intense inflammation early after SCT. The recognition that alloantigen presentation is also critical to the development of immunological tolerance via both deletional and regulatory mechanisms further adds to this complexity. Finally, GVHD itself appears capable of inhibiting the presentation of microbiological antigens by donor dendritic cells late after SCT that is mandatory for the establishment of effective pathogen-specific immunity. Here, we review our current understanding of alloantigen, its presentation by various antigen-presenting cells, subsequent recognition by donor T cells, and the potential of therapeutic strategies interrupting this disease-initiating process to modify transplant outcome.

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

    Science.gov (United States)

    Resende, Renata Gonçalves; Correia-Silva, Jeane de Fátima; Silva, Tarcília Aparecida; Salomão, Ulisses Eliezer; Marques-Silva, Luciano; Vieira, Érica Leandro Marciano; Dutra, Walderez Ornelas; Gomez, Ricardo Santiago

    2014-01-01

    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. PMID:25136146

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

    Directory of Open Access Journals (Sweden)

    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.

  3. Health related quality of life among patients with chronic graft-versus-host disease in China

    Institute of Scientific and Technical Information of China (English)

    MO Xiao-dong; XU Lan-ping; LIU Dai-hong; CHEN Yu-hong; ZHANG Xiao-hui; CHEN Huan; HAN Wei

    2013-01-01

    Background Chronic graft-versus-host disease (GVHD),the commonest long-term complication after allogeneic hematopoietic stem cell transplantation (HSCT),has a negative impact on patients' health related quality of life (HRQoL).This study was designed to investigate the HRQoL in patients with chronic GVHD in China.Methods Two hundred and sixty-four patients with chronic GVHD who were >24 months post-HSCT and had been in continuous complete remission since HSCT were enrolled in this retrospective study.HRQoL was evaluated using an SF-36 questionnaire.Multivariate analysis was used to identify the factors that affect HRQoL in patients with chronic GVHD.Results HRQoL in patients categorized as having mild and moderate chronic GVHD was significantly better than in those in the severe category.In the moderate chronic GVHD category,markedly poorer HRQoL was observed in patients with both multiple organ involvement and more severe organ impairment than in those without these factors.According to multivariate analysis,chronic GVHD severity had the greatest significant negative impact on patients' HRQoL; whereas being female was associated with a negative impact on psychological health.Conclusion Chronic GVHD severity strongly correlates with negative impacts on patients' HRQoL.

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

    Science.gov (United States)

    Westphal, Sabine; McGeary, Aleixandria; Rudloff, Sandra; Wilke, Andrea; Penack, Olaf

    2017-01-01

    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. PMID:28103249

  5. Intestinal microbiota-related effects on graft-versus-host disease.

    Science.gov (United States)

    Shono, Yusuke; Docampo, Melissa D; Peled, Jonathan U; Perobelli, Suelen M; Jenq, Robert R

    2015-05-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an increasingly important treatment for conditions including hematopoietic malignancies and inherited hematopoietic disorders, and is considered to be the most effective form of tumor immunotherapy available to date. However, graft-versus-host disease (GVHD) remains a major source of morbidity and mortality following allo-HSCT, and understanding the mechanisms of GVHD has been highlighted as a key research priority. During development of GVHD, activation of various immune cells, especially donor T cells, leads to damage of target organs including skin, liver, hematopoietic system, and of particular clinical importance, gut. In addition to histocompatibility complex differences between the donor and recipient, pretransplant conditioning with chemotherapy and irradiation also contributes to GVHD by damaging the gut, resulting in systemic exposure to microbial products normally confined to the intestinal lumen. The intestinal microbiota is a modulator of gastrointestinal immune homeostasis. It also promotes the maintenance of epithelial cells. Recent reports provide growing evidence of the impact of intestinal microbiota on GVHD pathophysiology. This review summarizes current knowledge of changes and effects of intestinal microbiota in the setting of allo-HSCT. We will also discuss potential future strategies of intestinal microbiota manipulation that might be advantageous in decreasing allo-HSCT-related morbidity and mortality.

  6. Memory CD4+ T cells do not induce graft-versus-host disease.

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    Anderson, Britt E; McNiff, Jennifer; Yan, Jun; Doyle, Hester; Mamula, Mark; Shlomchik, Mark J; Shlomchik, Warren D

    2003-07-01

    Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic stem cell transplantation (alloSCT). Donor T cells that accompany stem cell grafts cause GVHD by attacking recipient tissues; therefore, all patients receive GVHD prophylaxis by depletion of T cells from the allograft or through immunosuppressant drugs. In addition to providing a graft-versus-leukemia effect, donor T cells are critical for reconstituting T cell-mediated immunity. Ideally, immunity to infectious agents would be transferred from donor to host without GVHD. Most donors have been exposed to common pathogens and have an increased precursor frequency of memory T cells against pathogenic antigens. We therefore asked whether memory CD62L-CD44+ CD4+ T cells would induce less GVHD than unfractionated or naive CD4+ T cells. Strikingly, we found that memory CD4 cells induced neither clinical nor histologic GVHD. This effect was not due to the increased number of CD4+CD25+ regulatory T cells found in the CD62L-CD44+ fraction because memory T cells depletion of these cells did not cause GVHD. Memory CD4 cells engrafted and responded to antigen both in vivo and in vitro. If these murine results are applicable to human alloSCT, selective administration of memory T cells could greatly improve post-transplant immune reconstitution.

  7. Danger signals activating innate immunity in graft-versus-host disease.

    Science.gov (United States)

    Zeiser, Robert; Penack, Olaf; Holler, Ernst; Idzko, Marco

    2011-09-01

    Extensive cell death with consecutive release of danger signals can cause immune-mediated tissue destruction. The abundance of cell death is likely to determine the relevance of the danger signals as physiological mechanisms that counteract immune activation may be overruled. Such constellation is conceivable in chemo-/radiotherapy-induced tissue damage, reperfusion injury, trauma, and severe infection. Studies on graft-versus-host disease (GvHD) development have to consider the effects of chemo-/radiotherapy-related tissue damage leading to the release of exogenous and endogenous danger signals. Our previous work has demonstrated a role for adenosine-5'-triphosphate (ATP) as an endogenous danger signal in GvHD. Besides ATP, uric acid or soluble extracellular matrix components are functional danger signals that activate the NLRP3 inflammasome when released from dying cells or from extracellular matrix. In contrast to sterile inflammation, GvHD is more complex since bacterial components that leak through damaged intestinal barriers and the skin can activate pattern recognition receptors and directly contribute to GvHD pathogenesis. These exogenous danger signals transmit immune activation via toll-like receptors and NOD-like receptors of the innate immune system. This review covers both the impact of endogenous and exogenous danger signals activating innate immunity in GvHD.

  8. Glomerular diseases associated with chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation: case reports.

    Science.gov (United States)

    Chanswangphuwana, C; Townamchai, N; Intragumtornchai, T; Bunworasate, U

    2014-12-01

    Chronic graft-versus-host disease (cGVHD) is the major complication following allogeneic stem cell transplantation (allo-SCT). Nephrotic syndrome (NS) and other types of glomerulonephritis have been proposed to be the very rare forms of renal cGVHD. From 1991 to 2011, 253 patients underwent allo-SCT at our center. We report here 4 cases (1.6%) presenting with varieties of glomerular manifestations associated with cGVHD. The first case was typical NS. The renal pathology showed membranous nephropathy (MN). The second case was also MN, but this patient also had the pathology of focal segmental glomerulosclrosis (FSGS) and acute tubular necrosis (ATN). The third case showed lupus nephritis-like glomerular lesions with a high anti-nuclear antibody (ANA) titer. The fourth case presented with rapidly progressive glomerulonephritis (RPGN)-like symptoms. The kidney histology in this case was not available. The patient responded well to immunosuppressive therapy, but NS later recurred. Therefore, overt glomerular diseases after allo-SCT in Thai patients are not very rare. Monitoring urinalysis during withdrawal of immunosuppressive drugs and also during follow-up of patients with cGVHD may be considered.

  9. 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)

  10. Serum Gp96 is a chaperone of complement-C3 during graft-versus-host disease

    Science.gov (United States)

    Seignez, Antoine; Joly, Anne-Laure; Chaumonnot, Killian; Hazoumé, Adonis; Sanka, Michel; Boudesco, Christophe; Hammann, Arlette; Seigneuric, Renaud; Jégo, Gaetan; Ducoroy, Patrick; Delarue, Patrice; Senet, Patrick; Castilla-Llorente, Cristina; Solary, Eric; Durey, Marie-Agnès; Rubio, Marie-Thérèse; Hermine, Olivier; Kohli, Evelyne

    2017-01-01

    Better identification of severe acute graft-versus-host disease (GvHD) may improve the outcome of this life-threatening complication of allogeneic hematopoietic stem cell transplantation. GvHD induces tissue damage and the release of damage-associated molecular pattern (DAMP) molecules. Here, we analyzed GvHD patients (n = 39) to show that serum heat shock protein glycoprotein 96 (Gp96) could be such a DAMP molecule. We demonstrate that serum Gp96 increases in gastrointestinal GvHD patients and its level correlates with disease severity. An increase in Gp96 serum level was also observed in a mouse model of acute GvHD. This model was used to identify complement C3 as a main partner of Gp96 in the serum. Our biolayer interferometry, yeast two-hybrid and in silico modeling data allowed us to determine that Gp96 binds to a complement C3 fragment encompassing amino acids 749–954, a functional complement C3 hot spot important for binding of different regulators. Accordingly, in vitro experiments with purified proteins demonstrate that Gp96 downregulates several complement C3 functions. Finally, experimental induction of GvHD in complement C3–deficient mice confirms the link between Gp96 and complement C3 in the serum and with the severity of the disease. PMID:28352659

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    Hartwell, Matthew J.; Özbek, Umut; Holler, Ernst; 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; Chen, Yi-Bin; Devine, Steven; Jagasia, Madan; Kitko, Carrie L.; Litzow, Mark R.; Kröger, Nicolaus; Locatelli, Franco; Morales, George; Nakamura, Ryotaro; Reshef, Ran; Rösler, Wolf; Weber, Daniela; Yanik, Gregory A.; Levine, John E.; Ferrara, James L.M.

    2017-01-01

    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. PMID:28194439

  13. 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 activit

  14. CCR7 expressing mesenchymal stem cells potently inhibit graft-versus-host disease by spoiling the fourth supplemental Billingham's tenet.

    Directory of Open Access Journals (Sweden)

    Hong Li

    Full Text Available The clinical acute graft-versus-host disease (GvHD-therapy of mesenchymal stem cells (MSCs is not as satisfactory as expected. Secondary lymphoid organs (SLOs are the major niches serve to initiate immune responses or induce tolerance. Our previous study showed that CCR7 guide murine MSC line C3H10T1/2 migrating to SLOs. In this study, CCR7 gene was engineered into murine MSCs by lentivirus transfection system (MSCs/CCR7. The immunomodulatory mechanism of MSCs/CCR7 was further investigated. Provoked by inflammatory cytokines, MSCs/CCR7 increased the secretion of nitric oxide and calmed down the T cell immune response in vitro. Immunofluorescent staining results showed that transfused MSCs/CCR7 can migrate to and relocate at the appropriate T cell-rich zones within SLOs in vivo. MSCs/CCR7 displayed enhanced effect in prolonging the survival and alleviating the clinical scores of the GvHD mice than normal MSCs. Owing to the critical relocation sites, MSCs/CCR7 co-infusion potently made the T cells in SLOs more naïve like, thus control T cells trafficking from SLOs to the target organs. Through spoiling the fourth supplemental Billingham's tenet, MSCs/CCR7 potently inhibited the development of GvHD. The study here provides a novel therapeutic strategy of MSCs/CCR7 infusion at a low dosage to give potent immunomodulatory effect for clinical immune disease therapy.

  15. Lithothamnion muelleri Controls Inflammatory Responses, Target Organ Injury and Lethality Associated with Graft-versus-Host Disease in Mice

    Science.gov (United States)

    Rezende, Barbara M.; Bernardes, Priscila T. T.; Resende, Carolina B.; Arantes, Rosa M. E.; Souza, Danielle G.; Braga, Fernão C.; Castor, Marina G. M.; Teixeira, Mauro M.; Pinho, Vanessa

    2013-01-01

    Lithothamnion muelleri (Hapalidiaceae) is a marine red alga, which is a member of a group of algae with anti-inflammatory, antitumor, and immunomodulatory properties. The present study evaluated the effects of treatment with Lithothamnion muelleri extract (LM) in a model of acute graft-versus-host disease (GVHD), using a model of adoptive splenocyte transfer from C57BL/6 donors into B6D2F1 recipient mice. Mice treated with LM showed reduced clinical signs of disease and mortality when compared with untreated mice. LM-treated mice had reduced tissue injury, less bacterial translocation, and decreased levels of proinflammatory cytokines and chemokines (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 3 (CCL3) and chemokine (C-C motif) ligand 5 (CCL5)). The polysaccharide-rich fraction derived from LM could inhibit leukocyte rolling and adhesion in intestinal venules, as assessed by intravital microscopy. LM treatment did not impair the beneficial effects of graft-versus-leukaemia (GVL). Altogether, our studies suggest that treatment with Lithothamnion muelleri has a potential therapeutic application in GVHD treatment. PMID:23873335

  16. CCR7 expressing mesenchymal stem cells potently inhibit graft-versus-host disease by spoiling the fourth supplemental Billingham's tenet.

    Science.gov (United States)

    Li, Hong; Jiang, Yan-Ming; Sun, Yan-Feng; Li, Ping; Dang, Rui-Jie; Ning, Hong-Mei; Li, Yu-Hang; Zhang, Ying-Jie; Jiang, Xiao-Xia; Guo, Xi-Min; Wen, Ning; Han, Yan; Mao, Ning; Chen, Hu; Zhang, Yi

    2014-01-01

    The clinical acute graft-versus-host disease (GvHD)-therapy of mesenchymal stem cells (MSCs) is not as satisfactory as expected. Secondary lymphoid organs (SLOs) are the major niches serve to initiate immune responses or induce tolerance. Our previous study showed that CCR7 guide murine MSC line C3H10T1/2 migrating to SLOs. In this study, CCR7 gene was engineered into murine MSCs by lentivirus transfection system (MSCs/CCR7). The immunomodulatory mechanism of MSCs/CCR7 was further investigated. Provoked by inflammatory cytokines, MSCs/CCR7 increased the secretion of nitric oxide and calmed down the T cell immune response in vitro. Immunofluorescent staining results showed that transfused MSCs/CCR7 can migrate to and relocate at the appropriate T cell-rich zones within SLOs in vivo. MSCs/CCR7 displayed enhanced effect in prolonging the survival and alleviating the clinical scores of the GvHD mice than normal MSCs. Owing to the critical relocation sites, MSCs/CCR7 co-infusion potently made the T cells in SLOs more naïve like, thus control T cells trafficking from SLOs to the target organs. Through spoiling the fourth supplemental Billingham's tenet, MSCs/CCR7 potently inhibited the development of GvHD. The study here provides a novel therapeutic strategy of MSCs/CCR7 infusion at a low dosage to give potent immunomodulatory effect for clinical immune disease therapy.

  17. Postmortem examination of the kidney in allogeneic hematopoietic stem cell transplantation recipients: possible involvement of graft-versus-host disease.

    Science.gov (United States)

    Kusumi, Eiji; Kami, Masahiro; Hara, Shigeo; Hoshino, Junichi; Yamaguchi, Yutaka; Murashige, Naoko; Kishi, Yukiko; Shibagaki, Yugo; Shibata, Taro; Matsumura, Tomoko; Yuji, Koichiro; Masuoka, Kazuhiro; Wake, Atsushi; Miyakoshi, Shigesaburo; Taniguchi, Shuichi

    2008-03-01

    To investigate the association between graft-versus-host disease (GVHD) and renal injury after allogeneic stem cell transplantation (allo-SCT), we compared autopsy findings of 26 consecutive allo-SCT recipients with two control groups: patients with hematologic malignancies who received cytotoxic chemotherapy alone (Control 1, n = 21) and those with non-hematologic diseases (Control 2, n = 12). We evaluated the following renal pathology; renal tubulitis, allograft glomerulitis, intimal arteritis, allograft nephropathy, and peritubular capillaritis. These changes were found in 11 allo-SCT recipients and 10 patients in Control 1, but none in Control 2. While overall frequency of renal impairments was similar between allo-SCT recipients and Control 1 (3/26 vs. 1/21), allo-SCT recipients were more likely to have renal tubulitis and peritubular capillaritis compared to Control 1 (5/26 vs. 1/21), but less likely to present with glomerulitis (1/26 vs. 6/21). Grade III-IV acute or extensive-type chronic GVHD were seen in all of the three patients with renal tubulitis and four of the five patients with peritubular capillaritis. Allo-SCT recipients with severe GVHD tended to have tubulitis and peritubular capillaritis. These findings have implications of some renal impairment attributable to GVHD.

  18. Safety and Outcomes of Extracorporeal Photopheresis With the Therakos Cellex System for Graft-Versus-Host Disease in Pediatric Patients.

    Science.gov (United States)

    Uygun, Vedat; Daloglu, Hayriye; Karasu, Gulsun; Hazar, Volkan; Yeşilipek, Akif

    2015-04-01

    Extracorporeal photopheresis (ECP) is a difficult procedure to perform in the pediatric population. This is a retrospective review of 12 pediatric patients who underwent photopheresis with the Therakos Cellex system for graft-versus-host disease (GVHD). Acute GVHD (aGVHD) occurred in 6 patients, and overlap syndrome and chronic GVHD (cGVHD) occurred in 4 and 2 patients, respectively. The ECP regimen was the same for all aGVHD and cGVHD patients: initially, every week (2 sessions/wk) for 2 months; next, every 2 weeks for 2 months; and finally, every month for at least 1 year. Improvement was observed in 7 of 10 aGVHD patients (70%) and in 4 of 6 cGVHD patients (66%). Eleven patients had skin involvement before ECP; 9 of them responded to treatment (81%). Gastrointestinal involvement occurred in 8 patients; 5 of them experienced improvement during ECP treatment (62%). All 4 patients with liver involvement failed to respond. No serious adverse reactions occurred. In conclusion, our study demonstrates that ECP with the Therakos Cellex system is a safe treatment option for GVHD in children, allowing the tapering of immunosuppressants by at least half.

  19. Chronic graft-versus-host disease following umbilical cord blood transplantation: retrospective survey involving 1072 patients in Japan.

    Science.gov (United States)

    Narimatsu, Hiroto; Miyakoshi, Shigesaburo; Yamaguchi, Takuhiro; Kami, Masahiro; Matsumura, Tomoko; Yuji, Koichiro; Murashige, Naoko; Kusumi, Eiji; Kodama, Yuko; Komatsu, Tsunehiko; Sakamaki, Hisashi; Kouzai, Yasushi; Okada, Masaya; Osugi, Yuko; Kobayashi, Ryoji; Inoue, Masami; Takahashi, Satoshi; Kai, Shunro; Kato, Koji; Inoue-Nagamura, Tokiko; Taniguchi, Shuichi; Kato, Shunichi

    2008-09-15

    We have little information on chronic graft-versus-host disease (GVHD) after cord blood transplantation (CBT). We investigated its clinical features in 1072 Japanese patients with hematologic malignancies who received a transplant through the Japan Cord Blood Bank Network. The primary end point was to investigate the incidence of any chronic GVHD. Median age of the patients was 33 years (range, 0-79 years). The cumulative incidence of chronic GVHD 2 years after transplantation was 28%. Chronic GVHD was fatal in 29 patients. Multivariate analysis demonstrated that development of chronic GVHD was favorably associated with both overall survival and event-free survival. Multivariate analysis identified risk factors of chronic GVHD: higher patient body weight, higher number of mismatched antigens for GVHD direction, myeloablative preparative regimen, use of mycophenolate mofetil in GVHD prophylaxis, and development of grades II to IV acute GVHD. Although chronic GVHD is a significant problem after CBT, it is associated with improved survival, perhaps due to graft-versus-malignancy effects.

  20. The Activating NKG2C Receptor Is Significantly Reduced in NK Cells after Allogeneic Stem Cell Transplantation in Patients with Severe Graft-versus-Host Disease

    Science.gov (United States)

    Kordelas, Lambros; Steckel, Nina-Kristin; Horn, Peter A.; Beelen, Dietrich W.; Rebmann, Vera

    2016-01-01

    Natural killer (NK) cells play a central role in the innate immune system. In allogeneic stem cell transplantation (alloSCT), alloreactive NK cells derived by the graft are discussed to mediate the elimination of leukemic cells and dendritic cells in the patient and thereby to reduce the risk for leukemic relapses and graft-versus-host reactions. The alloreactivity of NK cells is determined by various receptors including the activating CD94/NKG2C and the inhibitory CD94/NKG2A receptors, which both recognize the non-classical human leukocyte antigen E (HLA-E). Here we analyze the contribution of these receptors to NK cell alloreactivity in 26 patients over the course of the first year after alloSCT due to acute myeloid leukemia, myelodysplastic syndrome and T cell Non-Hodgkin-Lymphoma. Our results show that NK cells expressing the activating CD94/NKG2C receptor are significantly reduced in patients after alloSCT with severe acute and chronic graft-versus-host disease (GvHD). Moreover, the ratio of CD94/NKG2C to CD94/NKG2A was reduced in patients with severe acute and chronic GvHD after receiving an HLA-mismatched graft. Collectively, these results provide evidence for the first time that CD94/NKG2C is involved in GvHD prevention. PMID:27801784

  1. The Activating NKG2C Receptor Is Significantly Reduced in NK Cells after Allogeneic Stem Cell Transplantation in Patients with Severe Graft-versus-Host Disease

    Directory of Open Access Journals (Sweden)

    Lambros Kordelas

    2016-10-01

    Full Text Available Natural killer (NK cells play a central role in the innate immune system. In allogeneic stem cell transplantation (alloSCT, alloreactive NK cells derived by the graft are discussed to mediate the elimination of leukemic cells and dendritic cells in the patient and thereby to reduce the risk for leukemic relapses and graft-versus-host reactions. The alloreactivity of NK cells is determined by various receptors including the activating CD94/NKG2C and the inhibitory CD94/NKG2A receptors, which both recognize the non-classical human leukocyte antigen E (HLA-E. Here we analyze the contribution of these receptors to NK cell alloreactivity in 26 patients over the course of the first year after alloSCT due to acute myeloid leukemia, myelodysplastic syndrome and T cell Non-Hodgkin-Lymphoma. Our results show that NK cells expressing the activating CD94/NKG2C receptor are significantly reduced in patients after alloSCT with severe acute and chronic graft-versus-host disease (GvHD. Moreover, the ratio of CD94/NKG2C to CD94/NKG2A was reduced in patients with severe acute and chronic GvHD after receiving an HLA-mismatched graft. Collectively, these results provide evidence for the first time that CD94/NKG2C is involved in GvHD prevention.

  2. A Novel Function for P2Y2 in Myeloid Recipient-Derived Cells during Graft-versus-Host Disease.

    Science.gov (United States)

    Klämbt, Verena; Wohlfeil, Sebastian A; Schwab, Lukas; Hülsdünker, Jan; Ayata, Korcan; Apostolova, Petya; Schmitt-Graeff, Annette; Dierbach, Heide; Prinz, Gabriele; Follo, Marie; Prinz, Marco; Idzko, Marco; Zeiser, Robert

    2015-12-15

    Acute graft-versus-host disease (GvHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation. During the initiation phase of acute GvHD, endogenous danger signals such as ATP are released and inform the innate immune system via activation of the purinergic receptor P2X7 that a noninfectious damage has occurred. A second ATP-activated purinergic receptor involved in inflammatory diseases is P2Y2. In this study, we used P2y2(-/-) mice to test the role of this receptor in GvHD. P2y2(-/-) recipients experienced reduced GvHD-related mortality, IL-6 levels, enterocyte apoptosis, and histopathology scores. Chimeric mice with P2y2 deficiency restricted to hematopoietic tissues survived longer after GvHD induction than did wild-type mice. P2y2 deficiency of the recipient was connected to lower levels of myeloperoxidase in the intestinal tract of mice developing GvHD and a reduced myeloid cell signature. Selective deficiency of P2Y2 in inflammatory monocytes decreased GvHD severity. Mechanistically, P2y2(-/-) inflammatory monocytes displayed defective ERK activation and reactive oxygen species production. Compatible with a role of P2Y2 in human GvHD, the frequency of P2Y2(+) cells in inflamed GvHD lesions correlated with histopathological GvHD severity. Our findings indicate a novel function for P2Y2 in ATP-activated recipient myeloid cells during GvHD, which could be exploited when targeting danger signals to prevent GvHD.

  3. Lichenoid exanthema mimicking graft-versus-host disease associated with obstructive lung disease in a non-transplanted patient.

    Science.gov (United States)

    Eberle, Franziska Carola; Holland, Angelique; Hörster, Stefan; Vogelmeier, Claus; Hertl, Michael

    2010-01-01

    Lichenoid graft-versus-host disease (GVHD) is commonly observed in patients who have received donor lymphocyte infusions or allogeneic bone marrow transplantation (BMT). Here we report a striking case of lichenoid GVH-like exanthema in a young woman without any history of blood transfusions or BMT. A polymorphous, multiforme-like exanthema was observed after systemic antibiotic therapy of bronchitis and was initially diagnosed as drug eruption. Later on, disseminated lichenoid papules were noticed on the trunk and extremities with all histologic and clinical characteristics of lichenoid GVHD. Cutaneous GVH-like disease developed, as did obstructive lung disease. Pulmonary as well as skin disease were both refractory to various immunosuppressive therapies. The immune pathogenesis that caused the skin and lung disease in this patient remains unclear. Multiple pregnancies with two abortions with the potential induction of microchimerism may play a role in the disease pathogenesis.

  4. Intestinal barrier loss as a critical pathogenic link between inflammatory bowel disease and graft-versus-host disease.

    Science.gov (United States)

    Nalle, S C; Turner, J R

    2015-07-01

    Compromised intestinal barrier function is a prominent feature of inflammatory bowel disease (IBD). However, links between intestinal barrier loss and disease extend much further, including documented associations with celiac disease, type I diabetes, rheumatoid arthritis, and multiple sclerosis. Intestinal barrier loss has also been proposed to have a critical role in the pathogenesis of graft-versus-host disease (GVHD), a serious, potentially fatal consequence of hematopoietic stem cell transplantation. Experimental evidence has begun to support this view, as barrier loss and its role in initiating and establishing a pathogenic inflammatory cycle in GVHD is emerging. Here we discuss similarities between IBD and GVHD, mechanisms of intestinal barrier loss in these diseases, and the crosstalk between barrier loss and the immune system, with a special focus on natural killer (NK) cells. Unanswered questions and future research directions on the topic are discussed along with implications for treatment.

  5. [Chronic graft-versus-host-disease involving the oral mucosa: clinical presentation and treatment].

    Science.gov (United States)

    Elad, S; Levitt, M; M Y, Shapira

    2008-11-01

    Graft versus host disease (GVHD) is an alloimmune inflammatory process, which results from a donor-origin cellular response against host tissues. The chronic syndrome of GVHD (cGVHD) occurs in approximately 50% of patients post hematopoietic stem cell transplantation (HSCT) and remains the leading cause of non-malignant mortality. Oral cavity is one of the most frequent sites involved in cGVHD, possibly only second to skin. The oral tissues targeted by cGVHD are the mucosae, the salivary glands, the musculoskeletal apparatus and the periodontal structures. The mucosal cGVHD is accompanied by pain and mucosal irritation. Patients with cGVHD present with mucosal erosion and atrophy, lichenoid-hyperkeratotic changes, pseudomembranous ulcerations and mucoceles. Dry mouth may exacerbate mucosal irritation and erosion. In addition to impaired oral functions, cGVHD may lead to secondary malignancies in the form of solid cancers, particularly squamous cell carcinomas of the oral cavity. Moreover, administration of systemic azathioprine, a commonly used immunosuppressive drug in cGVHD patients, may significantly increase the incidence of tumors of oral cavity. The increased risk of secondary malignancies indicates the need for lifelong surveillance, particularly in younger patients. Scoring of oral GVHD was first addressed by NIH only in 2005. The NIH consensus paper referred to standard criteria for diagnosis, classification, and response to treatment. These scales were introduced for clinical use, although they require prospective validation studies. In the past, other scales were suggested and may still be used for research purposes. Management of oral cGVHD is compromised of preventive protocols and when cGVHD is developed, systemic and topical treatment. Because the majority of patients with oral cGVHD will develop the extensive form of the disease, they will be treated systemically. Systemic treatment is based on steroids and immunosuppressants, and, thus, increases

  6. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multi-center survey

    Science.gov (United States)

    Zeiser, Robert; Burchert, Andreas; Lengerke, Claudia; Verbeek, Mareike; Maas-Bauer, Kristina; Metzelder, Stephan K.; Spoerl, Silvia; Ditschkowski, Markus; Ecsedi, Matyas; Sockel, Katja; Ayuk, Francis; Ajib, Salem; de Fontbrune, Flore Sicre; Na, Il-Kang; Penter, Livius; Holtick, Udo; Wolf, Dominik; Schuler, Esther; Meyer, Everett; Apostolova, Petya; Bertz, Hartmut; Marks, Reinhard; Lübbert, Michael; Wäsch, Ralph; Scheid, Christof; Stölzel, Friedrich; Ordemann, Rainer; Bug, Gesine; Kobbe, Guido; Negrin, Robert; Brune, Mats; Spyridonidis, Alexandros; Schmitt-Gräff, Annette; van der Velden, Walter; Huls, Gerwin; Mielke, Stephan; Grigoleit, Götz Ulrich; Kuball, Jürgen; Flynn, Ryan; Ihorst, Gabriele; Du, Jing; Blazar, Bruce R; Arnold, Renate; Kröger, Nicolaus; Passweg, Jakob; Halter, Jörg; Socié, Gerard; Beelen, Dietrich; Peschel, Christian; Neubauer, Andreas; Finke, Jürgen; Duyster, Justus; von Bubnoff, Nikolas

    2016-01-01

    Despite major improvements in allogeneic hematopoietic cell transplantation over the last decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Pre-clinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage-therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grade III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1–7) and SR-cGVHD (1–10). The ORR was 81.5% (44/54) in SR-aGVHD including 25 CRs (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3%–90.7%,95% CI) and 97.4% (92.3%–100%,95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and CMV-reactivation were observed during ruxolitinib-treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial. PMID:26228813

  7. A phase II study of bortezomib plus prednisone for initial therapy of chronic graft-versus-host disease.

    Science.gov (United States)

    Herrera, Alex F; Kim, Haesook T; Bindra, Bhavjot; Jones, Kyle T; Alyea, Edwin P; Armand, Philippe; Cutler, Corey S; Ho, Vincent T; Nikiforow, Sarah; Blazar, Bruce R; Ritz, Jerome; Antin, Joseph H; Soiffer, Robert J; Koreth, John

    2014-11-01

    Chronic graft-versus-host disease (GVHD) induces significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Corticosteroids are standard initial therapy, despite limited efficacy and long-term toxicity. Based on our experience using bortezomib as effective acute GVHD prophylaxis, we hypothesized that proteasome-inhibition would complement the immunomodulatory effects of corticosteroids to improve outcomes in chronic GVHD (cGVHD). We undertook a single-arm phase II trial of bortezomib plus prednisone for initial therapy of cGVHD. Bortezomib was administered at 1.3 mg/m(2) i.v. on days 1, 8, 15, and 22 of each 35-day cycle for 3 cycles (15 weeks). Prednisone was dosed at .5 to 1 mg/kg/day, with a suggested taper after cycle 1. All 22 enrolled participants were evaluable for toxicity; 20 were evaluable for response. Bortezomib plus prednisone therapy was well tolerated, with 1 occurrence of grade 3 sensory peripheral neuropathy possibly related to bortezomib. The overall response rate at week 15 in evaluable participants was 80%, including 2 (10%) complete and 14 (70%) partial responses. The organ-specific complete response rate was 73% for skin, 53% for liver, 75% for gastrointestinal tract, and 33% for joint, muscle, or fascia involvement. The median prednisone dose decreased from 50 mg/day to 20 mg/day at week 15 (P prednisone for initial treatment of cGVHD is feasible and well tolerated. We observed a high response rate to combined bortezomib and prednisone therapy; however, in this single-arm study, we could not directly measure the impact of bortezomib. Proteasome inhibition may offer benefit in the treatment of cGVHD and should be further evaluated.

  8. 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.

  9. Membranous nephropathy in autologous hematopoietic stem cell transplant: autologous graft-versus-host disease or autoimmunity induction?

    Science.gov (United States)

    Abudayyeh, Ala; Truong, Luan D.; Beck, Laurence H.; Weber, Donna M.; Rezvani, Katy; Abdelrahim, Maen

    2015-01-01

    With the increasing utility of hematopoietic stem cell transplantation (SCT) as a treatment for cancer and noncancerous disorders, more challenges and complications associated with SCT have emerged. Renal injury immediately after transplant is common and well understood, but long-term renal injury is becoming more evident. Chronic graft-versus-host disease (GVHD) is a known long-term complication of SCT, and membranous nephropathy (MN) is emerging as the most common cause of SCT-associated glomerular pathology. In this case report, we present a patient who developed features of anti-PLA2R antibody-negative MN following autologous SCT. The renal injury responded well to steroids and further response to rituximab therapy was noted, suggesting antibody-mediated autoimmune glomerular disease. We also present a review of the literature on autologous GVHD and the role of T and B cells in induction of autoimmunity by SCT. PMID:26251713

  10. Impact of cytomegalovirus and grafts versus host disease on the dynamics of CD57+CD28-CD8+ T cells after bone marrow transplant

    Directory of Open Access Journals (Sweden)

    Ana Verena Almeida Mendes

    2008-01-01

    Full Text Available OBJECTIVES: The present study aimed to evaluate the dynamics of CD28 and CD57 expression in CD8+ T lymphocytes during cytomegalovirus viremia in bone marrow transplant recipients. METHODS: In a prospective study, blood samples were obtained once weekly once from 33 healthy volunteers and weekly from 33 patients. To evaluate the expression of CD57 and CD28 on CD8+ T lymphocytes, flow cytometry analysis was performed on blood samples for four months after bone marrow transplant, together with cytomegalovirus antigenemia assays. RESULTS: Compared to cytomegalovirus-seronegative healthy subjects, seropositive healthy subjects demonstrated a higher percentage of CD57+ and a lower percentage of CD28+ cells (p<0.05. A linear regression model demonstrated a continuous decrease in CD28+ expression and a continuous increase in CD57+ expression after bone marrow transplant. The occurrence of cytomegalovirus antigenemia was associated with a steep drop in the percentage of CD28+ cells (5.94%, p<0.01 and an increase in CD57+ lymphocytes (5.60%, p<0.01. This cytomegalovirus-dependent effect was for the most part concentrated in the allogeneic bone marrow transplant patients. The development of acute graft versus host disease, which occurred at an earlier time than antigenemia (day 26 vs. day 56 post- bone marrow transplant, also had an impact on the CD57+ subset, triggering an increase of 4.9% in CD57+ lymphocytes (p<0.05. CONCLUSION: We found continuous relative changes in the CD28+ and CD57+ subsets during the first 120 days post- bone marrow transplant, as part of immune system reconstitution and maturation. A clear correlation was observed between the expansion of the CD57+CD28-CD8+ T lymphocyte subpopulation and the occurrence of graft versus host disease and cytomegalovirus viremia.

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

    Science.gov (United States)

    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; Salvatori, Giovanni; Parma, Matteo; Terruzzi, Elisabetta; Pagni, Fabio; Locatelli, Franco; Mantovani, Alberto; Fagioli, Franca; Biondi, Andrea; Garlanda, Cecilia; Valsecchi, Maria Grazia; Rovelli, Attilio; D'Amico, Giovanna

    2016-12-13

    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 GvHD biomarker. Using a murine model of the disease, we found increased PTX3 plasma levels after irradiation and at GvHD onset. Similarly, plasma PTX3 was enhanced in 115 pediatric patients on day of transplantation, likely due to conditioning, and at GvHD onset in patients experiencing clinical symptoms of the disease. PTX3 was also found increased in skin and colon biopsies from patients with active disease. Furthermore, PTX3 plasma levels at GvHD onset were predictive of disease outcome since they resulted significantly higher in both severe and therapy-unresponsive patients. Multiple injections of rhPTX3 in the murine model of GvHD did not influence the disease course. Taken together, our results indicate that PTX3 constitutes a biomarker of GvHD severity and therapy response useful to tailor treatment intensity according to early risk-stratification of GvHD patients.

  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

    Science.gov (United States)

    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; Salvatori, Giovanni; Parma, Matteo; Terruzzi, Elisabetta; Pagni, Fabio; Locatelli, Franco; Mantovani, Alberto; Fagioli, Franca; Biondi, Andrea; Garlanda, Cecilia; Valsecchi, Maria Grazia; Rovelli, Attilio; D'Amico, Giovanna

    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 GvHD biomarker. Using a murine model of the disease, we found increased PTX3 plasma levels after irradiation and at GvHD onset. Similarly, plasma PTX3 was enhanced in 115 pediatric patients on day of transplantation, likely due to conditioning, and at GvHD onset in patients experiencing clinical symptoms of the disease. PTX3 was also found increased in skin and colon biopsies from patients with active disease. Furthermore, PTX3 plasma levels at GvHD onset were predictive of disease outcome since they resulted significantly higher in both severe and therapy-unresponsive patients. Multiple injections of rhPTX3 in the murine model of GvHD did not influence the disease course. Taken together, our results indicate that PTX3 constitutes a biomarker of GvHD severity and therapy response useful to tailor treatment intensity according to early risk-stratification of GvHD patients. PMID:27893415

  13. Disease severity and mortality can be independently regulated in a mouse model of experimental graft versus host disease.

    Directory of Open Access Journals (Sweden)

    Rômulo G Galvani

    Full Text Available Graft versus host disease (GVHD is the major limitation of allogeneic hematopoietic stem cell transplantation (HSCT presenting high mortality and morbidity rates. However, the exact cause of death is not completely understood and does not correlate with specific clinical and histological parameters of disease. Here we show, by using a semi-allogeneic mouse model of GVHD, that mortality and morbidity can be experimentally separated. We injected bone marrow-derived dendritic cells (BMDC from NOD2/CARD15-deficient donors into semi-allogeneic irradiated chimaeras and observed that recipients were protected from death. However, no protection was observed regarding clinical or pathological scores up to 20 days after transplantation. Protection from death was associated with decreased bacterial translocation, faster hematologic recovery and epithelial integrity maintenance despite mononuclear infiltration at day 20 post-GVHD induction with no skew towards different T helper phenotypes. The protected mice recovered from aGVHD and progressively reached scores compatible with healthy animals. Altogether, our data indicate that severity and mortality can be separate events providing a model to study transplant-related mortality.

  14. OMISSION OF DAY +11 METHOTREXATE DOES NOT APPEAR TO INFLUENCE INCIDENCE AND SEVERITY OF GRAFT-VERSUS-HOST DISEASE AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

    Institute of Scientific and Technical Information of China (English)

    朱康儿; 张涛; 陈盛亭; 钟隽; 曾慧兰

    2004-01-01

    Objective: To explore the influence of omission of the day +11 dose of methotrexate (MIX) on the incidence and severity of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: From April 1997 to October 2002, 80 leukemia patients (46 men and 34 women aged from 12 to 56 years with a median age of 35) underwent allo-HSCT at our BMT unit. Among them, 58 patients received grafts from HLA-identical siblings, 8 from HLA one major antigen mismatched siblings and 14 from HLA-matched unrelated donors. All patients received a modified cyclosporine and short-course MTX regimen for GVHD prophylaxis, which included MTX 15 mg on day +1, and 10 mg on days +3 and +6 (MTX day +11 dose omitted) and cyclosporine given daily. Results: The overall incidence of grade I~IV acute GVHD was 57.5% (46/80 patients), with grade II~IV acute GVHD in 28 patients (35%) and grade III~IV acute GVHD in 7 patients (8.8%). Among 58 patients receiving grafts from HLA-identical siblings, 24 patients developed grade I~IV acute GVHD (41.4%), with grade II~IV acute GVHD in 13 patients (22.4%) and grade III~IV acute GVHD in 4 patients (6.9%). 2l out of 22 patients receiving grafts from HLA one major antigen mismatched siblings and HLA-matched unrelated donors developed grade I~IV acute GVHD (95.5%), with grade II~IV acute GVHD in 14 patients (63.6%) and grade III~IV acute GVHD in 3 patients (13.6%). Chronic GVHD occurred in 38 out of 56 evaluable patients (67.9%), with extensive form in 15 patients (26.8%) and limited form in 23 patients (41.1%). With a median follow-up of 960 days (range 180~1980 days), the probability of leukemia-free survival at 3 years was 61.3% for all patients. Conclusion: Our results suggest that the day +11 MTX can be omitted without a major deleterious effect on the incidence and severity of graft-versus-host disease after HLA-identical sibling transplantation as well as HLA one major antigen mismatched sibling and HLA

  15. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease.

    Science.gov (United States)

    Mathewson, Nathan D; Jenq, Robert; Mathew, Anna V; Koenigsknecht, Mark; Hanash, Alan; Toubai, Tomomi; Oravecz-Wilson, Katherine; Wu, Shin-Rong; Sun, Yaping; Rossi, Corinne; Fujiwara, Hideaki; Byun, Jaeman; Shono, Yusuke; Lindemans, Caroline; Calafiore, Marco; Schmidt, Thomas C; Honda, Kenya; Young, Vincent B; Pennathur, Subramaniam; van den Brink, Marcel; Reddy, Pavan

    2016-05-01

    The effect of alterations in intestinal microbiota on microbial metabolites and on disease processes such as graft-versus-host disease (GVHD) is not known. Here we carried out an unbiased analysis to identify previously unidentified alterations in gastrointestinal microbiota-derived short-chain fatty acids (SCFAs) after allogeneic bone marrow transplant (allo-BMT). Alterations in the amount of only one SCFA, butyrate, were observed only in the intestinal tissue. The reduced butyrate in CD326(+) intestinal epithelial cells (IECs) after allo-BMT resulted in decreased histone acetylation, which was restored after local administration of exogenous butyrate. Butyrate restoration improved IEC junctional integrity, decreased apoptosis and mitigated GVHD. Furthermore, alteration of the indigenous microbiota with 17 rationally selected strains of high butyrate-producing Clostridia also decreased GVHD. These data demonstrate a heretofore unrecognized role of microbial metabolites and suggest that local and specific alteration of microbial metabolites has direct salutary effects on GVHD target tissues and can mitigate disease severity.

  16. Bim is required for T-cell allogeneic responses and graft-versus-host disease in vivo.

    Science.gov (United States)

    Yu, Yu; Yu, Jing; Iclozan, Cristina; Kaosaard, Kane; Anasetti, Claudio; Yu, Xue-Zhong

    2012-01-01

    Bim, a BH3-only Bcl-2-family protein, is essential for T-cell negative selection in the thymus as well as for the death of activated T cells in the periphery. The role of Bim has been extensively studied in T-cell responses to self-antigens and viral infections. Recent findings on Bim in autoimmunity triggered our interest in investigating whether Bim may play a role in another disease with inflammatory symptoms as graft-versus-host disease (GVHD). Here we report that Bim is required for optimal T-cell responses to alloantigens in vivo and for the development of GVHD. Using murine models of allogeneic bone marrow transplantation (BMT), we found that donor T cells deficient for Bim are impaired in the induction of GVHD primarily due to a significant defect in T cell activation and expansion in vivo. Upon TCR engagement, Bim(-/-) T cells exhibited selective defects in CD69 expression and phosphorylation of PLCγ1. Our studies uncover a novel aspect of Bim function in T-cell activation with important implications in understanding the mechanisms of T-cell activation and tolerance under allogeneic transplantation.

  17. Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease

    Science.gov (United States)

    Le Texier, Laëtitia; Lineburg, Katie E.; Leveque-El Mouttie, Lucie; Nicholls, Jemma; Melino, Michelle; Nalkurthi, Blessy C.; Alexander, Kylie A.; Teal, Bianca; Blake, Stephen J.; Souza-Fonseca-Guimaraes, Fernando; Engwerda, Christian R.; Kuns, Rachel D.; Lane, Steven W.; Teh, Charis; Gray, Daniel; Clouston, Andrew D.; Nilsson, Susan K.; Blazar, Bruce R.; Hill, Geoffrey R.; MacDonald, Kelli P.A.

    2016-01-01

    Regulatory T cells (Tregs) play a crucial role in the maintenance of peripheral tolerance. Quantitative and/or qualitative defects in Tregs result in diseases such as autoimmunity, allergy, malignancy, and graft-versus-host disease (GVHD), a serious complication of allogeneic stem cell transplantation (SCT). We recently reported increased expression of autophagy-related genes (Atg) in association with enhanced survival of Tregs after SCT. Autophagy is a self-degradative process for cytosolic components that promotes cell homeostasis and survival. Here, we demonstrate that the disruption of autophagy within FoxP3+ Tregs (B6.Atg7fl/fl-FoxP3cre+) resulted in a profound loss of Tregs, particularly within the bone marrow (BM). This resulted in dysregulated effector T cell activation and expansion, and the development of enterocolitis and scleroderma in aged mice. We show that the BM compartment is highly enriched in TIGIT+ Tregs and that this subset is differentially depleted in the absence of autophagy. Moreover, following allogeneic SCT, recipients of grafts from B6.Atg7fl/fl-FoxP3cre+ donors exhibited reduced Treg reconstitution, exacerbated GVHD, and reduced survival compared with recipients of B6.WT-FoxP3cre+ grafts. Collectively, these data indicate that autophagy-dependent Tregs are critical for the maintenance of tolerance after SCT and that the promotion of autophagy represents an attractive immune-restorative therapeutic strategy after allogeneic SCT. PMID:27699243

  18. Magnetic resonance enterography for assessment of intestinal graft-versus-host disease after allogeneic stem cell transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Derlin, Thorsten [University Medical Center Hamburg-Eppendorf, Department of Diagnostic and Interventional Radiology, Hamburg (Germany); Hanover Medical School, Department of Nuclear Medicine, Hanover (Germany); Laqmani, Azien; Adam, Gerhard; Bannas, Peter [University Medical Center Hamburg-Eppendorf, Department of Diagnostic and Interventional Radiology, Hamburg (Germany); Veldhoen, Simon [University Medical Center Hamburg-Eppendorf, Department of Diagnostic and Interventional Radiology, Hamburg (Germany); University Medical Center Wuerzburg, Department of Diagnostic and Interventional Radiology, Wuerzburg (Germany); Apostolova, Ivayla [Otto-von-Guericke University, Department of Radiology and Nuclear Medicine, Magdeburg (Germany); Ayuk, Francis; Kroeger, Nicolaus [University Medical Center Hamburg-Eppendorf, Department of Stem Cell Transplantation, Hamburg (Germany)

    2015-05-01

    To determine the diagnostic performance of MR enterography (MRE) for detection and grading of gastrointestinal graft-versus-host disease (GI GvHD) after hematopoietic stem cell transplantation (SCT). Forty-one patients with known GvHD or suspected GvHD underwent MRE and GI endoscopy with multi-level biopsies. MRE images were reviewed for presence of intestinal wall inflammation. Clinical grading of GI GvHD was performed. Histopathological evaluation (HPE) served as the reference standard. Overall, MRE demonstrated a per-patient sensitivity of 81.5 % for detection of GI GvHD. The most common findings were intestinal wall thickening (81.5 % of GvHD patients), luminal stenosis (81.5 %), mural contrast enhancement (70.4 %), and ascites (59.3 %). These findings were also observed in other conditions than GvHD. The most frequently involved intestinal segment was the sigmoid colon (63.0 %), followed by the ileum (59.3 %) and the jejeunum (51.9 %). The number of involved segments (r{sub s} =0.54, p =0.009) correlated significantly with clinical severity as determined by GvHD grading. After allogeneic stem cell transplantation, MRE may (1) contribute to detection and localization of GI GvHD, and (2) add information indicating the clinical severity of disease, but findings are unspecific. False negative results may be observed not only in low-grade GI GvHD. (orig.)

  19. Immunomodulation with donor regulatory T cells armed with Fas-ligand alleviates graft-versus-host disease.

    Science.gov (United States)

    Yolcu, Esma S; Kaminitz, Ayelet; Mizrahi, Keren; Ash, Shifra; Yaniv, Isaac; Stein, Jerry; Shirwan, Haval; Askenasy, Nadir

    2013-10-01

    Infusion of large numbers of donor regulatory T cells (Tregs) is an effective approach to suppress graft-versus-host disease (GvHD). We have reported previously that enhancing the killing activity of CD25(+) Tregs by decoration with short-lived Fas-ligand (FasL) protein (killer Tregs) is effective in abrogation of autoimmunity. In this study, we assessed the therapeutic efficacy of killer Tregs in murine models of lethal GvHD. In a model in which disease-associated mortality was not prevented by infusion of naive donor Tregs (3 days after transplant) at an effector:suppressor ratio of 10:1, killer Tregs rescued 70% of the mice and improved the clinical and histologic scores. We found that both effector lymphocytes and therapeutic Tregs migrate to and proliferate in the mesenteric lymph nodes of irradiated recipients; however, only killer Tregs increased fractional apoptosis of effector lymphocytes. Although the lymphoid organs were primarily reconstituted from the bone marrow with little contribution of the infused effector and suppressor subsets, immunomodulation with FasL caused a durable rise in fractions of CD4(+)FoxP3(+) Tregs. Our findings demonstrate that a short-lived apoptotic protein increases the suppressive activity of Tregs and ameliorates GvHD severity.

  20. Ixazomib suppresses human dendritic cell and modulates murine graft-versus-host disease in a schedule-dependent fashion.

    Science.gov (United States)

    Al-Homsi, Ahmad Samer; Goodyke, Austin; Cole, Kelli; Muilenburg, Marlee; McLane, Michael; Abdel-Mageed, Sarah; Feng, Yuxin

    2017-04-01

    There is an abiding need for innovative approaches to the prevention of graft-versus-host disease (GvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Interest in prevention of GvHD by dendritic cell (DC) suppression has re-emerged since the introduction of proteasome inhibitors into clinical practice. Ixazomib is an orally bioavailable proteasome inhibitor with a rapid proteasome dissociation rate. We studied the effects of ixazomib on human DC maturation, viability, and cytokine production in vitro. We also determined the effects of ixazomib in a murine GvHD model. Although ixazomib suppressed naïve human DC maturation, it had only a limited effect on cell viability. Ixazomib decreased pro-inflammatory cytokine production of resting DCs. This effect was diminished or reversed when DCs were pre-stimulated. In vivo, ixazomib administered post-transplantation on days +1 and +4 or days -1, +2, and +5 ameliorated GvHD in comparison to the GvHD group. Although a fraction of mice treated according to the prolonged schedule died abruptly after the day +5 treatment, both schedules resulted in improved overall survival. When we examined the effects of ixazomib on splenic cells and serum cytokines, we found that ixazomib exerted complex schedule-dependent immunomodulatory effects. Our study provides a rationale for the potential use of ixazomib in the prevention of GvHD.

  1. 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.)

  2. Loss of T Follicular Helper Cells in the Peripheral Blood of Patients with Chronic Graft-versus-Host Disease.

    Science.gov (United States)

    Knorr, David A; Wang, Hongbo; Aurora, Mukta; MacMillan, Margaret L; Holtan, Shernan G; Bergerson, Rachel; Cao, Qing; Weisdorf, Daniel J; Cooley, Sarah; Brunstein, Claudio; Miller, Jeffery S; Wagner, John E; Blazar, Bruce R; Verneris, Michael R

    2016-05-01

    B cell antihost antibody production plays a central role in chronic graft-versus-host disease (cGVHD). T follicular helper (TFH) cells drive B cell responses and are implicated in this process. Given differences in cGVHD incidence between umbilical cord blood (UCB) and adult donor transplant recipients, we evaluated TFH cell reconstitution kinetics to define graft source differences and their potential pathogenic role in cGVHD. Although we observed significantly fewer TFH cells in the blood of UCB recipients (versus matched related donors [MRD]) early after transplantation, by 1 year the numbers of TFH cells were similar. Additionally, at both early (day 60) and late (1 year) time points, TFH cell phenotype was predominantly central memory cells in both cohorts. TFH cells were functional and able to produce multiple cytokines (INF-γ, TNF-α, IL-2, IL-17, and IL-21) after stimulation. In contrast to mouse models, where an enhanced frequency of splenic TFH cells contributes to cGVHD, patients with cGVHD showed significantly depleted circulating TFH cells after both UCB and MRD transplantation. Low numbers of TFH cells early after UCB transplantation could directly contribute to less cGVHD in this cohort. Additionally, systemic therapy (including steroids and calcineurin inhibitors) may contribute to decreases in TFH cells in patients with cGVHD. These data provide further evidence supporting the importance of TFH cells in cGVHD pathogenesis.

  3. [The impact of donor naive and memory T cell subsets on patient outcome following allogeneic stem cell transplantation: relationship between infused donor CD4+/CCR7+ T cell subsets and acute graft-versus-host disease].

    Science.gov (United States)

    Choufi, B; Thiant, S; Trauet, J; Cliquennois, M; Cherrel, M; Boulanger, F; Coiteux, V; Magro, L; Labalette, M; Yakoub-Agha, I

    2014-06-01

    In a previous prospective study on 62 patients who underwent an HLA-matched allogeneic stem cell transplantation, we have observed that proportion of donor-derived CCR7(+)/CD4(+) T cells in the graft provided a predictive indicator of acute GVHD without interfering on chronic GVHD and relapse rate. Here we present our results on a confirmatory cohort of 137 consecutive patients. Indeed patients who received more than 76% of CCR7(+)/CD4(+) T cells in the graft developed more often acute GVHD be it of low or high grade than those who did not. Determination of the CCR7(+)/CCR7(neg) ratio of CD4(+) T cells in the graft provides a predictive indicator of acute GVHD and could help to define strategies of partial selective T cell depleted transplantation.

  4. Insights into the mechanism of FTY720 and compatibility with regulatory T cells for the inhibition of graft-versus-host disease (GVHD)

    OpenAIRE

    Taylor, Patricia A.; Ehrhardt, Michael J.; Lees, Christopher J.; Tolar, Jakub; Weigel, Brenda J; Panoskaltsis-Mortari, Angela; Serody, Jonathan S.; Brinkmann, Volker; Blazar, Bruce R.

    2007-01-01

    The immunomodulator FTY720 (FTY) has been shown to be beneficial in experimental models of organ transplantation and autoimmunity. We show that FTY significantly inhibited but did not prevent graft-versus-host disease (GVHD) in lethally irradiated or nonirradiated allogeneic recipients. Although most studies implicate prevention of lymphocyte egress from lymphoid organs as the primary mechanism of action, our data indicate that FTY effects on the host are more likely to be responsible for GVH...

  5. Novel Approaches for Graft-versus-Host Disease Prevention Compared to Contemporary Controls (BMT CTN 1203)

    Science.gov (United States)

    2016-11-21

    Acute Leukemia; Chronic Myelogenous Leukemia; Myelodysplasia; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Lymphoma, B-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Hodgkin's Lymphoma

  6. Monocyte-induced development of Th17 cells and the release of S100 proteins are involved in the pathogenesis of graft-versus-host disease.

    Science.gov (United States)

    Reinhardt, Katharina; Foell, Dirk; Vogl, Thomas; Mezger, Markus; Wittkowski, Helmut; Fend, Falko; Federmann, Birgit; Gille, Christian; Feuchtinger, Tobias; Lang, Peter; Handgretinger, Rupert; Andreas Bethge, Wolfgang; Holzer, Ursula

    2014-10-01

    Graft-versus-host disease (GvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. However, the pathophysiology of GvHD remains poorly understood. In this study, we analyzed the induction of Th17 cells by monocytes of patients with GvHD in vitro, demonstrating that monocytes isolated from patients with acute skin and intestinal GvHD stage I-IV and chronic GvHD induce significantly increased levels of Th17 cells compared with patients without GvHD. S100 proteins are known to act as innate amplifier of inflammation. We therefore investigated the presence of S100 proteins in the stool, serum, and bowel tissue of patients with GvHD and the influence of S100 proteins on the induction of Th17 cells. Elevated levels of S100 proteins could be detected in patients with acute GvHD, demonstrating the release of these phagocyte-specific proteins during GvHD. Furthermore, stimulation of monocytes with S100 proteins was found to promote Th17 development, emphasizing the role of S100 proteins in Th17-triggered inflammation. Altogether, our results indicate that induction of Th17 cells by activated monocytes and the stimulatory effects of proinflammatory S100 proteins might play a relevant role in the pathogenesis of acute GvHD. Regarding our data, S100 proteins might be novel markers for the diagnosis and follow-up of GvHD.

  7. The addition of sirolimus to the graft-versus-host disease prophylaxis regimen in reduced intensity allogeneic stem cell transplantation for lymphoma: a multicentre randomized trial.

    Science.gov (United States)

    Armand, Philippe; Kim, Haesook T; Sainvil, Marie-Michele; Lange, Paulina B; Giardino, Angela A; Bachanova, Veronika; Devine, Steven M; Waller, Edmund K; Jagirdar, Neera; Herrera, Alex F; Cutler, Corey; Ho, Vincent T; Koreth, John; Alyea, Edwin P; McAfee, Steven L; Soiffer, Robert J; Chen, Yi-Bin; Antin, Joseph H

    2016-04-01

    Inhibition of the mechanistic target of rapamycin (mTOR) pathway has clinical activity in lymphoma. The mTOR inhibitor sirolimus has been used in the prevention and treatment of graft-versus-host disease (GVHD) after allogeneic haematopoietic stem cell transplantation (HSCT). A retrospective study suggested that patients with lymphoma undergoing reduced intensity conditioning (RIC) HSCT who received sirolimus as part of their GVHD prophylaxis regimen had a lower rate of relapse. We therefore performed a multicentre randomized trial comparing tacrolimus, sirolimus and methotrexate to standard regimens in adult patients undergoing RIC HSCT for lymphoma in order to assess the possible benefit of sirolimus on HSCT outcome. 139 patients were randomized. There was no difference overall in 2-year overall survival, progression-free survival, relapse, non-relapse mortality or chronic GVHD. However, the sirolimus-containing arm had a significantly lower incidence of grade II-IV acute GVHD (9% vs. 25%, P = 0·015), which was more marked for unrelated donor grafts. In conclusion, the addition of sirolimus for GVHD prophylaxis in RIC HSCT is associated with no increased overall toxicity and a lower risk of acute GVHD, although it does not improve survival; this regimen is an acceptable option for GVHD prevention in RIC HSCT. This trial is registered at clinicaltrials.gov (NCT00928018).

  8. The role of pattern-recognition receptors in graft-versus-host disease and graft-versus-leukemia after allogeneic stem cell transplantation.

    Science.gov (United States)

    Heidegger, Simon; van den Brink, Marcel R M; Haas, Tobias; Poeck, Hendrik

    2014-01-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with curative potential for certain aggressive hematopoietic malignancies. Its success is limited by acute graft-versus-host disease (GVHD), a life-threatening complication that occurs when allo-reactive donor T cells attack recipient organs. There is growing evidence that microbes and innate pattern-recognition receptors (PRRs) such as toll-like receptors (TLR) and nod-like receptors (NLR) are critically involved in the pathogenesis of acute GVHD. Currently, a widely accepted model postulates that intensive chemotherapy and/or total-body irradiation during pre-transplant conditioning results in tissue damage and a loss of epithelial barrier function. Subsequent translocation of bacterial components as well as release of endogenous danger molecules stimulate PRRs of host antigen-presenting cells to trigger the production of pro-inflammatory cytokines (cytokine storm) that modulate T cell allo-reactivity against host tissues, but eventually also the beneficial graft-versus-leukemia (GVL) effect. Given the limitations of existing immunosuppressive therapies, a better understanding of the molecular mechanisms that govern GVHD versus GVL is urgently needed. This may ultimately allow to design modulators, which protect from GvHD but preserve donor T-cell attack on hematologic malignancies. Here, we will briefly summarize current knowledge about the role of innate immunity in the pathogenesis of GVHD and GVL following allo-HSCT.

  9. The role of pattern-recognition receptors in Graft-versus-host disease and Graft-versus-leukemia after allogeneic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Simon eHeidegger

    2014-07-01

    Full Text Available Allogeneic hematopoietic stem cell transplantation (allo-HSCT is the only treatment with curative potential for certain aggressive hematopoietic malignancies. Its success is limited by acute graft-versus-host disease (GVHD, a life-threatening complication that occurs when alloreactive donor T cells attack recipient organs. There is growing evidence that microbes and innate pattern-recognition receptors (PRRs such as toll-like (TLR and nod-like receptors (NLR are critically involved in the pathogenesis of acute GVHD. A now widely accepted model postulates that intensive chemotherapy and / or total-body irradiation during pre-transplant conditioning result in tissue damage and a loss of epithelial barrier function. Subsequent translocation of bacterial components as well as release of endogenous danger molecules stimulate PRRs of host antigen-presenting cells (APCs to trigger the production of pro-inflammatory cytokines (‘cytokine storm’ that modulate T cell alloreactivity against host tissues, but eventually also the beneficial graft-versus-leukemia (GVL effect. Given the limitations of existing immunosuppressive therapies, a better understanding of the molecular mechanisms which govern GVHD vs GVL is urgently needed. This may ultimately allow to design modulators which protect from GvHD but preserve donor T-cell attack on hematologic malignancies. Here, we will briefly summarize current knowledge about the role of innate immunity in the pathogenesis of GVHD and GVL following allo-HSCT.

  10. Colonoscopy in the diagnosis of intestinal graft versus host disease and cytomegalovirus enteritis following allogeneic haematopoietic stem cell transplantation

    Institute of Scientific and Technical Information of China (English)

    HE Jin-de; LIU Yu-lan; WANG Zhi-feng; LIU Dai-hong; CHEN Huan; CHEN Yu-hong

    2008-01-01

    Background Gastrointestinal graft versus host disease (GI-GVHD) and cytomegalovirus (CMV) enteritis are important complications following allogeneic haematopoietic stem cell transplantation (alIo-HSCT). We explored the role of colonoscopy in the diagnosis of GI-GVHD and CMV enteritis following alIo-HSCT to identify the endoscopic manifestations of GI-GVHD and CMV enteritis was made.Methods A retrospective analysis of the colonoscopic manifestations of GI-GVHD, CMV enteritis and GI-GVHD with concurrent CMV enteritis (GconC) and their related clinical issues.Results Forty-seven patients underwent 50 colonoscopies with diagnoses of 32 GI-GVHD, 7 CMV enteritis and 11 GconC. Both GI-GVHD and CMV enteritis had colonic mucosal lesions with various manifestations under colonoscopy. Tortoise shell like changes of the mucosa (12 of 32) and deep ulcers (2 of 7) were specific endoscopic manifestations for GI-GVHD and CMV enteritis, respectively, while mucosal oedema, erythema, congestion, erosion and shallow ulcers could not be used to differentiate GI-GVHD from CMV enteritis. GconC patients were prone to have oozing bleeding of the end ileal mucosa and typhlodicliditis. Of the biopsed specimens for GI-GVHD, CMV enteritis and GconC, 64%, 70% and 44% were taken from the rectum and sigmoid colon respectively.Conclusions Following alIo-HSCT, tortoise shell like changes and deep ulcers of the colonic mucosa are characteristic changes for Gl-GVHD and CMV enteritis, respectively, while the other lesions are not. Most of the GI-GVHDs and CMV enteritis cases can be diagnosed by left colon examination and tissue biopsy, but total colon examination to the terminal ileum is preferred.

  11. CT-analysis of the course of gastrointestinal graft-versus-host disease-Patterns of involvement

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    Ketelsen, D., E-mail: dominik.ketelsen@med.uni-tuebingen.de [Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, 72076 Tuebingen (Germany); Vogel, W.; Bethge, W.; Faul, C. [Department of Internal Medicine-Oncology, Eberhard-Karls-University, Ottfried-Mueller-Str. 5, 72070 Tuebingen (Germany); Claussen, C.D.; Horger, M. [Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, 72076 Tuebingen (Germany)

    2011-07-15

    Objective: To describe the main patterns of distribution of gastrointestinal graft-versus-host disease (GVHD) and their chronological course. Methods: Twenty-five adult patients (17 men, 8 women, mean age 47 years) were enrolled from 11/2003 to 11/2007. All patients underwent abdominopelvic CT shortly after onset of GVHD-related symptoms and also at follow up. The mean number of CT examinations per patient was 3.2 {+-} 2.7 with a total of 81 in a median time period of 97 days after HCT. The gastrointestinal tract was divided into 7 segments. Gastrointestinal abnormalities were defined as follows: presence of wall thickening (>4 mm), increased mucosal enhancement, bowel dilatation (>3 cm for the small bowel, >8 cm for the colon), fluid-filled loops of the bowel, bowel loop separation and double-halo sign. Results: 40% (10/25) of the patients presented a classical pattern of evolution of involved segments by GI-GVHD. In these cases, especially the small bowel was initially involved showing a retreat with time towards the terminal ileum with longer length of stay in this location. 28% (7/25) of the patients presented with a nonclassical permanently migratory involvement of the GI jumping from one GI segment to another. Other 32% (8/25) of our patients revealed a nonclassical persistent, unchanged involvement pattern of GI involvement by GVHD at time. Conclusion: Contrary to existing reports, our data collected in 25 patients diagnosed with GI-GVHD after allogeneic hematopoietic stem cell transplantation suggest the presence of three different courses (classical, nonclassical migratory and nonclassical persistent) of this disorder. Awareness of this knowledge enables more accurate risk stratification.

  12. 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.

  13. 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 ...

  14. Extracorporeal photopheresis performed on the CELLEX® compared with the UVAR-XTS® instrument is more efficient and better tolerated in children with steroid-refractory graft-versus-host disease.

    Science.gov (United States)

    Kapadia, Ekta; Wong, Edward; Perez-Albuerne, Evelio; Jacobsohn, David

    2015-08-01

    Extracorporeal photopheresis (ECP) is an effective therapy in children with refractory graft-versus-host disease (GVHD). The two most frequently used instruments are UVAR-XTS® and CELLEX®. We performed a retrospective chart review of ten patients who underwent ECP with both UVAR-XTS® and CELLEX® instruments for steroid-refractory acute or chronic GVHD to compare instrument run times, percentages of cells treated, and complication rates. We found that compared to the UVAR-XTS® instrument, use of the CELLEX® instrument resulted in shorter run times, increased percentage of mononuclear cells treated, reduced incidence of line occlusions requiring TPA treatment, and decreased incidence of patient-related complications.

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

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    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.

  16. Do FY antigens act as minor histocompatibility antigens in the graft-versus-host disease paradigm after human leukocyte antigen-identical sibling hematopoietic stem cell transplantation?

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    Sellami, Mohamed Hichem; Chaabane, Manel; Kaabi, Houda; Torjemane, Lamia; Ladeb, Saloua; Ben Othmane, Tarek; Hmida, Slama

    2012-03-01

    FY antigens are candidate minor histocompatibility antigens relevant to renal allograft rejection, but no data have been reported about their role in graft-versus-host disease (GVHD) incidence after human leukocyte antigen (HLA)-identical siblings hematopoietic stem cell transplantation (HSCT). The aim of this study was to examine the effect of donor/recipient disparity at FY antigens on the incidence of GVHD in Tunisian patients receiving an HLA-identical HSCT. This work enrolled 105 Tunisian pairs of recipients and their HLA-identical sibling donors of HSCs. FY genotyping was performed with the polymerase chain reaction-sequence-specific primer method and donor/recipient disparity for these antigens was analyzed at two levels: incompatibility and nonidentity. The case-control analyses showed no significant correlation between FY disparity and the incidence of either acute or chronic GVHD. Sample size calculation showed that 572 cases and 1716 controls would be necessary to be able to detect a significant association with 80% power and two-sided type I error level of 5% (α=0.05). The lack of association in the studied cohort may be explained by the low immunogenicity of FY antigens in HSCT context, compared with other antigens such as HA-1 and CD31.

  17. Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research.

    Science.gov (United States)

    Arai, Sally; Arora, Mukta; Wang, Tao; Spellman, Stephen R; He, Wensheng; Couriel, Daniel R; Urbano-Ispizua, Alvaro; Cutler, Corey S; Bacigalupo, Andrea A; Battiwalla, Minoo; Flowers, Mary E; Juckett, Mark B; Lee, Stephanie J; Loren, Alison W; Klumpp, Thomas R; Prockup, Susan E; Ringdén, Olle T H; Savani, Bipin N; Socié, Gérard; Schultz, Kirk R; Spitzer, Thomas; Teshima, Takanori; Bredeson, Christopher N; Jacobsohn, David A; Hayashi, Robert J; Drobyski, William R; Frangoul, Haydar A; Akpek, Görgün; Ho, Vincent T; Lewis, Victor A; Gale, Robert Peter; Koreth, John; Chao, Nelson J; Aljurf, Mahmoud D; Cooper, Brenda W; Laughlin, Mary J; Hsu, Jack W; Hematti, Peiman; Verdonck, Leo F; Solh, Melhelm M; Norkin, Maxim; Reddy, Vijay; Martino, Rodrigo; Gadalla, Shahinaz; Goldberg, Jenna D; McCarthy, Philip L; Pérez-Simón, José A; Khera, Nandita; Lewis, Ian D; Atsuta, Yoshiko; Olsson, Richard F; Saber, Wael; Waller, Edmund K; Blaise, Didier; Pidala, Joseph A; Martin, Paul J; Satwani, Prakash; Bornhäuser, Martin; Inamoto, Yoshihiro; Weisdorf, Daniel J; Horowitz, Mary M; Pavletic, Steven Z

    2015-02-01

    Although transplant practices have changed over the last decades, no information is available on trends in incidence and outcome of chronic graft-versus-host disease (cGVHD) over time. This study used the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe time trends for cGVHD incidence, nonrelapse mortality, and risk factors for cGVHD. The 12-year period was divided into 3 intervals, 1995 to 1999, 2000 to 2003, and 2004 to 2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. Multivariate analysis showed an increased incidence of cGVHD in more recent years (odds ratio = 1.19, P < .0001), and this trend was still seen when adjusting for donor type, graft type, or conditioning intensity. In patients with cGVHD, nonrelapse mortality has decreased over time, but at 5 years there were no significant differences among different time periods. Risk factors for cGVHD were in line with previous studies. This is the first comprehensive characterization of the trends in cGVHD incidence and underscores the mounting need for addressing this major late complication of transplantation in future research.

  18. Kinetics of lymphocyte reconstitution after allogeneic bone marrow transplantation: markers of graft-versus-host disease.

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    Zinöcker, Severin; Sviland, Lisbet; Dressel, Ralf; Rolstad, Bent

    2011-07-01

    GVHD causes extensive morbidity and mortality in patients who receive alloHCT. Predictive and reliable markers for GVHD are currently lacking but required to improve the safety and accessibility of alloHCT. We present an experimental rat model of myeloablative total body irradiation and fully mismatched major and minor histoincompatible, T cell-depleted BMT, followed by delayed infusion of donor lymphocytes. This treatment, in contrast to marrow transplantation alone, resulted in severe aGVHD and 100% lethality within 2-6 weeks. We investigated the reconstitution kinetics and phenotypes of donor leukocyte subpopulations as well as the histopathology of selected organs that may correlate with GVHD, with the goal to find potential disease-related markers. We observed histological changes mainly confined to the skin, with degenerative changes in the basal layer. LNs and spleen showed deranged architecture with markedly increased accumulation of lymphocytes, whereas the gut, liver, and lungs appeared normal. Of the lymphocyte markers tested, donor-derived CD62L(+) T cells were markedly decreased in animals suffering from GVHD. Furthermore, we observed peripheral depletion of CD4(+)CD25(hi)FoxP3(+) T(reg), which was in contrast to controls. The relative frequency of these lymphocyte subpopulations in blood may therefore serve as accessible cellular markers of aGVHD. We propose that the animal model presented is instructive for the identification of clinically relevant markers of GVHD, which could improve disease diagnosis and management in alloHCT.

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

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    Satoshi Nishiwaki

    Full Text Available 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.

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

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    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

  1. 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.

  2. Ferritin concentrations correlate to outcome of hematopoietic stem cell transplantation but do not serve as biomarker of graft-versus-host disease.

    Science.gov (United States)

    Großekatthöfer, M; Güclü, E D; Lawitschka, A; Matthes-Martin, S; Mann, G; Minkov, M; Peters, C; Seidel, M G

    2013-08-01

    Clinical presentation and laboratory data are often too unspecific to distinguish the onset or activity of graft-versus-host disease (GvHD) from infections or toxicity. Antigen-presenting cells such as monocytes/macrophages and dendritic cells are involved in GvHD pathogenesis after allogeneic hematopoietic stem cell transplantation (HSCT). To test whether ferritin, an iron storage marker and macrophage activation-linked acute-phase protein, represents a candidate biomarker for acute or chronic GvHD in pediatric HSCT, we retrospectively evaluated a 2-year follow-up data from 131 eligible consecutive patients with different malignant and nonmalignant diseases who underwent allogeneic HSCT. Thirteen patients (10 %) suffered from acute GvHD II-IV°, 18 (14 %) had limited, and 14 (11 %) had extensive chronic GvHD. In extension of previous studies in adults investigating pre-transplant ferritin, our data show that post-HSCT hyperferritinemia (analyzed on days 0, +30, +60, +100, +180, +360, and +720) was significantly associated with decreased long-term survival (p children and adolescents. Increased ferritin concentrations were associated with number and timing of red blood cell transfusions and toxic or infectious multi-organ failure but did not show significant differences between patients without GvHD and with acute grades II-IV, limited, or extensive chronic GvHD. Thus, our data do not identify ferritin as specifically GvHD-linked biomarker; however, they support the prognostic value of ferritin levels for outcome after HSCT in children.

  3. Incidence, risk factors, and outcome of cytomegalovirus viremia and gastroenteritis in patients with gastrointestinal graft-versus-host disease.

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    Bhutani, Divaya; Dyson, Gregory; Manasa, Richard; Deol, Abhinav; Ratanatharathorn, Voravit; Ayash, Lois; Abidi, Muneer; Lum, Lawrence G; Al-Kadhimi, Zaid; Uberti, Joseph P

    2015-01-01

    Gastrointestinal (GI) graft-versus-host disease (GVHD) is one of the most common causes of morbidity and mortality after allogeneic stem cell transplantation. In addition, cytomegalovirus (CMV) infection of the gastrointestinal tract can complicate the post-transplantation course of these patients and it can be difficult to differentiate the 2 diagnoses given that they can present with similar symptoms. We retrospectively analyzed 252 patients who were diagnosed with GI GVHD to evaluate the incidence, risk factors, and outcomes of CMV viremia and CMV gastroenteritis in these patients. The median age at the time of transplantation was 51 years, 35% were related donor transplantations, and 65% were unrelated donor transplantations. A total of 114 (45%) patients developed CMV viremia at a median of 34 days (range, 14 to 236 days) after transplantation. Only recipient CMV IgG serostatus was significantly associated with development of CMV viremia (P gastroenteritis; 2 patients had evidence of CMV gastroenteritis and GVHD on the first biopsy and 29 on the second biopsy. Median time to development of CMV gastroenteritis was 52 days (range, 19 to 236 days) after transplantation. Using death as a competing risk, the cumulative incidence of CMV gastroenteritis at 1 year was 16.4%. The incidence of CMV gastroenteritis in relation to the donor/recipient serostatus was as follows: D+/R+, 22%; D-/R+, 31%; D+/R-, 12%; and D-/R-, 0. Median follow-up time for the 252 patients was 35.4 (95% CI 23.8 to 44.8) months. The estimated overall survival rate at 1 and 2 years was .45 (95% confidence interval [CI], .39 to .52) and .39 (95% CI, .33 to .46), respectively. Of the examined variables, those related to the overall survival were maximal clinical GVHD grade (P gastroenteritis (P = .008). Development of CMV viremia was not associated with increased mortality. In conclusion, CMV gastroenteritis is common complication in patients with GI GVHD and can adversely affect the prognosis.

  4. Comparison of cyclosporine and tacrolimus combined with mycophenolate mofetil in prophylaxis for graft-versus-host disease after reduced-intensity umbilical cord blood transplantation.

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    Miyamoto, Toshihiro; Takashima, Shuichiro; Kato, Koji; Takase, Ken; Yoshimoto, Goichi; Yoshida, Shuro; Henzan, Hideho; Osaki, Koichi; Kamimura, Tomohiko; Iwasaki, Hiromi; Eto, Tetsuya; Teshima, Takanori; Nagafuji, Koji; Akashi, Koichi

    2017-01-01

    Umbilical cord blood transplantation with a reduced-intensity conditioning regimen (RIC-UCBT) is used increasingly in patients who have comorbid organ functions and lack human leukocyte antigen-identical donors. We compared the outcomes in 35 patients who received mycophenolate mofetil plus cyclosporine (MMF/CSP, n = 17) or MMF plus tacrolimus (MMF/TAC, n = 18) for graft-versus-host disease (GVHD) prophylaxis after RIC-UCBT. Cumulative incidence of neutrophil engraftment was 94 and 89 % in MMF/CSP and MMF/TAC groups, respectively (p = 0.34). The incidence of pre-engraftment immune reaction did not differ between the MMF/CSP (41 %) and MMF/TAC (39 %, p = 1.00) groups; however, patients in the MMF/TAC group tended to have a lower incidence of grade II-IV acute GVHD than those in MMF/CSP group (28 vs 53 %, p = 0.11). Overall survival (OS) at 1 year was 43 and 60 % in MMF/CSP and MMF/TAC groups, respectively (p = 0.39). Progression-free survival, non-relapse mortality, and relapse rate were comparable between the two groups (p = 0.76, 0.59, and 0.88, respectively). In multivariate analyses, MMF/TAC GVHD prophylaxis was closely associated with improved OS, but not with incidence of engraftment and acute GVHD. These results suggest that more intensive GVHD prophylaxis with MMF/TAC decreased acute GVHD without affecting other clinical outcomes, resulting in improved OS after RIC-UCBT.

  5. Isolation of human CD4/CD8 double-positive, graft-versus-host disease-protective, minor histocompatibility antigen-specific regulatory T cells and of a novel HLA-DR7-restricted HY-specific CD4 clone.

    Science.gov (United States)

    Eljaafari, Assia; Yuruker, Ozel; Ferrand, Christophe; Farre, Annie; Addey, Caroline; Tartelin, Marie-Laure; Thomas, Xavier; Tiberghien, Pierre; Simpson, Elizabeth; Rigal, Dominique; Scott, Diane

    2013-01-01

    Minor histocompatibility (H) Ags are classically described as self-peptides derived from intracellular proteins that are expressed at the cell surface by MHC class I and class II molecules and that induce T cell alloresponses. We have isolated three different T cell populations from a skin biopsy of a patient suffering from acute graft-versus-host disease following sex-mismatched HLA-identical bone marrow transplantation. The first population was: 1) CD4(+)/CD8(+) double-positive; 2) specific for an HLA class I-restricted autosomal Ag; 3) expressed a Tr1 profile with high levels of IL-10, but low IL-2 and IFN-γ; and 4) exerted regulatory function in the presence of recipient APCs. The second was CD8 positive, specific for an HLA class I-restricted autosomally encoded minor H Ag, but was only weakly cytotoxic. The third was CD4 single positive, specific for an HLA-DR7-restricted HY epitope and exerted both proliferative and cytotoxic functions. Identification of the peptide recognized by these latter cells revealed a new human HY epitope, TGKIINFIKFDTGNL, encoded by RPS4Y and restricted by HLA-DR7. In this paper, we show human CD4/CD8 double-positive, acute graft-versus-host disease-protective, minor H Ag-specific regulatory T cells and identify a novel HLA-DR7/ HY T cell epitope, encoded by RPS4Y, a potential new therapeutic target.

  6. Alloreactivity of Virus-Specific T Cells: Possible Implication of Graft-Versus-Host Disease and Graft-Versus-Leukemia Effects

    Science.gov (United States)

    Fuji, Shigeo; Kapp, Markus; Einsele, Hermann

    2013-01-01

    Immune reconstitution of functional virus-specific T cells after allogeneic hematopoietic stem cell transplantation (HSCT) has been intensively investigated. However, the possible role of crossreactivity of these virus-specific T cells against allogeneic targets is still unclear. Theoretically, as in the field of organ transplantation, virus-specific T cells possess crossreactivity potential after allogeneic HSCT. Such crossreactivity is assumed to play a role in graft-versus-host disease and graft-versus-leukemia effects. In this article, we aim to give a comprehensive overview of current understanding about crossreactivity of virus-specific T cells. PMID:24133497

  7. Role of CD8 Regulatory T Cells versus Tc1 and Tc17 Cells in the Development of Human Graft-versus-Host Disease

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    Gutiérrez-Hoya, Adriana; López-Santiago, Rubén; Vela-Ojeda, Jorge; Montiel-Cervantes, Laura; Rodríguez-Cortés, Octavio; Rosales-García, Víctor; Flores-Mejía, Raúl; Sandoval-Borrego, Daniela

    2017-01-01

    CD8+ T cells that secrete proinflammatory cytokines play a central role in exacerbation of inflammation; however, a new subpopulation of CD8 regulatory T cells has recently been characterized. This study analyzes the prominent role of these different subpopulations in the development of graft-versus-host disease (GVHD). Samples from 8 healthy donors mobilized with Filgrastim® (G-CSF) and 18 patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) were evaluated by flow cytometry. Mobilization induced an increase in Tc1 (p < 0.01), Th1 (p < 0.001), Tc17 (p < 0.05), and CD8+IL-10+ cells (p < 0.05), showing that G-CSF induces both pro- and anti-inflammatory profiles. Donor-patient correlation revealed a trend (p = 0.06) toward the development of GVHD in patients who receive a high percentage of Tc1 cells. Patients with acute GVHD (aGVHD), either active or controlled, and patients without GVHD were evaluated; patients with active aGVHD had a higher percentage of Tc1 (p < 0.01) and Tc17 (p < 0.05) cells, as opposed to patients without GVHD in whom a higher percentage of CD8 Treg cells (p < 0.01) was found. These findings indicate that the increase in Tc1 and Tc17 cells is associated with GVHD development, while regulatory CD8 T cells might have a protective role in this disease. These tests can be used to monitor and control GVHD. PMID:28164135

  8. Role of CD8 Regulatory T Cells versus Tc1 and Tc17 Cells in the Development of Human Graft-versus-Host Disease

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    Adriana Gutiérrez-Hoya

    2017-01-01

    Full Text Available CD8+ T cells that secrete proinflammatory cytokines play a central role in exacerbation of inflammation; however, a new subpopulation of CD8 regulatory T cells has recently been characterized. This study analyzes the prominent role of these different subpopulations in the development of graft-versus-host disease (GVHD. Samples from 8 healthy donors mobilized with Filgrastim® (G-CSF and 18 patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT were evaluated by flow cytometry. Mobilization induced an increase in Tc1 (p<0.01, Th1 (p<0.001, Tc17 (p<0.05, and CD8+IL-10+ cells (p<0.05, showing that G-CSF induces both pro- and anti-inflammatory profiles. Donor-patient correlation revealed a trend (p=0.06 toward the development of GVHD in patients who receive a high percentage of Tc1 cells. Patients with acute GVHD (aGVHD, either active or controlled, and patients without GVHD were evaluated; patients with active aGVHD had a higher percentage of Tc1 (p<0.01 and Tc17 (p<0.05 cells, as opposed to patients without GVHD in whom a higher percentage of CD8 Treg cells (p<0.01 was found. These findings indicate that the increase in Tc1 and Tc17 cells is associated with GVHD development, while regulatory CD8 T cells might have a protective role in this disease. These tests can be used to monitor and control GVHD.

  9. 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.

  10. Skin manifestations and treatment of graft-versus-host disease%移植物抗宿主病的皮肤表现及治疗进展

    Institute of Scientific and Technical Information of China (English)

    惠云; 胡文星; 陈军; 刘娟; 邓德权; 孔庆涛; 桑红

    2015-01-01

    Graft-versus-host disease (GVHD) is an autoimmune disease caused by graft-versus-host reaction,occurring most frequently in patients receiving allogeneic hematopoietic stem cell transplantation and occasionally in patients receiving organ transplantation.It often involves multiple organ systems,of which,skin and mucous membranes are the most frequently affected system with various clinical manifestations.Acute GVHD often appears as measles-or scarlet fever-like skin rashes with severe systemic symptoms such as fever and poor appetite,and may rapidly progress into toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS) in a few days.Lichen planus and sclerodermoid lesions are the most common clinical manifestations of chronic GVHD.With further understanding of this disease in recent years,some new manifestations have been observed,such as psoriasis-and atopic dermatitis-like skin lesions,as well as nail changes in some cases.It is especially important to select appropriate treatment protocols according to clinical manifestations.Glucocorticoids combined with immunosuppressive agents are a conventional treatment for GVHD,and innovative treatments have emerged with the development of therapeutics.%移植物抗宿主病是由移植物抗宿主反应所引起的一种免疫性疾病,好发于同种异体造血干细胞移植的患者,少数发生于器官移植后的患者.常累及全身多个器官,皮肤黏膜最常受累且临床表现多样.急性移植物抗宿主病常出现麻疹样及猩红热样的皮肤改变,发热、食欲不振等全身不适症状较重,且皮疹进展较快,数日内可出现中毒性表皮坏死松解症或Stevens-Johnson综合征等皮肤改变,而扁平苔藓及硬皮病样的皮损为慢性移植物抗宿主病最常见的皮肤表现.随着近年来对该病的认识,发现了较多新症状,如银屑病样、特应性皮炎样的皮疹,部分还会出现甲改变等症状.针对不同的临床表现选择合适的治疗

  11. Comparison of Subcutaneous versus Intravenous Alemtuzumab for Graft-versus-Host Disease Prophylaxis with Fludarabine/Melphalan-Based Conditioning in Matched Unrelated Donor Allogeneic Stem Cell Transplantation.

    Science.gov (United States)

    Patel, Khilna; Parmar, Sapna; Shah, Shreya; Shore, Tsiporah; Gergis, Usama; Mayer, Sebastian; van Besien, Koen

    2016-03-01

    The objective of this study was to compare infusion-related reactions and outcomes of using subcutaneous (subQ) alemtuzumab versus intravenous (i.v.) alemtuzumab as graft-versus-host disease (GVHD) prophylaxis for matched unrelated donor stem cell transplantations. Outcomes include incidence of cytomegalovirus (CMV)/Epstein-Barr (EBV) viremia, development of CMV disease or post-transplantation lymphoproliferative disorder, fatal infections, acute and chronic GVHD, time to engraftment, relapse rate, and survival. We conducted a retrospective study of all adult matched unrelated donor stem cell transplantations patients who received fludarabine/melphalan with subQ or i.v. alemtuzumab in combination with tacrolimus as part of their conditioning for unrelated donor transplantation at New York-Presbyterian/Weill Cornell Medical Center from January 1, 2012 to March 21, 2014. Alemtuzumab was administered at a total cumulative dose of 100 mg (divided over days -7 to -3). Forty-six patients received an unrelated donor stem cell transplantation with fludarabine/melphalan and either subQ (n = 26) or i.v. (n = 20) alemtuzumab in combination with tacrolimus. Within the evaluable population, 130 subQ and 100 i.v. alemtuzumab doses were administered. For the primary outcome, ≥grade 2 infusion-related reactions occurred in 11 (8%) versus 25 (25%) infusions in the subQ and i.v. cohorts, respectively (P = .001). Overall, 12 injections (9%) in the subQ arm versus 26 infusions (26%) in the i.v. arm experienced an infusion-related reaction of any grade (P = .001). There were no significant differences between the subQ and i.v. arms in rates of reactivation of CMV/EBV, development of CMV disease or post-transplantation lymphoproliferative disorder, fatal infections, acute and chronic GVHD, relapse, or survival. Subcutaneous administration of alemtuzumab for GVHD prophylaxis was associated with fewer infusion-related reactions compared with i.v. administration in the SCT setting

  12. Cannabidiol for the Prevention of Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study.

    Science.gov (United States)

    Yeshurun, Moshe; Shpilberg, Ofer; Herscovici, Corina; Shargian, Liat; Dreyer, Juliet; Peck, Anat; Israeli, Moshe; Levy-Assaraf, Maly; Gruenewald, Tsipora; Mechoulam, Raphael; Raanani, Pia; Ram, Ron

    2015-10-01

    Graft-versus-host-disease (GVHD) is a major obstacle to successful allogeneic hematopoietic cell transplantation (alloHCT). Cannabidiol (CBD), a nonpsychotropic ingredient of Cannabis sativa, possesses potent anti-inflammatory and immunosuppressive properties. We hypothesized that CBD may decrease GVHD incidence and severity after alloHCT. We conducted a phase II study. GVHD prophylaxis consisted of cyclosporine and a short course of methotrexate. Patients transplanted from an unrelated donor were given low-dose anti-T cell globulin. CBD 300 mg/day was given orally starting 7 days before transplantation until day 30. Forty-eight consecutive adult patients undergoing alloHCT were enrolled. Thirty-eight patients (79%) had acute leukemia or myelodysplastic syndrome and 35 patients (73%) were given myeloablative conditioning. The donor was either an HLA-identical sibling (n = 28), a 10/10 matched unrelated donor (n = 16), or a 1-antigen-mismatched unrelated donor (n = 4). The median follow-up was 16 months (range, 7 to 23). No grades 3 to 4 toxicities were attributed to CBD. None of the patients developed acute GVHD while consuming CBD. In an intention-to-treat analysis, we found that the cumulative incidence rates of grades II to IV and grades III to IV acute GVHD by day 100 were 12.1% and 5%, respectively. Compared with 101 historical control subjects given standard GVHD prophylaxis, the hazard ratio of developing grades II to IV acute GVHD among subjects treated with CBD plus standard GVHD prophylaxis was .3 (P = .0002). Rates of nonrelapse mortality at 100 days and at 1 year after transplantation were 8.6% and 13.4%, respectively. Among patients surviving more than 100 days, the cumulative incidences of moderate-to-severe chronic GVHD at 12 and 18 months were 20% and 33%, respectively. The combination of CBD with standard GVHD prophylaxis is a safe and promising strategy to reduce the incidence of acute GVHD. A randomized double-blind controlled study is warranted

  13. 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

    approaches used in the diagnosis and treatment of cGVHD in a group of health-care providers specialized in the oral care of oncology patients. The secondary objective was to assess the level of implementation of the National Institutes of Health (NIH) guidelines for cGVHD patients. METHODS: One hundred...... twenty questionnaires were sent to the members of the Oral Care Study Group (OCSG) of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). The questionnaire included 50 questions about the responder's demographics, level of exposure to c......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...

  14. Graft-versus-Host Disease-Like Pattern in Mycophenolate Mofetil Related Colon Mucosal Injury: Role of FISH in Establishing the Diagnosis

    Directory of Open Access Journals (Sweden)

    Kathryn C. Behling

    2009-12-01

    Full Text Available Mycophenolate mofetil (CellCept®, a commonly used immunosuppressive drug in solid organ transplantation, has recently been shown to cause graft-versus-host disease (GVHD-like changes in the gastrointestinal tract. On rare occasions, true GVHD has also been documented in the gastrointestinal tract of solid organ transplant patients. Because the treatment for these two entities is different, i.e. removal of the offending agent versus the administration of steroids, proper identification of the cause is imperative. We present a case of mycophenolate mofetil colitis mimicking grade I GVHD of the gut. In our study, we used fluorescence in situ hybridization for the Y chromosome to document the lack of male donor lymphocytes in the female recipient colon biopsy. We suggest that molecular techniques including fluorescence in situ hybridization could be used to discriminate between MMF-related colitis and true GVHD in order to help guide therapy.

  15. Association between acute graft versus host disease and lung injury after allogenic hematopoietic stem cell transplantation%异基因造血干细胞移植后急性移植物抗宿主病与肺损伤的关系

    Institute of Scientific and Technical Information of China (English)

    刘启发; 罗晓丹; 范志平; 宁涓; 徐丹; 孙竞; 张钰; 徐兵; 魏永强

    2009-01-01

    Objective To investigate the characteristics of chest hiigh-resolution computed tomography(HRCT)and pathogenesis of acute graft versus host disease(aGVHD)-induced lung injury after allogenic hematopoietic stem cell transplantation(allo-HSCT).Methods Chest HRCT was performed in 47 patients with aGVHD of grade Ⅱ-Ⅳ after allo-HSCT.Twenty-four of the patients underwent different treatment regimens against aGVHD.Before the treatment peripheral blood samples were collected to detect the serum interferon-γ(IFN-γ)and tumor necrosis factor-α(TNF-α).Transbronchial biopsy was performed in 4 patients that failed to recover completely after treatment.Pulmonary function was examined in the patients who survived more than 6 months in every 3 months.Resuits Twenty of tlle 47 patients showed abnormal images by chest HRCT and 17 of the 20 patients were suspected to be witll aGVHD-induced lung iniury.The HRCT images were characterized by diffused interstitial infiltrate in 5 cases.diflused intemtitial and alveolar infiltrate in 7 cases.and diffused interstitial and segmental lobar alveolar infiltrate in 5 cases.Nine cases had bilateral pleural effusion and hydropericardium,including 4 eases accompanied by myocardial hypertrophy.The levels of serum IFN-γ and TNF-α of the patients with lung injury were(6.9±1.8)μg/L and(400±102)μg/L respectively,both not significantly different from those of the patients without lung injury[(6.3±1.2)μg/L and(428±83)μg/L respectively,P=0.202,0.306].The histopathology of the lung tissue was characterized by disorganization,epithelial cell damage,interstitial fibroplasias,and interstitial T lymphocyte or macrophage infiltrate.The effective rate of treatment for aGVHD-induced lung iniury was positively correlated witll that for aGVHD(r=0.771,P=0.01).Eleven of the 24 patients who survived more than 6 months had abnormal pulmonary function.including 7 out of tlle 9 patients with aGVHD-induced lung injury and 4 out the 15 patients without a

  16. 肠道急性移植物抗宿主病黏膜通透性与肠黏膜病理改变的相关性研究%Study on Correlation Between Intestinal Permeability and Morphological Change After Intestinal Acute Graft- versus -host Disease In Mice

    Institute of Scientific and Technical Information of China (English)

    蔡芳芳; 庄强; 朱融和; 梁彬; 俞康; 江松福

    2012-01-01

    目的 研究肠道急性移植物抗宿主病( aGVHD)黏膜通透性变化与肠黏膜病理改变以及二者之间的关系.方法 32只BALB/C小鼠随机分为4组:单纯照射组(对照组)和3个时段aGVHD组(aGVHD后7、11和15天组),各8只.TBI剂量8.0Gy,剂量率1.0Gy/min.高效液相色谱-蒸发光散射检测器分析(HPLC - ELSD)检测尿液标本中乳果糖(lactulose,L)和甘露醇( mannitol,M)的排出率比值(L/M),评价各组小鼠的肠道通透性;收集空肠组织标本做病理评估.结果 肠道aGVHD后7、11和15天组L/M比值均明显高于对照组(P<0.05),分别为0.509±0.353,0.717±0.012,0.762±0.014,0.291±0.053.aGVHD 后7、11和15天组aGVHD严重程度评分较对照组显著增加(P<0.05),分别为0.810±0.259,1.940±0.176,2.750±0.267,0.000±0.000.各组L/M与肠道aGVHD严重程度水平呈显著相关(r=0.903,P<0.01).结论 aGVHD后随着时间延长肠黏膜通透性逐渐增加且肠道aGVHD严重程度评分逐渐增高;aGVHD后肠道通透性与肠道aGVHD严重程度呈显著相关,尿液L/M可作为肠道aGVHD严重程度的无创评估方法.%To investigate the change of the intestinal permeability and the morphology, and study the relationship between them after intestinal acute graft - versus - host disease(aGVHD) in mice. Methods BALB/C mice were randomly divided into 4 groups; 3 aGVHD groups (7 day, 11 day and 15 day after aGVHD) and the control group, and each group had 8 mice. Total body irradiation was: dosage 8.0Gy, doBe rate 1.0Gy/min. High -performance liquid chromatography evaporative light -scattering detector ( HPLC-ELSD) by using two -sugar absorption test for evaluating the intestinal permeability was developed. Urine mannitol/lactulose (L/M) excretion ratios were measured, Jejunum tissues were collected, and the degree of pathology of aGVHD was analysed. Results The urine L/M ratio was significantly increased in aGVHD groups (0. 509 ?. 353,0.717 ?.012,0.762 ?.014) than the control (0. 291

  17. TLR5激动剂鞭毛蛋白预防小鼠异基因造血干细胞移植后急性移植物抗宿主病的初步研究%Prophylactic Effect of TLR5 Agonist Flagellin on Acute Graft versus Host Disease after Allogeneic Hematopietic Stem Cell Transplantation and Its Mechanism

    Institute of Scientific and Technical Information of China (English)

    龚旭东; 马梁明; 朱镭; 郭慧敏; 任连生; 任瑞瑞; 张华屏; 卫芬; 牛燕燕

    2012-01-01

    本研究旨在探讨Toll样受体(TLR5)激动剂鞭毛蛋白(flagellin)对小鼠异基因造血干细胞移植(allo-HSCT)后急性移植物抗宿主病(aGVHD)的预防作用和可能作用机制.用主要组织相容性抗原完全不合的纯种近交系小鼠[供体鼠:雄性C57BL/6鼠;受体鼠:雌性BALB/c鼠]建立allo-HSCT的aGVHD动物模型.受鼠随机分为3组:鞭毛蛋白组,于移植前后2次尾静脉注射高纯度(纯度≥95%)的鞭毛蛋白50μl[5μg/(只·次)]预防aGVHD;单纯移植组,移植后仅给予等容量PBS;单纯照射组,仅照射不移植,亦给予等容量PBS.观察比较移植后aGVHD的表现.结果表明,移植小鼠均出现典型的aGVHD症状,单纯移植组小鼠死亡高峰在移植后第4-5天.用鞭毛蛋白作为aGVHD预防方案小鼠的aGVHD症状明显减轻,平均生存时间较单纯移植组显著延长(P<0.05).三组小鼠移植前外周血白细胞数比较均无显著性差异,但在照射后第14、21天,鞭毛蛋白组较单纯移植组外周血白细胞数显著性升高(P<0.05).鞭毛蛋白预防组移植小鼠aGVHD病理表现较单纯移植组明显减轻.流式细胞仪检测鞭毛蛋白组与单纯移植组移植前后不同时间点Treg细胞/CD4+T细胞含量结果也表明,移植后2-4周鞭毛蛋白组小鼠的Treg细胞数较单纯移植组明显增加(P<0.05).结论:鞭毛蛋白对小鼠allo-HSCT后发生aGVHD有预防作用,能减轻其症状和病理损害程度,显著延长其平均生存时间,其机制有可能通过增加移植后小鼠的Treg细胞含量,从而有效改善并减轻移植后小鼠aGVHD.%This study was aimed to investigate the prophylactic effect of Toll like receptor (TLR)5 agonist flagellin on acute graft versus host disease (aGVHD) after allogeneic hematopietic stem cell transplantation (allo-HSCT) and its possible mechemism. The animal model with allo-HSCT aGVHD was established by using purebreed mice (male mouse C57BL/6 as donor, femal mouse BALB/c as recipient

  18. 硼替佐米对小鼠急性移植物抗宿主病作用及其机制研究%Effect of bortezomib on acute graft-versus-host disease in mice model and its mechanism

    Institute of Scientific and Technical Information of China (English)

    李振宇; 吴圣豪; 徐开林; 鹿群先; 潘秀英; 孙海英

    2009-01-01

    目的 探讨硼替佐米(Bortezomib)对小鼠急性移植物抗宿主病(aGVHD)的预防作用及其机制.方法 建立小鼠aGVHD动物模型,将小鼠随机分3组,A:移植对照组;B:移植+早期输注硼替佐米组;C:移植+延期输注硼替佐米组.比较各组受鼠aGVHD临床及病理改变、生存率,流式细胞术检测移植后供鼠来源细胞(H-2b+)率.体外建立单向混合淋巴细胞培养(MLC)体系,植物血凝素刺激后,分别用0、2、4、8 nmol/L的硼替佐米作用于反应体系,在不同的时间点收集细胞,采用CCK-8法检测细胞活性,流式细胞术检测细胞凋亡率,ELISA法检测培养上清IL-2、IFN-γ、TNF-α含量.结果 移植对照组小鼠出现典型的aGVHD症状,3周内死于aGVHD,平均存活时间为16.1 d,移植加早期输注硼替佐米组小鼠aGVHD症状明显减轻,平均生存时间较移植对照组显著延长,60 d时生存率为70%,高于其他组(P<0.05),60 d时H-2b+细胞的百分率为(98.1±1.1)%.移植加延期输注硼替佐米组小鼠aGVHD症状明显较移植对照组加重,平均存活时间较A组缩短.硼替佐米对MLC体系细胞活性的抑制作用表现为剂量依赖关系,8 nmol/L硼替佐米作用24 h后细胞活性抑制率为(41.4±6.0)%;硼替佐米作用于细胞后12、24、36 h的凋亡率逐渐增加,8 nmol/L硼替佐米作用36 h后细胞凋亡率为(62.8±7.0)%;硼替佐米作用24 h后上清液中IL-2、IFN-γ、TNF-α浓度减少.结论 移植后早期输注硼替佐米可显著减轻小鼠异基因移植后的aGVHD、提高生存率,同时不影响骨髓植入;而移植后延期给予硼替佐米则加重aGVHD,导致受鼠死亡率增加.其机制可能是通过抑制淋巴细胞活性,诱导淋巴细胞凋亡,抑制同种反应性细胞分泌IL-2、IFN-γ、TNF-α.%Objective To investigate the effect of bortezomib on prophylaxis of acute graft-versus-host disease(aGVHD) after mouse allogeneic-bone marrow transplantation (allo-BMT) and its mechanism. Methods

  19. Preliminary study on IL-7Rα intervening acute graft-versus-host disease after mice allogeneic bone marrow transplantation%白细胞介素7受体α干预小鼠异基因骨髓移植后急性移植物抗宿主病的初步研究

    Institute of Scientific and Technical Information of China (English)

    卫芬; 马梁明; 龚旭东; 任连生; 朱镭; 郭慧敏; 张华屏

    2013-01-01

    Objective To establish a mouse model of acute graft-versus-host disease (aGVHD) after allogeneic bone marrow transplantation,and using exogenous interleukin-7 receptor alpha (IL-7Rα) intervene mice aGVHD and analyse its possible mechanism.Methods The BALB/C (H-2d) female mice as recipients were grouped by rat: the irradiation group (group A),irradiation transplantation group (group B) and IL-7Rα in the intervention group (group C),each 10.ALL mice were accepted 9 Gy60Co total body irradiation.1×107 bone marrow cells and 2×107 spleen cells of donor C57BL/6 (H-2b) via the tail vein were infused to recipient mice.The signs of the recipient mice,hematopoietic functional recovery and survival time of change,and pathology,chimerism and cytokine levels in checkwere observed.Results Mice in A group after irradiation were gradually death,in group B and group C mice after transplantation had typical aGVHD symptoms,but lighter signs and a longer survival time of Group C than in group B.WBC count in Group C was +14 d (4.53± 0.21) ×109/L,+21 d (3.63±0.06) ×109/L,+28 d (4.31±0.04) ×109/L,was hematopoietic recovery compared with Group B [+14 d (1.81±0.05) ×109/L,+21 d (1.32±0.04) ×109/L,+28 d (1.76±0.04) ×109/L],the difference was statistically significant (t =0.237,0.108,0.359,P < 0.05).The pathological results of liver,spleen,skin histopathology in group C were better than group B.Chimera implants,plasma IL-7 levels after transplant +7 d,concentration was significantly increased.IL-7 concentration in group C was +14 d (194.32±1.02) pg/ml,+21 d (131.63±1.54) pg/ml and in group B was +14 d (330.24±8.08) pg/ml,+21 d (184.09±2.05) pg/ml,the difference was statistically significant (t =1.590,1.285,P <0.05).Conclusion The stable aGVHD mouse model was established.In aGVHD early,plasma IL-7 levels were significantly increased.Exogenous IL-7Rαcan reduce the plasma IL-7 levels,thereby reducing the incidence of aGVHD after allogeneic bone marrow transplantation

  20. Evaluation of risk for graft-versus-host disease in children who receive less than the full doses of mini-dose methotrexate for graft-versus-host disease prophylaxis in allogeneic hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Sook Kyung Yum

    2013-11-01

    Full Text Available Purpose: The use of cyclosporine and mini-dose methotrexate (MTX is a common strategy for graftversus- host disease (GVHD prophylaxis in allogeneic transplants. We investigated whether patients who receive fewer than the planned MTX doses are at increased risk for GVHD. Methods: The study cohort included 103 patients who received allogeneic transplants at the Department of Pediatrics of The Catholic University of Korea College of Medicine, from January 2010 to December 2011. MTX was administered on days 1, 3, 6, and 11 after transplant at a dose of 5 mg/ m2 each. Within the cohort, 76 patients (74% received all 4 doses of MTX [MTX(4 group], while 27 patients (26% received 0&#8211;3 doses [MTX(0–3 group]. Results: Although there was no difference in neutrophil engraftment between the 2 groups, platelet engraftment was significantly faster in the MTX(4 group (median, 15 days, compared to the MTX(0&#8211; 3 group (median, 25 days; P =0.034. The incidence of grades II&#8211;IV acute GVHD was not different between the MTX(4 and MTX(0&#8211;3 groups (P =0.417. In the multivariate study, human leukocyte antigen mismatch was the most significant factor causing grades II&#8211;IV acute GVHD (P =0.002, followed by female donor to male recipient transplant (P =0.034. No difference was found between the MTX(4 and MTX (0&#8211;3 groups regarding grades III&#8211;IV acute GVHD, chronic GVHD, and disease-free survival. Conclusion: Our results indicate that deviations from the full dose schedule of MTX for GVHD prophylaxis do not lead to increased incidence of either acute or chronic GVHD.

  1. Correlation of lung abnormalities on high-resolution CT with clinical graft-versus-host disease after allogeneic versus autologous bone marrow transplantation in children

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    Merlini, Laura; Borzani, Irene Maria Olivia; Anooshiravani, Mehrak; Hanquinet, Sylviane [University of Geneva Children' s Hospital, Paediatric Radiology Unit, Geneva (Switzerland); Rochat, Isabelle [University of Geneva Children' s Hospital, Paediatric Pneumology Unit, Geneva (Switzerland); Ozsahin, Ayse Hulya [University of Geneva Children' s Hospital, Paediatric Oncology Unit, Geneva (Switzerland)

    2008-11-15

    Late-onset noninfectious pulmonary complications (LONIPCs) are life-threatening complications of bone marrow transplantation (BMT). Several pathological patterns are described in the literature with different prognoses, and with different relationships to graft-versus-host disease (GVHD). The role of high-resolution CT (HRCT) is not yet well established. To illustrate different patterns of LONIPCs on HRCT in allogeneic versus autologous BMT in order to investigate the correlation with chronic GVHD (cGVHD). A total of 67 HRCT scans were performed in 24 patients with noninfectious pulmonary disease at least 3 months after BMT (16 allogeneic, 8 autologous). Abnormality patterns and extension on HRCT images were correlated with the clinical outcome and with the severity of cGVHD. Of 24 patients, 9 showed LONIPCs (1 autologous, 8 allogeneic). There was a significant association between abnormalities on HRCT and severe cGVHD (P = 0.038), with no specific pattern. Prognosis seemed to be related to the severity of cGVHD and not to the extent of abnormalities on HRCT. The significant association between abnormalities on HRCT and severe GVHD suggests that LONIPCs can be a pulmonary manifestation of the disease. HRCT is a useful tool when combined with clinical data. (orig.)

  2. Transplantation of Donor-Origin Mouse Embryonic Stem Cell-Derived Thymic Epithelial Progenitors Prevents the Development of Chronic Graft-Versus-Host Disease in Mice.

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    Hu, Rong; Liu, Yalan; Su, Min; Song, Yinhong; Rood, Debra; Lai, Laijun

    2016-08-02

    : Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for many malignant and nonmalignant diseases. However, chronic graft-versus-host disease (cGVHD) remains a significant cause of late morbidity and mortality after allogeneic HSCT. cGVHD often manifests as autoimmune syndrome. Thymic epithelial cells (TECs) play a critical role in supporting negative selection and regulatory T-cell (Treg) generation. Studies have shown that damage in TECs is sufficient to induce cGVHD. We have previously reported that mouse embryonic stem cells (mESCs) can be selectively induced to generate thymic epithelial progenitors (TEPs) in vitro. When transplanted in vivo, mESC-TEPs further develop into TECs that support T-cell development. We show here that transplantation of donor-origin mESC-TEPs into cGVHD recipients induces immune tolerance to both donor and host antigens and prevents the development of cGVHD. This is associated with more TECs and Tregs. Our results suggest that embryonic stem cell-derived TEPs may offer a new tool to control cGVHD.

  3. Ex vivo expansion of regulatory T cells for clinical applications against graft-versus-host disease in allogeneic hematopoietic stem cell transplantation

    Institute of Scientific and Technical Information of China (English)

    ZHANG Lan-fang; XIA Chang-qing

    2013-01-01

    Objective To review the characteristics of regulatory T cells (Tregs) and ex vivo expansion of Tregs for treatment of graftversus-host disease (GVHD).Data sources The data used in this review were retrieved from PubMed (1970-2013).The terms "ex vivo expansion","regulatory T cell",and "graft-versus-host disease" were used for literature search.Study selection The publications about the characteristics of Tregs,ex vivo expansion of Tregs and clinical applications of Tregs against GVHD were identified,retrieved and reviewed.Results Tregs can be classified as natural Tregs (nTregs) and induced Tregs (iTregs).Both subsets share most Treg features.Given their immunosuppressive property,Tregs have been tested for their capability of preventing GVHD.The bottleneck of Treg therapy is the limited numbers of naturally existing Tregs.To solve this problem,ex vivo expansion of nTregs or iTregs has been executed.The initial data indicate Treg therapy is effective in reducing GVHD without compromising graft-versus-leukemia (GVL).Conclusion Ex vivo expansion of Tregs is a reliable way to prepare sufficient number of Tregs for management of GVHD.

  4. 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.

  5. The use of novel Therakos™ Cellex® for extracorporeal photopheresis in treatment of graft-versus-host disease in paediatric patients.

    Science.gov (United States)

    Rangarajan, Hemalatha G; Punzalan, Rowena C; Camitta, Bruce M; Talano, Julie-An M

    2013-11-01

    Extracorporeal photopheresis (ECP) is an established second line treatment option for graft-versus-host disease (GVHD) post-haematopoietic progenitor cell transplant. At our centre, the Therakos™ Cellex(®) has replaced the Therakos™ UVAR-XTS™ machine for ECP since 2009. We reviewed the records of 385 procedures using the Therakos™ Cellex(®) for safety and tolerability. Nine patients underwent ECP for GVHD. The median age was 13·5 years (range 3·7-24) and weight was 49·2 kg (range 18·5-86·3). The mean duration per procedure was 106 min (range 60-205). Fifteen (3·9%) procedures were cancelled and 10 (2·6%) were delayed, with central venous line (CVL) issues being the most frequent problem. With the use of prophylactic tissue plasminogen activator, fewer CVL-related occlusions were observed (4·7% vs. 2·3%). There was one episode of a CVL-associated thrombosis and one episode of delayed bleeding. There were four episodes of viral reactivation, four CVL-associated infections (1142 catheter days) and one episode of systemic inflammatory response syndrome. No patient experienced symptomatic hypotension. This is the first report outlining the safety and tolerability of the Therakos™ Cellex(®) device for ECP in children and young adults.

  6. Insights into the mechanism of FTY720 and compatibility with regulatory T cells for the inhibition of graft-versus-host disease (GVHD).

    Science.gov (United States)

    Taylor, Patricia A; Ehrhardt, Michael J; Lees, Christopher J; Tolar, Jakub; Weigel, Brenda J; Panoskaltsis-Mortari, Angela; Serody, Jonathan S; Brinkmann, Volker; Blazar, Bruce R

    2007-11-01

    The immunomodulator FTY720 (FTY) has been shown to be beneficial in experimental models of organ transplantation and autoimmunity. We show that FTY significantly inhibited but did not prevent graft-versus-host disease (GVHD) in lethally irradiated or nonirradiated allogeneic recipients. Although most studies implicate prevention of lymphocyte egress from lymphoid organs as the primary mechanism of action, our data indicate that FTY effects on the host are more likely to be responsible for GVHD inhibition. FTY reduced splenic CD11c+ cells by 50%, and similarly reduced CD4+ and CD8+ T-cell responder frequencies in the spleen early after transplantation. Imaging of GFP+ effectors indicated that FTY modified donor effector T-cell migration to secondary lymphoid organs, but did not uniformly trap T cells in lymph nodes or prevent early effector migration to GVHD parenchymal target organs. Administration of FTY only prior to transplantation inhibited GVHD, indicating that the primary function of FTY may be targeted to host cells. FTY was additive with regulatory T cells for GVHD inhibition. FTY slightly impaired but did not abrogate a graft-versus-leukemia (GVL) effect against C1498, a myeloid leukemia. Our data further define the mechanisms of action and provide insight as to the potential clinical uses of FTY in allogeneic bone marrow transplant recipients.

  7. Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development

    Directory of Open Access Journals (Sweden)

    Mª Carmen Herrero-Sánchez

    2016-10-01

    Full Text Available Abstract Background Graft-versus-host disease (GvHD remains the major obstacle to successful allogeneic hematopoietic stem cell transplantation, despite of the immunosuppressive regimens administered to control T cell alloreactivity. PI3K/AKT/mTOR pathway is crucial in T cell activation and function and, therefore, represents an attractive therapeutic target to prevent GvHD development. Recently, numerous PI3K inhibitors have been developed for cancer therapy. However, few studies have explored their immunosuppressive effect. Methods The effects of a selective PI3K inhibitor (BKM120 and a dual PI3K/mTOR inhibitor (BEZ235 on human T cell proliferation, expression of activation-related molecules, and phosphorylation of PI3K/AKT/mTOR pathway proteins were analyzed. Besides, the ability of BEZ235 to prevent GvHD development in mice was evaluated. Results Simultaneous inhibition of PI3K and mTOR was efficient at lower concentrations than PI3K specific targeting. Importantly, BEZ235 prevented naïve T cell activation and induced tolerance of alloreactive T cells, while maintaining an adequate response against cytomegalovirus, more efficiently than BKM120. Finally, BEZ235 treatment significantly improved the survival and decreased the GvHD development in mice. Conclusions These results support the use of PI3K inhibitors to control T cell responses and show the potential utility of the dual PI3K/mTOR inhibitor BEZ235 in GvHD prophylaxis.

  8. Low-dose alemtuzumab vs. standard policy for prevention of graft-versus-host disease in unrelated and related allogeneic stem cell transplantation-a matched pair analysis.

    Science.gov (United States)

    Busemann, Christoph; Neumann, Thomas; Schulze, Meike; Klenner, Anne; Thiele, Thomas; Greinacher, Andreas; Dölken, Gottfried; Krüger, William H

    2013-07-01

    Antibody-mediated in vivo T cell depletion is common prior to unrelated (URD) or mismatched allogeneic stem cell transplantation (alloSCT) and optional in HLA-identical sibling (FAM) alloSCT. While anti-thymocyte globulin (ATG) is the current standard, alemtuzumab is an alternative. The optimal dose of alemtuzumab has not been defined. This retrospective analysis compares low-dose alemtuzumab with ATG in URD alloSCT and with no antibody in FAM alloSCT. Twenty-eight patients treated with alemtuzumab (10 mg; HLA mismatch, 20 mg) were matched to 28 patients who have either received ATG (URD) or no antibody (noAB) according to disease, disease stage, age, transplant type and risk state. Both groups were compared for engraftment, outcome, disease-free (DFS) and overall survival (OS), graft-versus-host disease (GvHD), freedom from GvHD (ffGvHD) and transplant-related mortality (TRM). No significant differences were found between the groups for leukocyte engraftment, GvHD, ffGvHD, TRM, DFS and OS. There was a trend for reduction of cGvHD by alemtuzumab (p = 0.05). A transplant-type stratified subanalysis consolidated equivalency of alemtuzumab and ATG in URD-SCT and indicates possible superiority of low-dose alemtuzumab compared to noAB in FAM-SCT. Low-dose alemtuzumab, as part of conditioning regimen prior to alloSCT, is safe and comparable to standard ATG. Prospective trials, particularly comparing alemtuzumab vs. noAB in FAM alloSCT, should be conducted.

  9. Heavy Chain-Hyaluronan/Pentraxin 3 from Amniotic Membrane Suppresses Inflammation and Scarring in Murine Lacrimal Gland and Conjunctiva of Chronic Graft-versus-Host Disease

    Science.gov (United States)

    Ogawa, Yoko; He, Hua; Mukai, Shin; Imada, Toshihiro; Nakamura, Shigeru; Su, Chen-Wei; Mahabole, Megha; Tseng, Scheffer C. G.; Tsubota, Kazuo

    2017-01-01

    Chronic graft-versus-host disease (cGVHD) is a major complication of hematopoietic stem cell transplantation. Dry eye disease is the prominent ocular sequel of cGVHD and is caused by excessive inflammation and fibrosis in the lacrimal glands. Heavy chain-Hyaluronan/Pentraxin 3 (HC-HA/PTX3) is a complex purified from human amniotic membrane (AM) and known to exert anti-inflammatory and anti-scarring actions. In this study, we utilized a mouse model of cGVHD to examine whether HC-HA/PTX3 could attenuate dry eye disease elicited by cGVHD. Our results indicated that subconjunctival and subcutaneous injection of HC-HA/PTX3 preserved tear secretion and conjunctival goblet cell density and mitigated inflammation and scarring of the conjunctiva. Such therapeutic benefits were associated with suppression of scarring and infiltration of inflammatory/immune cells in the lacrimal glands. Furthermore, HC-HA/PTX3 significantly reduced the extent of infiltration of CD45+ CD4+ IL-17+ cells, CD45+ CD34+ collagen I+ CXCR4+ fibrocytes, and HSP47+ activated fibroblasts that were accompanied by upregulation of collagen type Iα1, collagen type IIIα1 and NF-kB in lacrimal glands. Collectively, these pre-clinical data help prove the concept that subcutaneous and subconjunctival injection of HC-HA/PTX3 is a novel approach to prevent dry eye disease caused by cGVHD and allow us to test its safety and efficacy in future human clinical trials. PMID:28165063

  10. Graft-Versus-Host Disease Prophylaxis in Treating Patients With Hematologic Malignancies Undergoing Unrelated Donor Peripheral Blood Stem Cell Transplant

    Science.gov (United States)

    2016-08-18

    Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Aggressive Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Diffuse Large B-Cell Lymphoma; Hematopoietic and Lymphoid Cell Neoplasm; Indolent Non-Hodgkin Lymphoma; Mantle Cell Lymphoma; Myelodysplastic Syndrome; Myeloproliferative Neoplasm; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Plasma Cell Myeloma; Refractory Chronic Lymphocytic Leukemia; Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Hodgkin Lymphoma; Small Lymphocytic Lymphoma; T-Cell Chronic Lymphocytic Leukemia; Waldenstrom Macroglobulinemia

  11. Analysis of DNA methylation with 5-Azac induced immune hyporesponsiveness following acute graft-versus-host disease%5-Azac诱导急性移植物抗宿主病免疫低反应的甲基化研究

    Institute of Scientific and Technical Information of China (English)

    张晓宁; 赵玉霞; 王建海; 苗绪红; 李克秋; 李光

    2016-01-01

    目的 建立小鼠急性移植物抗宿主病(aGVHD)模型,检测DNA甲基化转移酶抑制剂5-氮杂胞苷(5-aza-cytidine,5-Azac)诱导aGVHD免疫低反应后的甲基化变化,探讨5-Azac对小鼠aGVHD的免疫调节作用.方法 选择雄性C57BL/6(H-2b)与雌性BALB/c(H-2d)小鼠分别作为异基因移植供、受体建立移植物抗宿主病小鼠模型.BABL/c受体按照体质量相近进行配对,分为移植对照组和5-Azac实验组.5-Azac实验组于移植后1~7、14、21、28 d尾静脉注射5-Azac 0.25 mg/kg(0.3 mL/只);移植对照组尾静脉注射生理盐水0.3 mL/只.提取3只移植对照组和3只5-Azac实验组小鼠的外周血DNA,分别等量混匀,采用甲基化DNA免疫共沉淀测序(MeDIP-seq)的方法检测甲基化变化,筛选差异甲基化基因,并对其功能及生物学通路进行分析.结果 5-Azac实验组小鼠的生存时间延长,排斥反应减弱,成功诱导移植物抗宿主病免疫低反应状态.2组小鼠DNA MeDIP-seq结果对比显示:5-Azac实验组启动子区存在369个差异甲基化基因,其中上调239个、下调130个;外显子区存在184个差异甲基化基因,其中上调113个、下调71个.利用KEGG(Kyoto Encyclopedia of Genes and Genomes)数据库对差异甲基化基因分析,结果显示其主要参与10个免疫学信号通路,其中TGF-β、GSK-3β、SYK、PI3K、NFAT、CD28、α4β7与aGVHD的发生发展密切相关.结论 5-Azac可以通过改变基因的甲基化状态有效诱导aGVHD的免疫低反应.%Objective To analyse the change of DNA methylation with 5-Azac injection in acute graft-versus-host dis- ease (aGVHD) mouse model, which received allogeneic bone marrow transplantation, and explore the immunomodulatory ef-fects of 5-Azac. Methods Male C57BL/6 (H-2b)and female BALB/c (H-2d) mice were selected as donor and recipient of complete allotransplantation. BABL/c mice were divided into two groups, transplantation control group and 5-Azac experi-mental group. At 1-7, 14, 21

  12. Sequential expression of adhesion and costimulatory molecules in graft-versus-host disease target organs after murine bone marrow transplantation across minor histocompatibility antigen barriers.

    Science.gov (United States)

    Eyrich, Matthias; Burger, Gudrun; Marquardt, Katja; Budach, Wilfried; Schilbach, Karin; Niethammer, Dietrich; Schlegel, Paul G

    2005-05-01

    Graft-versus-host disease (GVHD) is a potentially fatal complication after allogeneic bone marrow transplantation. However, few data exist thus far on the molecular signals governing leukocyte trafficking during the disease. We therefore investigated the sequential pattern of distinct adhesion, costimulatory, and apoptosis-related molecules in GVHD organs (ileum, colon, skin, and liver) after transplantation across minor histocompatibility barriers (B10.D2 --> BALB/c, both H-2d). To distinguish changes induced by the conditioning regimen from effects achieved by allogeneic cell transfer, syngeneic transplant recipients (BALB/c --> BALB/c) and irradiated nontransplanted mice were added as controls. Irradiation upregulated the expression of vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-l, and B7-2 in ileum, as well as VCAM-1 and B7-2 in colon, on day 3 in all animals. Whereas in syngeneic mice these effects were reversed from day 9 on, allogeneic recipients showed further upregulation of VCAM-1, ICAM-1, B7-1, and B7-2 in these organs on day 22, when GVHD became clinically evident. Infiltration of CD4+ and CD8+ donor T cells was noted on day 9 in skin and liver and on day 22 in ileum and colon. Surprisingly, the expression of several other adhesion molecules, such as ICAM-2, platelet-endothelial cell adhesion molecule 1, E-selectin, and mucosal addressin cell adhesion molecule 1, did not change. Proapoptotic and antiapoptotic markers were balanced in GVHD organs with the exception of spleen, in which a preferential expression of the proapoptotic Bax could be noted. Our results indicate that irradiation-induced upregulation of VCAM-1, ICAM-1, and B7-2 provides early costimulatory signals to incoming donor T cells in the intestine, followed by a cascade of proinflammatory signals in other organs once the alloresponse is established.

  13. 异基因造血干细胞移植受者外周血单核细胞趋化蛋白-2和IL-12水平变化与急性移植物抗宿主病的相关性%Chan ges of monocyte chemoattractant protein-2 and IL-12 levels in peripheral blood of recipients of allogeneic hemapoietic stem cell transplantation and their correlation with acute graft versus host disease

    Institute of Scientific and Technical Information of China (English)

    费晓莉; 刘林

    2012-01-01

    Objective To investigate the changes of monocyte chemoattractant protein-2 / C-C motif ligand 8 ( MCP-2 / CCL8 ) and IL-12 levels in peripheral blood of recipients of allogeneic hemapoietic stem cell transplantation (allo-HSCT) as well as their correlation with acute graft versus host disease (aGVHD), and provide reliable indexes for early diagnosis of aGVHD in clinic. Methods Twenty recipients of allo-HSCT were served as trial group, while those of autoplastic HSCT as control group. The MCP-2 and IL-12 levels in sera were determined 14(before pre-treatment) and 1 d(after pre-treatment and before stem cell reinfusion) before transplantation, and once a week after transplantation for 8 weeks, while those of patients with aGVHD were determined twice a week after appearance of clinical symptoms. Results In both trial and control groups, no significant differences were observed between the MCP-2 and IL-12 levels in sera 14 and 1 d before transplantation (P > 0. 05), or between those 7 after and 1 d before transplantation (P > 0. 05). Six cases of aGVHD were observed in trial group, of which clinical symptoms appeared 16 ~ 52 d after transplantation, and the time when serum MCP-2 and IL-12 levels increased firstly as compared with those 7 d after transplantation was earlier than that when the clinical symptoms appeared. The serum MCP-2 and IL-12 levels of the patients at time of diagnosis increased significantly as compared with those 7 d after transplantation (P 0. 05). Conclusion MCP-2 and IL-12 were correlated with aGVHD, of which the levels changed earlier than the appearance of clinical symptoms. The determination of serum MCP-2 and IL-12 levels was helpful to the early diagnosis of aGVHD.%目的 探讨异基因造血干细胞移植(allogeneic hemapoietic stem cell transplantation,allo-HSCT)受者外周血单核细胞趋化蛋白-2(Monocyte chemoattractant protein-2/C-C motif ligand 8,MCP-2/CCL8)和白细胞介素- 12( Interleukin- 12,IL-12)水平变化与急性移植物抗宿主病(acute

  14. Aberrant germinal center formation, follicular T-helper cells, and germinal center B-cells were involved in chronic graft-versus-host disease.

    Science.gov (United States)

    Shao, Liang; Lie, Albert K W; Zhang, You; Wong, Cheuk-Hong; Kwong, Yok-Lam

    2015-09-01

    Chronic graft-versus-host disease (cGVHD) is an important complication after allogeneic hematopoietic stem cell transplantation (HSCT). To define the roles of T-cells and B-cells in cGVHD, a murine minor histocompatibility complex-mismatched HSCT model was used. Depletion of donor splenocyte CD4(+) T-cells and B220(+) B-cells alleviated cGVHD. Allogeneic recipients had significantly increased splenic germinal centers (GCs), with significant increases in follicular T-helper (Tfh) cells and GC B-cells. There were increased expressions in Tfh cells of inducible T-cell co-stimulator (ICOS), interleukin (IL)-4 and IL-17, and in GC B-cells of B-cell activating factor receptor and ICOS ligand. Depletion of donor splenocyte CD4(+) T-cells abrogated aberrant GC formation and suppressed Tfh cells and GC B-cells. Interestingly, depletion of donor splenocyte B200(+) B-cells also suppressed Tfh cells in addition to GC B-cells. These results suggested that in cGVHD, both Tfh and GC B-cells were involved, and their developments were mutually dependent. The mammalian target of rapamycin (mTOR) inhibitor everolimus was effective in suppressing cGVHD, Tfh cells, and GC B-cells, either as a prophylaxis or when cGVHD had established. These results implied that therapeutic targeting of both T-cells and B-cells in cGVHD might be effective. Signaling via mTOR may be another useful target in cGVHD.

  15. Canine DLA-79 gene: an improved typing method, identification of new alleles and its role in graft rejection and graft-versus-host disease.

    Science.gov (United States)

    Venkataraman, G M; Geraghty, D; Fox, J; Graves, S S; Zellmer, E; Storer, B E; Torok-Storb, B J; Storb, R

    2013-04-01

    Developing a preclinical canine model that predicts outcomes for hematopoietic cell transplantation in humans requires a model that mimics the degree of matching between human donor and recipient major histocompatibility complex (MHC) genes. The polymorphic class I and class II genes in mammals are typically located in a single chromosome as part of the MHC complex. However, a divergent class I gene in dogs, designated dog leukocyte antigen-79 (DLA-79), is located on chromosome 18 while other MHC genes are on chromosome 12. This gene is not taken into account while DLA matching for transplantation. Though divergent, this gene shares significant similarity in sequence and exon-intron architecture with other class I genes, and is transcribed. Little is known about the polymorphisms of DLA-79 and their potential role in transplantation. This study was aimed at exploring the reason for high rate of rejection seen in DLA-matched dogs given reduced intensity conditioning, in particular, the possibility that DLA-79 allele mismatches may be the cause. We found that about 82% of 407 dogs typed were homozygous for a single, reference allele. Owing to the high prevalence of a single allele, 87 of the 108 dogs (∼80%) transplanted were matched for DLA-79 with their donor. In conclusion, we have developed an efficient method to type alleles of a divergent MHC gene in dogs and identified two new alleles. We did not find any statistical correlation between DLA-79 allele disparity and graft rejection or graft-versus-host disease, among our transplant dogs.

  16. Innate immune activation by the viral PAMP poly I:C potentiates pulmonary graft-versus-host disease after allogeneic hematopoietic cell transplant.

    Science.gov (United States)

    Kinnier, Christine V; Martinu, Tereza; Gowdy, Kymberly M; Nugent, Julia L; Kelly, Francine L; Palmer, Scott M

    2011-01-15

    Respiratory viral infections cause significant morbidity and increase the risk for chronic pulmonary graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT). Our overall hypothesis is that local innate immune activation potentiates adaptive alloimmunity. In this study, we hypothesized that a viral pathogen-associated molecular pattern (PAMP) alone can potentiate pulmonary GVHD after allogeneic HCT. We, therefore, examined the effect of pulmonary exposure to polyinosinic:polycytidylic acid (poly I:C), a viral mimetic that activates innate immunity, in an established murine HCT model. Poly I:C-induced a marked pulmonary T cell response in allogeneic HCT mice as compared to syngeneic HCT, with increased CD4+ cells in the lung fluid and tissue. This lymphocytic inflammation persisted at 2 weeks post poly I:C exposure in allogeneic mice and was associated with CD3+ cell infiltration into the bronchiolar epithelium and features of epithelial injury. In vitro, poly I:C enhanced allospecific proliferation in a mixed lymphocyte reaction. In vivo, poly I:C exposure was associated with an early increase in pulmonary monocyte recruitment and activation as well as a decrease in CD4+FOXP3+ regulatory T cells in allogeneic mice as compared to syngeneic. In contrast, intrapulmonary poly I:C did not alter the extent of systemic GVHD in either syngeneic or allogeneic mice. Collectively, our results suggest that local activation of pulmonary innate immunity by a viral molecular pattern represents a novel pathway that contributes to pulmonary GVHD after allogeneic HCT, through a mechanism that includes increased recruitment and maturation of intrapulmonary monocytes.

  17. Child and parent perspectives of the chronic graft-versus-host disease (cGVHD) symptom experience: a concept elicitation study

    Science.gov (United States)

    Baird, Kristin; Crum, Caroline; Powers, Kimberly; Carpenter, Paul; Baker, K. Scott; MacMillan, Margaret L.; Nemecek, Eneida; Lai, Jin-Shei; Mitchell, Sandra A.; Jacobsohn, David A.

    2016-01-01

    Purpose Chronic graft-versus-host disease (cGVHD) is a significant cause of mortality and morbidity after allogeneic hematopoietic cell transplant and is associated with a wide range of distressing symptoms. A pediatric measure of cGVHD-related symptoms is needed to advance clinical research. Our aim was to elicit descriptions of the cGVHD symptom experience directly from children and to compare the specific language used by children to describe their symptoms and the comprehension of symptom concepts across the developmental spectrum. Methods We used qualitative methods to identify the phrases, terms, and constructs that children (ages 5–8 [n =8], 9–12 [n =8], and 13–17 [n =8]) with cGVHD employ when describing their symptoms. The symptom experience of each participant was determined through individual interviews with each participant and parent (5–7 year olds were interviewed together with a parent). Medical practitioners with experience in evaluating cGVHD performed clinical assessments of each participant. Results Pediatric transplant survivors and their parents identified a wide range of bothersome cGVHD symptoms, and common concepts and terminologies to describe these experiences emerged. Overall concordance between patient and parent reports was moderate (70–75 %). No consistent pattern of child under- or over-reporting in comparison to the parent report was observed. Conclusion These study results identify concepts and vocabulary to inform item generation for a new pediatric self-report measure of cGVHD symptoms for use in clinical research. The findings also confirm the prevalence and nature of symptom distress in pediatric patients with cGVHD and support implementation of systematic approaches to symptom assessment and intervention in routine clinical practice. PMID:24077685

  18. 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.

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

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    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.

  20. Human Mesenchymal Stem Cell-Educated Macrophages Are a Distinct High IL-6-Producing Subset that Confer Protection in Graft-versus-Host-Disease and Radiation Injury Models.

    Science.gov (United States)

    Bouchlaka, Myriam N; Moffitt, Andrea B; Kim, Jaehyup; Kink, John A; Bloom, Debra D; Love, Cassandra; Dave, Sandeep; Hematti, Peiman; Capitini, Christian M

    2017-02-28

    Mesenchymal stem cells (MSCs) have immunosuppressive and tissue repair properties, but clinical trials using MSCs to prevent or treat graft-versus-host disease (GVHD) have shown mixed results. Macrophages (MØs) are important regulators of immunity and can promote tissue regeneration and remodeling. We have previously shown that MSCs can educate MØs toward a unique anti-inflammatory immunophenotype (MSC-educated macrophages [MEMs]); however, their implications for in vivo models of inflammation have not been studied yet. We now show that in comparison with MØs, MEMs have increased expression of the inhibitory molecules PD-L1, PD-L2, in addition to markers of alternatively activated macrophages: CD206 and CD163. RNA-Seq analysis of MEMs, as compared with MØs, show a distinct gene expression profile that positively correlates with multiple pathways important in tissue repair. MEMs also show increased expression of IL-6, transforming growth factor-β, arginase-1, CD73, and decreased expression of IL-12 and tumor necrosis factor-α. We show that IL-6 secretion is controlled in part by the cyclo-oxygenase-2, arginase, and JAK1/STAT1 pathway. When tested in vivo, we show that human MEMs significantly enhance survival from lethal GVHD and improve survival of mice from radiation injury. We show these effects could be mediated in part through suppression of human T cell proliferation and may have attenuated host tissue injury in part by enhancing murine fibroblast proliferation. MEMs are a unique MØ subset with therapeutic potential for the management of GVHD and/or protection from radiation-induced injury.

  1. Mammalian target of rapamycin inhibitor-associated stomatitis in hematopoietic stem cell transplantation patients receiving sirolimus prophylaxis for graft-versus-host disease.

    Science.gov (United States)

    Villa, Alessandro; Aboalela, Ali; Luskin, Katharine A; Cutler, Corey S; Sonis, Stephen T; Woo, Sook Bin; Peterson, Douglas E; Treister, Nathaniel S

    2015-03-01

    The mammalian target of rapamycin (mTOR) inhibitor sirolimus is effective in reducing incidence of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Agents that inhibit the mTOR pathway are known to be associated with significant and potentially dose-limiting toxicities, including stomatitis. The objective of this study was to report the clinical features and management outcomes of sirolimus-associated oral ulcers in the context of post-HSCT prophylaxis of GVHD. Seventeen patients, from a study cohort of 967, who were treated with sirolimus as prophylaxis for GVHD after allogeneic HSCT at the Dana-Farber/Brigham and Women's Cancer Center developed oral ulcers and were referred to the oral medicine clinic for evaluation and treatment over a period of 6 years. Clinical characteristics (appearance, anatomic site, size) and therapeutic outcomes (time to complete resolution) were documented. Median time to onset of oral ulceration was 55 days after allogeneic HSCT (range, 6 to 387 days); 92.9% of ulcers were located on nonkeratinized mucosa, with the ventrolateral tongue the most common site of involvement. Thirteen patients were treated with topical corticosteroid therapy; 12 of these patients also required intralesional corticosteroid injections. Clinical improvement (resolution of the lesions and improvement of symptoms) was noted in all cases, with no reported adverse events. Median time to complete resolution after onset of therapy was 14 days (range, 2 to 70 days). Patients receiving sirolimus for GVHD prophylaxis may develop painful oral ulcerations, which can be effectively managed with topical steroid treatment. Further prospective studies are needed to better elucidate the incidence of this complication, identify risk factors, and evaluate the effectiveness of interventions.

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

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    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.

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

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    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.

  4. IL-2-targeted therapy ameliorates the severity of graft-versus-host disease: ex vivo selective depletion of host-reactive T cells and in vivo therapy.

    Science.gov (United States)

    Yarkoni, Shai; Prigozhina, Tatyana B; Slavin, Shimon; Askenasy, Nadir

    2012-04-01

    T cell depletion prevents graft-versus-host disease (GVHD) but also removes T cell-mediated support of hematopoietic cell engraftment. A chimeric molecule composed of IL-2 and caspase-3 (IL2-cas) has been evaluated as a therapeutic modality for GVHD and selective ex vivo depletion of host-reactive T cells. IL2-cas does not affect hematopoietic cell engraftment and significantly reduces the clinical and histological severity of GVHD. Early administration of IL2-cas reduced the lethal outcome of haploidentical transplants, and survivor mice displayed markedly elevated levels of X-linked forkhead/winged helix (FoxP3(+); 50%) and CD25(+)FoxP3(+) T cells (35%) in the lymph nodes. The chimeric molecule induces in vitro apoptosis in both CD4(+)CD25(-) and CD4(+)CD25(+) subsets of lymphocytes from alloimmunized mice, and stimulates proliferation of cells with highest levels of CD25 expression. Adoptive transfer of IL2-cas-pretreated viable splenocytes into sublethally irradiated haploidentical recipients resulted in 60% survival after a lethal challenge with lipopolysaccharide, which is associated with elevated fractions of CD25(high)FoxP3(+) T cells in the lymph nodes of survivors. These data demonstrate that ex vivo purging of host-presensitized lymphocytes is effectively achieved with IL2-cas, and that IL-2-targeted apoptotic therapy reduces GVHD severity in vivo. Both approaches promote survival in lethal models of haploidentical GVHD. The mechanism of protection includes direct killing of GVHD effectors, prevention of transition to effector/memory T cells, and induction of regulatory T cell proliferation, which becomes the dominant subset under conditions of homeostatic expansion.

  5. T lymphocytes and cytokines in graft-versus-host disease : a study in mice with emphasis on prevention and treatment.

    NARCIS (Netherlands)

    A.C. Knulst (André)

    1992-01-01

    textabstractThis thesis describes the results of experiments aimed to improve the insight into this complex disease using a murine model. Based on previous work from our laboratory we investigated the possibilities to prevent GVHD in a specific manner, namely by pretreatment of prospective donors wi

  6. Increasing Incidence of Chronic Graft-versus-Host Disease in Allogeneic Transplantation – A Report from CIBMTR

    Science.gov (United States)

    Arai, Sally; Arora, Mukta; Wang, Tao; Spellman, Stephen R.; He, Wensheng; Couriel, Daniel R.; Urbano-Ispizua, Alvaro; Cutler, Corey S.; Bacigalupo, Andrea A.; Battiwalla, Minoo; Flowers, Mary E.; Juckett, Mark B.; Lee, Stephanie J.; Loren, Alison W.; Klumpp, Thomas R.; Prockup, Susan E.; Ringdén, Olle T.H.; Savani, Bipin N.; Socié, Gérard; Schultz, Kirk R.; Spitzer, Thomas; Teshima, Takanori; Bredeson, Christopher N.; Jacobsohn, David A.; Hayashi, Robert J.; Drobyski, William R.; Frangoul, Haydar A.; Akpek, Görgün; Ho, Vincent T.; Lewis, Victor A.; Gale, Robert Peter; DSc(hon); Koreth, John; Chao, Nelson J.; Aljurf, Mahmoud D.; Cooper, Brenda W.; Laughlin, Mary J.; Hsu, Jack W.; Hematti, Peiman; Verdonck, Leo F.; Solh, Melhelm M.; Norkin, Maxim; Reddy, Vijay; Martino, Rodrigo; Gadalla, Shahinaz; Goldberg, Jenna D.; McCarthy, Philip L.; Pérez-Simón, José A.; Khera, Nandita; Lewis, Ian D.; Atsuta, Yoshiko; Olsson, Richard F.; Saber, Wael; Waller, Edmund K.; Blaise, Didier; Pidala, Joseph A.; Martin, Paul J.; Satwani, Prakash; Bornhäuser, Martin; Inamoto, Yoshihiro; Weisdorf, Daniel J.; Horowitz, Mary M.; Pavletic, Steven Z.

    2015-01-01

    Although transplant practices have changed over the last decades there is no information on trends in incidence and outcome of cGVHD over time. This study utilized the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe the time trends for cGVHD incidence, non-relapse mortality, and the risk factors for cGVHD. The 12-year period was divided into three intervals: 1995-1999, 2000-2003, 2004-2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia and myelodysplastic syndrome. In the multivariate analysis, the incidence of cGVHD was shown to be increased in more recent years (odds ratio= 1.19, p<0.0001) and this trend was still seen when adjusting for donor type, graft type, or conditioning intensity. In patients with cGVHD, non-relapse mortality has decreased over time, but at 5-years there were no significant differences among different time periods. Risk factors for cGVHD were in line with previous studies. This is the first comprehensive characterization of the trends in cGVHD incidence and underscores the mounting need for addressing this major late complication of transplantation in future research. PMID:25445023

  7. 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.

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    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.

  8. Effect of donor CTLA-4 alleles and haplotypes on graft-versus-host disease occurrence in Tunisian patients receiving a human leukocyte antigen-identical sibling hematopoietic stem cell transplant.

    Science.gov (United States)

    Sellami, Mohamed Hichem; Bani, Meriem; Torjemane, Lamia; Kaabi, Houda; Ladeb, Saloua; Ben Othmane, Tarek; Hmida, Slama

    2011-02-01

    The CTLA-4 genetic variation, such as single nucleotide polymorphisms (SNPs) may be critical and can affect the functional activity of cells that initiate the graft-versus-host disease (GVHD) effects. The aim of this study is to examine the effect of donor CTLA-4 alleles and haplotypes for the -318C>T and the 49A>G polymorphisms on the occurrence of GVHD in Tunisians recipients of HSCs. A total of 112 patients and their 112 respective sibling donors of HSCs were enrolled in this study. All patients had either grades 0-I or grades II-IV acute GVHD, or chronic GVHD. The SNPs genotyping assay was performed using sets of sequence specific primers (SSP-PCR). The single marker association analysis showed that the 49G allele, in a genetic recessive model, may be a potential risk factor only for the chronic GVHD (p = 0.032, odds ratio [OR] = 2.58, 95% confidence interval = 1.05-6.32). The haplotypes analyses showed that the CTLA-4 -318C49G nucleotide combination is significantly associated with the incidence of chronic GVHD (p = 0.043, χ² = 3.27). Donor CTLA-4 -318C49G haplotype may be a significant risk factor for developing chronic GVHD after allo-stem cell transplantation. We suppose that donor T cells expressing this haplotype in a homozygous state have higher proliferation than those expressing other haplotypes, especially after recognition of the recipient's minor histocompatibility antigens.

  9. The role of extracorporeal photopheresis in the management of cutaneous T-cell lymphoma, graft-versus-host disease and organ transplant rejection: a consensus statement update from the UK Photopheresis Society.

    Science.gov (United States)

    Alfred, Arun; Taylor, Peter C; Dignan, Fiona; El-Ghariani, Khaled; Griffin, James; Gennery, Andrew R; Bonney, Denise; Das-Gupta, Emma; Lawson, Sarah; Malladi, Ram K; Douglas, Kenneth W; Maher, Tracey; Guest, Julie; Hartlett, Laura; Fisher, Andrew J; Child, Fiona; Scarisbrick, Julia J

    2017-02-21

    Extracorporeal photopheresis (ECP) has been used for over 35 years in the treatment of erythrodermic cutaneous T-cell lymphoma (CTCL) and over 20 years for chronic and acute graft-versus-host disease (GvHD) and solid organ transplant rejection. ECP for CTCL and GvHD is available at specialised centres across the UK. The lack of prospective randomised trials in ECP led to the development of UK Consensus Statements for patient selection, treatment schedules, monitoring protocols and patient assessment criteria for ECP. The recent literature has been reviewed and considered when writing this update. Most notably, the national transition from the UVAR XTS(®) machine to the new CELLEX machine for ECP with dual access and a shorter treatment time has led to relevant changes in these schedules. This consensus statement updates the previous statement from 2007 on the treatment of CTCL and GvHD with ECP using evidence based medicine and best medical practise and includes guidelines for both children and adults.

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

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    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.

  11. 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.

  12. 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

    2015-01-01

    Background Extracorporeal photopheresis (ECP) has been shown as active therapy for graft-versus-host disease (GVHD). Study Design and Methods 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. Results 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. Conclusions 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. PMID:25355659

  13. Associação dos níveis de citocinas no pós-transplante de células-tronco hematopoiéticas com a Doença do Enxerto Contra o Hospedeiro aguda Association of cytokine levels with acute graft versus host disease following full match allogeneic stem cell transplantation

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    Jeane E. L. Visentainer

    2005-09-01

    Full Text Available Este estudo foi realizado para investigar se os níveis séricos de sIL-2R, TNF-alfa, IFN-gama, IL-6, IL-10 e TGF-beta1 estavam associados com o desenvolvimento de DECH (Doença do Enxerto Contra o Hospedeiro aguda. Os níveis de citocinas foram seqüencialmente mensurados por Elisa em 13 pacientes que haviam sido submetidos ao transplante alogênico de células progenitoras hematopoiéticas. Os níveis de sIL-2R e IL-10 da 1ª a 15ª semanas pós-transplante foram significativamente maiores no grupo que desenvolveu DECH aguda que naquele sem a doença. Os níveis de sIL-2R aumentaram em direta correlação com a pega do enxerto e ao tempo do DECH aguda, enquanto os níveis de IL-10 aumentaram transitoriamente pós-transplante. A média da concentração de TNF-alfa nas primeiras semanas após o transplante foi maior no grupo que desenvolveu DECH aguda. Além disso, uma queda dos níveis de TGF-beta1 após a pega esteve significativamente associada à DECH aguda. Nenhuma correlação foi encontrada entre DECH aguda e as outras citocinas investigadas. Estes resultados suportam a idéia de que um balanço entre as citocinas derivadas de linfócitos T auxiliadores do tipo 1 e 2 pode ser importante no desenvolvimento e controle da DECH aguda. Embora os níveis de sIL-2R, TNF-alfa, IL-10 e TGF-beta1 tenham sido correlacionados com a DECH aguda, os níveis de sIL-2R ao tempo da pega podem prover um melhor parâmetro para a detecção precoce de DECH aguda após o transplante alogênico.This study was performed to investigate whether the serum levels of sIL-2R, TNF-alpha, IFN-gamma, IL-6, IL-10, and TGF-beta1 are associated with the development of acute GVHD. Serum cytokine levels were sequentially measured by sandwich Enzyme Linked-Immuno-Sorbent Assay (Elisa in 13 patients who had received full match allogeneic stem cell transplantation. Serum sIL-2R and IL-10 levels from the 1st to the 15th week post transplantation were significantly higher in the

  14. Ongoing graft-versus-host disease is a risk factor for azoospermia after allogeneic hematopoietic stem cell transplantation: a survey of the Late Effects Working Party of the European Group for Blood and Marrow Transplantation.

    Science.gov (United States)

    Rovó, Alicia; Aljurf, Mahmoud; Chiodi, Sandra; Spinelli, Simonetta; Salooja, Nina; Sucak, Gülsan; Hunter, Ann; Kim, Tan Swee; Socié, Gérard; van Lint, Maria Teresa; Passweg, Jakob R; Arat, Mutlu; Badoglio, Manuela; Tichelli, André

    2013-03-01

    The aim of this study was to assess the degree of spermatogenesis defects in sperm analysis in long-term male survivors after allogeneic hematopoietic stem cell transplantation in order to identify the risk factors related to potential infertility after hematopoietic stem cell transplantation and to provide data on longitudinal sperm recovery after hematopoietic stem cell transplantation. Here, the Late Effects Working Party of the European Group for Blood and Marrow Transplantation reports data of sperm analysis from 224 males who underwent hematopoietic stem cell transplantation. Median time between transplantation and sperm analysis was 63 months (8-275 months). At last sperm analysis, presence of any degree of spermatozoa was reported in 70 (31%) and complete azoospermia in 154 (69%) patients. In multivariate analysis, being conditioned with total body irradiation (RR 7.1; 95% CI: 3.4-14.8) and age over 25 years at transplantation (RR 2.4; 95% CI: 1.09-5.2) were significantly associated with higher risk for azoospermia. In patients not conditioned with total body irradiation, ongoing chronic graft-versus-host disease is the main adverse factor for sperm recovery (RR of 3.11; 95% CI: 1.02-9.47; P=0.045). Already established risk factors, such as total body irradiation and age older than 25 years at hematopoietic stem cell transplantation, were seen to be the most relevant adverse risk factor for sperm production after hematopoietic stem cell transplantation. Furthermore, for the first time, ongoing graft-versus-host disease has been shown to be the most relevant adverse factor for sperm recovery, particularly in patients conditioned without total body irradiation. We also introduce a useful scoring system to predict the probability of male long-term survivors' azoospermia.

  15. Humanized Chronic Graft-versus-Host Disease in NOD-SCID il2rγ-/- (NSG Mice with G-CSF-Mobilized Peripheral Blood Mononuclear Cells following Cyclophosphamide and Total Body Irradiation.

    Directory of Open Access Journals (Sweden)

    Hisaki Fujii

    Full Text Available Chronic graft-versus-host disease (cGvHD is the major source of late phase morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Humanized acute GvHD (aGvHD in vivo models using NOD-SCID il2rγ-/- (NSG mice are well described and are important tools for investigating pathogenicity of human cells in vivo. However, there have been only few reported humanized cGvHD mouse models. We evaluated if prolonged inflammation driven by low dose G-CSF-mobilized human PBMCs (G-hPBMCs would lead to cGvHD following cyclophosphamide (CTX administration and total body irradiation (TBI in NSG mice. Engraftment was assessed in peripheral blood (PB and in specific target organs by either flow cytometry or immunohistochemistry (IHC. Tissue samples were harvested 56 days post transplantation and were evaluated by a pathologist. Some mice were kept for up to 84 days to evaluate the degree of fibrosis. Mice that received CTX at 20mg/kg did not show aGvHD with stable expansion of human CD45+ CD3+ T-cells in PB (mean; 5.8 to 23.2%. The pathology and fibrosis scores in the lung and the liver were significantly increased with aggregation of T-cells and hCD68+ macrophages. There was a correlation between liver pathology score and the percentage of hCD68+ cells, suggesting the role of macrophage in fibrogenesis in NSG mice. In order to study long-term survival, 6/9 mice who survived more than 56 days showed increased fibrosis in the lung and liver at the endpoint, which suggests the infiltrating hCD68+ macrophages may be pathogenic. It was shown that the combination of CTX and TBI with a low number of G-hPBMCs (1x106 leads to chronic lung and liver inflammation driven by a high infiltration of human macrophage and mature human T cells from the graft, resulting in fibrosis of lung and liver in NSG mice. In conclusion this model may serve as an important pre-clinical model to further current understanding of the roles of human macrophages in cGvHD.

  16. Humanized Chronic Graft-versus-Host Disease in NOD-SCID il2rγ-/- (NSG) Mice with G-CSF-Mobilized Peripheral Blood Mononuclear Cells following Cyclophosphamide and Total Body Irradiation.

    Science.gov (United States)

    Fujii, Hisaki; Luo, Zhi-Juan; Kim, Hye Jin; Newbigging, Susan; Gassas, Adam; Keating, Armand; Egeler, R Maarten

    2015-01-01

    Chronic graft-versus-host disease (cGvHD) is the major source of late phase morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Humanized acute GvHD (aGvHD) in vivo models using NOD-SCID il2rγ-/- (NSG) mice are well described and are important tools for investigating pathogenicity of human cells in vivo. However, there have been only few reported humanized cGvHD mouse models. We evaluated if prolonged inflammation driven by low dose G-CSF-mobilized human PBMCs (G-hPBMCs) would lead to cGvHD following cyclophosphamide (CTX) administration and total body irradiation (TBI) in NSG mice. Engraftment was assessed in peripheral blood (PB) and in specific target organs by either flow cytometry or immunohistochemistry (IHC). Tissue samples were harvested 56 days post transplantation and were evaluated by a pathologist. Some mice were kept for up to 84 days to evaluate the degree of fibrosis. Mice that received CTX at 20mg/kg did not show aGvHD with stable expansion of human CD45+ CD3+ T-cells in PB (mean; 5.8 to 23.2%). The pathology and fibrosis scores in the lung and the liver were significantly increased with aggregation of T-cells and hCD68+ macrophages. There was a correlation between liver pathology score and the percentage of hCD68+ cells, suggesting the role of macrophage in fibrogenesis in NSG mice. In order to study long-term survival, 6/9 mice who survived more than 56 days showed increased fibrosis in the lung and liver at the endpoint, which suggests the infiltrating hCD68+ macrophages may be pathogenic. It was shown that the combination of CTX and TBI with a low number of G-hPBMCs (1x106) leads to chronic lung and liver inflammation driven by a high infiltration of human macrophage and mature human T cells from the graft, resulting in fibrosis of lung and liver in NSG mice. In conclusion this model may serve as an important pre-clinical model to further current understanding of the roles of human macrophages in cGvHD.

  17. Endoscopic evaluation and histological findings in graft-versus-host disease Evaluación endoscópica y hallazgos histológicos en la enfermedad de injerto contra huésped

    Directory of Open Access Journals (Sweden)

    Antonio Velasco-Guardado

    2012-06-01

    Full Text Available Background: the gastrointestinal (GI tract is the major target site of the graft-versus-host disease (GVHD. Diagnosis is based on endoscopic and histological findings. Material and methods: we performed a retrospective study from January 1st, 1990 to December 31st, 2008 on 338 upper gastrointestinal endoscopies (gastroscopies performed to 197 patients that underwent an allogeneic transplant with clinical suspicion of GI-GVHD. Results: endoscopic findings to the diagnosis of GVHD have a sensitivity (S of 34%, specificity levels (SP of 65%, a positive predictive value (PPV of 73% and a negative predictive value (NPV of 48%. The histological study of the endoscopic biopsies has a global sensibility of 85.6% SP = 34.6% PPV = 64.2% and NPV = 63.7%. Histological grade was correlated with the clinical grade of acute GVHD (p = 0.018. Conclusion: upper gastrointestinal endoscopy is useful for the diagnosis of GVHD, as it allows biopsies that can ultimately lead to the diagnosis, but with limited accuracy because the histological findings have low sensitivity and specificity, while the endoscopic findings are generally nonspecific.Introducción: el tracto gastrointestinal es la diana principal de afectación en la enfermedad de injerto contra huésped (EICH. Su diagnóstico se basa en los hallazgos endoscópicos e histológicos. Material y métodos: hemos realizado un estudio retrospectivo, desde el 1 de enero de 1990 hasta el 30 de diciembre de 2008, de 338 endoscopias digestivas altas realizadas a 197 pacientes sometidos a trasplante alogénico de células hematopoyéticas con sospecha de EICH gastrointestinal. Resultados: los hallazgos endoscópicos tienen una sensibilidad (S del 34%, especificidad (E del 65%, valor predictivo positivo (VPP del 73% y valor predictivo negativo (VPN del 48% para el diagnóstico de EICH. El estudio histológico de las biopsias tiene una S del 85,6%, E del 34,6%, VPP del 64,2% y VPN del 63,7%. El grado histológico se

  18. Relationship Between CCR5 and Acute Graft-Versus-Host Disease in Murine Bone Marrow Transplantation%在小鼠骨髓移植中CCR5与急性移植物抗宿主病的相关性研究

    Institute of Scientific and Technical Information of China (English)

    王昭; William J.Murphy

    2006-01-01

    This study was aimed to eveluate the role of CCR5 on donor cells in recipient models received intensive conditioning, so as provide the scientific evidence for clinical application of allo-HSCT. Lethally irradiated BALB/cmice received allogeneic bone marrow transplants from C57BL/6 mice. Mice divided into 4 groups according to receiving variant donor cells: B6 CCR5 KO group, receiving C57BL/6 CCR5 -/- mice bone marrow cells and splenocytes; B6 WT BMC group, receiving C57BL/6 mice bone marrow cells and splenocytes; B6 CCR5 KO BMC group, receiving C57BL/6 CCR5 -/ bone marrow cells alone; B6 WT BMC group, receiving C57BL/6 mice bone marrow cells alone.The result showed that compared to B6 WT BMC group, B6 CCR5 KO group succumbed to acute GVHD at an accelerated rate. Donor CD8 + T cells expanded to a significantly greater extent in recipients of CCR5 KO, compared with B6 WT control cells. T cells recovered from recipients of CCR5 KO cells produced more IFN-γ and TNF-α and proliferated to a T-cell at a significantly higher level than T cells from recipients of WT cells, indicating that CCR5 plays a role in downregualting donor alloreative CD8 + T-cells expansion. Histological assessment of the mice indicated pathological le sions in the kidneys and a greater degree of liver pathological changes in mice that received CCR5 KO donor grafts. It is concluded that the knock-out of CCR5 on donor cells results in increase of GVHD and donor CD8 + T cell expansion, as well as hepatic and renal lesions in allo-HSCT, which indicates that CCR5 is very important in allo-BMT.%本研究评价供者CCR5在经过强化预处理的骨髓移植动物模型受者体内的作用,为今后的异基因造血干细胞移植的临床应用提供科学依据.经过致死剂量照射的BALB/c小鼠接受异基因C57BL/6小鼠的骨髓移植.根据回输的细胞不同实验分为4组:B6 CCR5 KO组,受者接受C57BL/6 CCR5-/-小鼠骨髓和脾脏细胞;B6 WT组,受者接受野生型C57BL/6

  19. Lichenoid Variant of Chronic Cutaneous Graft Versus Host Reaction Post Blood Transfusion: A Rare Event Post Blood Transfusion.

    Science.gov (United States)

    Ramakrishnaiah, Pushpa Kodipalya; Lakshman, Archana; Aradhya, Sacchidanand Sarvajnamurthy; Veerabhadrappa, Nataraja Holavanahally

    2015-01-01

    Chronic graft versus host disease (GVHD) is a less frequently seen disease that occurs post solid organ or bone marrow transplantation. Chronic GVHD occurring post blood transfusion is an even more uncommon disease. It can present either as a lichenoid disease or as a sclerodermatous disease involving multiple systems. In this article, we report a case of chronic graft versus host reaction occurring in skin secondary to blood transfusion.

  20. [Etanercept on steroid-refractary acute graft-versus-host disease].

    Science.gov (United States)

    González Munguía, Silvia; Pérez León, Moisés; Piñero González, Marta; Díaz Pestano, Marina Magnolia; Molero Gómez, Rafael; Luzardo Henríquez, Hugo Daniel

    2015-05-01

    Objetivo: Describir el uso y la efectividad de etanercept como terapia en la enfermedad de injerto contra huésped refractaria a corticoides tras el trasplante alogénico de progenitores hematopoyéticos. Método: Se seleccionaron los pacientes en los que se utilizó etanercept fuera de indicación para el tratamiento de la enfermedad de injerto contra huésped y se revisaron retrospectivamente sus historias clínicas para evaluar la respuesta al tratamiento. Resultados: De un total fueron cinco pacientes tratados cuatro presentaban enfermedad con afectación digestiva y otro con manifestación pulmonar y hepática. En el 80% de los casos se alcanzó alguna respuesta clínica: 60% respuesta parcial y 20% respuesta completa. En cuatro pacientes se utilizo etanecept 25mg dos veces por semana con duración variable, obteniendo una respuesta nula en uno (3 semanas), parcial en dos (4 y 8 semanas) y total en otro (8 semanas). Sólo en un caso se usó etanercept 50mg dos veces en semana durante 5 semanas con respuesta parcial. Conclusiones: Los resultados obtenidos de respuesta clínica son coherentes con los publicados previamente y vienen a incrementar la escasa bibliografía sobre la utilidad de etanercept en el tratamiento en la enfermedad de injerto contra huésped aguda y refractaria a corticoides. Dadas las limitaciones del diseño y el reducido número de pacientes, estudios controlados deberán evaluar en el futuro la eficacia y la seguridad de etanercept en estos pacientes.

  1. 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

    of the various HLA class II antigens was observed between the groups. Similarly, no significant differences in stimulatory capability in secondary mixed lymphocyte culture (MLC) were seen. The distribution of T helper/inducer (CD4+), T suppressor/cytotoxic (CD8+), and NK cells was similar in active JCA, JCA...

  2. Human peripheral blood leucocyte non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain gene mouse model of xenogeneic graft-versus-host-like disease and the role of host major histocompatibility complex

    Science.gov (United States)

    King, M A; Covassin, L; Brehm, M A; Racki, W; Pearson, T; Leif, J; Laning, J; Fodor, W; Foreman, O; Burzenski, L; Chase, T H; Gott, B; Rossini, A A; Bortell, R; Shultz, L D; Greiner, D L

    2009-01-01

    Immunodeficient non-obese diabetic (NOD)-severe combined immune-deficient (scid) mice bearing a targeted mutation in the gene encoding the interleukin (IL)-2 receptor gamma chain gene (IL2rγnull) engraft readily with human peripheral blood mononuclear cells (PBMC). Here, we report a robust model of xenogeneic graft-versus-host-like disease (GVHD) based on intravenous injection of human PBMC into 2 Gy conditioned NOD-scid IL2rγnull mice. These mice develop xenogeneic GVHD consistently (100%) following injection of as few as 5 × 106 PBMC, regardless of the PBMC donor used. As in human disease, the development of xenogeneic GVHD is highly dependent on expression of host major histocompatibility complex class I and class II molecules and is associated with severely depressed haematopoiesis. Interrupting the tumour necrosis factor-α signalling cascade with etanercept, a therapeutic drug in clinical trials for the treatment of human GVHD, delays the onset and progression of disease. This model now provides the opportunity to investigate in vivo mechanisms of xenogeneic GVHD as well as to assess the efficacy of therapeutic agents rapidly. PMID:19659776

  3. Depletion of naïve lymphocytes with fas ligand ex vivo prevents graft-versus-host disease without impairing T cell support of engraftment or graft-versus-tumor activity.

    Science.gov (United States)

    Askenasy, Nadir; Mizrahi, Keren; Ash, Shifra; Askenasy, Enosh M; Yaniv, Isaac; Stein, Jerry

    2013-02-01

    Graft-versus-host disease (GVHD) can be prevented by Fas-mediated selective depletion of host-sensitized donor lymphocytes ex vivo. We tested the hypothesis that Fas-mediated depletion of lymphocytes in the absence of host-specific antigenic stimulation can alleviate GVHD. Brief exposure (24 hours) of unstimulated donor lymphocytes to Fas ligand (FasL) ex vivo results in balanced apoptosis of CD8(+) and CD4(+) subsets with preferential depletion of CD62L and CD69, increased T regulatory fractions, and sustained responses to stimulation. This procedure ameliorates weight loss and improves the clinical and histologic score of skin and gastrointestinal GVHD with and without concurrent transplantation of hematopoietic progenitors and irrespective of conditioning-induced tissue injury. Although FasL-resistant donor T cells are less potent effectors of GVHD, they facilitate hematopoietic progenitor engraftment when infused with or after the graft and retain the potential to elaborate graft-versus-tumor reactions. These findings in a preclinical model together with the known trophic effects of FasL on primitive hematopoietic progenitors suggest that brief ex vivo incubation of hematopoietic grafts with FasL may improve the outcome and safety of clinical T cell-replete allogeneic and haploidentical transplants.

  4. 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.

  5. Sirolimus, Cyclosporine, and Mycophenolate Mofetil in Preventing Graft-versus-Host Disease in Treating Patients With Hematologic Malignancies Undergoing Donor Peripheral Blood Stem Cell Transplant

    Science.gov (United States)

    2016-09-06

    Adult Acute Lymphoblastic Leukemia; Adult Acute Myeloid Leukemia; Adult Diffuse Large B-Cell Lymphoma; Adult Myelodysplastic Syndrome; Adult Non-Hodgkin Lymphoma; Aggressive Non-Hodgkin Lymphoma; Childhood Acute Lymphoblastic Leukemia; Childhood Acute Myeloid Leukemia; Childhood Diffuse Large B -Cell Lymphoma; Childhood Myelodysplastic Syndrome; Childhood Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Chronic Lymphocytic Leukemia in Remission; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Hematopoietic and Lymphoid Cell Neoplasm; Mantle Cell Lymphoma; Plasma Cell Myeloma; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; T-Cell Chronic Lymphocytic Leukemia; T-Cell Prolymphocytic Leukemia; Waldenstrom Macroglobulinemia

  6. Benzimidazoisoquinolines: a new class of rapidly metabolized aryl hydrocarbon receptor (AhR ligands that induce AhR-dependent Tregs and prevent murine graft-versus-host disease.

    Directory of Open Access Journals (Sweden)

    Sumit Punj

    Full Text Available The aryl hydrocarbon receptor (AhR is a ligand-activated transcription factor that plays multiple roles in regulation of immune and inflammatory responses. The ability of certain AhR ligands to induce regulatory T cells (Tregs has generated interest in developing AhR ligands for therapeutic treatment of immune-mediated diseases. To this end, we designed a screen for novel Treg-inducing compounds based on our understanding of the mechanisms of Treg induction by the well-characterized immunosuppressive AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD. We screened a ChemBridge small molecule library and identified 10-chloro-7H-benzimidazo[2,1-a]benzo[de]Iso-quinolin-7-one (10-Cl-BBQ as a potent AhR ligand that was rapidly metabolized and not cytotoxic to proliferating T cells. Like TCDD,10-Cl-BBQ altered donor CD4(+ T cell differentiation during the early stages of a graft versus host (GVH response resulting in expression of high levels of CD25, CTLA-4 and ICOS, as well as several genes associated with Treg function. The Treg phenotype required AhR expression in the donor CD4(+ T cells. Foxp3 was not expressed in the AhR-induced Tregs implicating AhR as an independent transcription factor for Treg induction. Structure-activity studies showed that unsubstituted BBQ as well as 4, 11-dichloro-BBQ were capable of inducing AhR-Tregs. Other substitutions reduced activation of AhR. Daily treatment with 10-Cl-BBQ during the GVH response prevented development of GVH disease in an AhR-dependent manner with no overt toxicity. Together, our data provide strong support for development of select BBQs that activate the AhR to induce Tregs for treatment of immune-mediated diseases.

  7. NLRP3 inflammasome and its role in graft versus host disease%NLRP3炎性复合体及其在移植物抗宿主病中的作用

    Institute of Scientific and Technical Information of China (English)

    仲小敏

    2015-01-01

    Nucleotide-binding oligomerization domain receptor (NLR) family pyrin domain containing protein (NLRP)3 inflammasome is a kind of macromolecular protein complex.It regulates the maturity and secretion of cytokine interleukin (IL)-1β,-18,and cysteine-aspartic protease (caspase)-1 dependented cell death (pyroptosis),through caspase-1.Its activation was strictly controlled.In recent years,many research results showed that the NLRP3 inflammasome was closely related to the occurrence,development and severity of graft versus host disease (GVHD).This article reviews literatures on NLRP3 inflammasome complex and its role in the prevention and control of GVHD.%核苷酸结合寡聚化结构域样受体(NLR)家族含热蛋白结构域蛋白(NLRP)3炎性复合体为大分子蛋白复合物,通过半胱氨酸天冬氨酸蛋白酶(caspase)-1调控细胞因子白细胞介素(IL)-1β、-18成熟与分泌,诱导caspase-1依赖性细胞死亡(pyroptosis),其激活过程受到严密调控.近年来,多项研究结果显示NLRP3炎性复合体与移植物抗宿主病(GVHD)的发生、发展及其严重程度密切相关.笔者拟就NLRP3炎性复合体及其在GVHD防治中的作用进行综述.

  8. Chronic cutaneous graft-versus-host disease: a case report and literature review%皮肤慢性移植物抗宿主病1例并文献复习

    Institute of Scientific and Technical Information of China (English)

    熊晓刚; 刘业强; 徐晓; 刘波; 雷晴; 卢军; 余泽莹; 陈方元; 涂圣安

    2012-01-01

    报告1例皮肤慢性移植物抗宿主病.患者男,25岁.全身泛发性皮损5年,主要表现为全身弥漫性色素减退伴色素加深的苔藓样斑片.面部呈现激素依赖性皮炎样表现.毛发稀疏,眉毛和腋毛脱落,睫毛及阴毛发白.手(足)指(趾)甲失去光泽,表面有纵嵴,部分缺损、萎缩.臀部皮损组织病理检查表现为苔藓样浸润模式.诊断:皮肤慢性移植物抗宿主病.给予糖皮质激素及他克莫司系统治疗,皮损改善不明显.%A 25-year-old man presented with a 5-year history of hyperpigmented and hypopigmented lichenoid skin lesions all over the body. There was steroid-dependent dermatitis-like manifestation on the face. Hair loss was evident on the scalp, eyebrows, armpit. Eyelashes and pubic hairs were white. Nail changes included brittleness, roughness, longitudinal ridges, and onychomadesis and onychatrophia. Histopathology of skin lesions on the buttocks revealed a pattern of lichenoid infiltration. The diagnosis was made as chronic cutaneous Graft-versus-host disease. The patient received daily oral corticosteroids in combination with systemic tacrolimus. No improvement had been obtained.

  9. De novo glomerulitis associated with graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: A single-center experience

    Directory of Open Access Journals (Sweden)

    Yul Hee Cho

    2013-09-01

    Conclusion: In this study the findings of 15 renal biopsies were analyzed and to our knowledge this is the largest clinicopathological study of GVHD-related biopsy-proven nephropathy. Approximately 80% of the patients were MN and 73% responded either partially or completely to immunosuppressive treatment. Currently, there is an increase in the incidence of GVHD-mediated renal disease, and therefore, renal biopsy is essential for diagnosing the nephropathy and preventing the progression of renal disease.

  10. Human Gingiva-Derived Mesenchymal Stem Cells Inhibit Xeno-Graft-versus-Host Disease via CD39–CD73–Adenosine and IDO Signals

    Science.gov (United States)

    Huang, Feng; Chen, Maogen; Chen, Weiqian; Gu, Jian; Yuan, Jia; Xue, Yaoqiu; Dang, Junlong; Su, Wenru; Wang, Julie; Zadeh, Homayoun H.; He, Xiaoshun; Rong, Limin; Olsen, Nancy; Zheng, Song Guo

    2017-01-01

    Mesenchymal stem cells have the capacity to maintain immune homeostasis and prevent autoimmunity. We recently reported that human-derived gingival mesenchymal stem cells (GMSCs) have strong capacity to suppress immune responses and T cell-mediated collagen-induced arthritis in animals. However, it is unclear whether these cells can suppress human T cell-mediated diseases. Here, we used a xenogenic GVHD model in the NOD/SCID mouse, which is a useful preclinical construct for evaluating the therapeutic and translational potential of this approach for applications in human disease. We found that GMSCs potently suppressed the proliferation of PBMC and T cells in vitro. Co-transfer of GMSC with human PBMC significantly suppressed human cell engraftment and markedly prolonged the mouse survival. Moreover, we demonstrated that GMSCs inhibited human PBMC-initiated xenogenic responses via CD39/CD73/adenosine and IDO signals. These findings suggest the potential for GMSCs to suppress human immune responses in immune system-mediated diseases, offering a potential clinical option to be used for modulating GVHD and autoimmune diseases. PMID:28210258

  11. Chronic inflammatory demyelinating polyradiculoneuropathy in chronic graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: case report Polirradiculoneuropatia desmielinizante inflamatória crônica na doença do enxerto contra o hospedeiro após transplante de células hematopoiéticas alogênicas: relato de caso

    Directory of Open Access Journals (Sweden)

    Paulo José Lorenzoni

    2007-09-01

    Full Text Available The chronic inflammatory demyelinating polyradiculoneuropathy (CIDP is an unusual but important complication of hematopoietic stem cell transplantation (HSCT rarely reported to date. We describe a 17-year-old woman with a diagnosis of acute myeloid leukemia due to Fanconi's anemia who was submitted to allogeneic HSCT and developed CIDP as part of graft-versus-host disease. Investigation showed high cerebrospinal fluid protein; electrophysiological studies revealed sensory-motor demyelinating polyradiculoneuropathy; muscle and nerve biopsy were compatible with CIDP.A polirradiculoneuropatia desmielinizante inflamatória crônica (CIDP é uma incomum, porém, importante complicação do transplante de células hematopoiéticas (HSCT raramente relatada até a data. Nós descrevemos uma mulher de 17 anos com diagnóstico de leucemia mielóide aguda por anemia de Fanconi que foi submetida à HSCT e desenvolveu CIDP como parte da doença do enxerto contra o hospedeiro. A investigação mostrou elevação na proteína no líquor; estudo eletrofisiológico revelando polirradiculoneuropatia desmielinizante sensitivo-motora; e biópsia de músculo e nervo compatível com CIDP.

  12. Allogeneic splenocyte transfer and lipopolysaccharide inhalations induce differential T cell expansion and lung injury: a novel model of pulmonary graft-versus-host disease.

    Directory of Open Access Journals (Sweden)

    Tereza Martinu

    Full Text Available BACKGROUND: Pulmonary GVHD (pGVHD is an important complication of hematopoietic cell transplant (HCT and is thought to be a consequence of the HCT conditioning regimen, allogeneic donor cells, and posttransplant lung exposures. We have previously demonstrated that serial inhaled lipopolysaccharide (LPS exposures potentiate the development of pGVHD after murine allogeneic HCT. In the current study we hypothesized that allogeneic lymphocytes and environmental exposures alone, in the absence of a pre-conditioning regimen, would cause features of pGVHD and would lead to a different T cell expansion pattern compared to syngeneic cells. METHODS: Recipient Rag1-/- mice received a transfer of allogeneic (Allo or syngeneic (Syn spleen cells. After 1 week of immune reconstitution, mice received 5 daily inhaled LPS exposures and were sacrificed 72 hours after the last LPS exposure. Lung physiology, histology, and protein levels in bronchoalveolar lavage (BAL were assessed. Lung cells were analyzed by flow cytometry. RESULTS: Both Allo and Syn mice that undergo LPS exposures (AlloLPS and SynLPS have prominent lymphocytic inflammation in their lungs, resembling pGVHD pathology, not seen in LPS-unexposed or non-transplanted controls. Compared to SynLPS, however, AlloLPS have significantly increased levels of BAL protein and enhancement of airway hyperreactivity, consistent with more severe lung injury. This injury in AlloLPS mice is associated with an increase in CD8 T cells and effector CD4 T cells, as well as a decrease in regulatory to effector CD4 T cell ratio. Additionally, cytokine analysis is consistent with a preferential Th1 differentiation and upregulation of pulmonary CCL5 and granzyme B. CONCLUSIONS: Allogeneic lymphocyte transfer into lymphocyte-deficient mice, followed by LPS exposures, causes features of pGVHD and lung injury in the absence of a pre-conditioning HCT regimen. This lung disease associated with an expansion of allogeneic effector

  13. 慢性移植物抗宿主病相关性多发性肌炎一例临床和骨骼肌病理特点%Clinical and muscular pathological features with chronic graft-versus-host disease-related polymyositis: one case report

    Institute of Scientific and Technical Information of China (English)

    孟令超; 张巍; 王朝霞; 高枫; 袁云

    2012-01-01

    Objective To report the clinical and pathological features of chronic graft-versus-host disease-related polymyositis by summarizing the clinical data of the patient with chronic graft-versus-host disease-related polymyositis. Methods One patient with chronic graft-versus-host disease-related polymyositis was hospitalized in our hospital on December 29,2010.The patient,40 years old,female,underwent allogeneic haematopoietic stem cell transplantation because of acute granulocytic-monocytic leukemia.Fourteen months later she manifested as slowly progressive muscle weakness and myalgia in all limbs.Serum creatine kinase level was between 426-1948 U/L. Myositis antibody EJ was strongly positive.Electromyogram showed a neurogenic impairment and slow peripheral nerve conduction speed.Muscle biopsies were carried out in the left biceps brechii.In addition of standard histological and enzyme histochemical staining for the muscle sections,immunohistochemical workup was performed with mouse antiCDs,anti-CD20,anti-CD68 and anti major histocompatibility complex- Ⅰ ( MHC- Ⅰ ) monoclonal antibodies as first antibodies.Results The muscle biopsy showed large variation of fiber size,with muscle fiber necrosis,regeneration.Some angular fibers distributed in small cluster.The inflammatory cells infiltrated around the small vessel or in the endomysium,mainly CD8+ T-lymphocytes and CD6+8 macrophages.The most muscle fibers were MHC-Ⅰ positive. Conclusion The graft-versus-host disease-related polymyositis manifests as chronic myositis process with neurogenic lesions.%目的 报道1例慢性移植物抗宿主病相关性多发性肌炎患者的临床和骨骼肌病理改变特点.方法 我院于2010年12月29日收治1例慢性移植物抗宿主病相关性多发性肌炎患者,该患者为女性,40岁,因急性粒单核细胞白血病于20个月前行异基因造血干细胞移植术.术后给予环孢素A抗排异治疗13个月,6个月前缓慢出现进行性四肢近端无力,

  14. 胃肠型GVHD患者不同营养方案的临床疗效%Clinical effect of different nutrition supporting schemes on gastrointestinal graft-versus-host disease

    Institute of Scientific and Technical Information of China (English)

    李云龙; 张曦; 高蕾; 刘耀; 高力; 张诚; 刘焕凤; 刘学; 陈幸华

    2011-01-01

    Objective To compare the effect of two nutrition supporting schemes for the improvement of the nutrition situation and the therapy of patients with gastrointestinal graft-versus-host disease(GVHD). Methods 35 cases of patients with gastrointes tinal GVHD were randomly divided into total praenteral nutrition(TPN) group and oral diet(OD) group. The nutrition situation and therapeutic effect of the two groups were evaluated before therapy,and on the 14th and 28th day after therapy. Results Nitrogen balance was negative in all subjects on the 14th and 28th day. The remission rate of TPN group was higher than that of OD group(P<0.05). Conclusion The nutritional situation of patients with gastrointestinal GVHD are poor, and might get worse with the extension of the course of disease. The aggravating speed of nutritional situation in patients with gastrointestinal GVHD accepting TPN scheme might be slow,indicating that TPN scheme could be beneficial to patients with gastrointestinal GVHD.%目的 比较不同营养支持方案对胃肠道移植物抗宿主病(GVHD)患者营养状况改善的作用,并对不同营养方案进行评价,观察不同营养方案对胃肠道GVHD辅助治疗的疗效.方法 对35例胃肠道GVHD患者随机分为完全肠外营养组(TPN)和经口饮食组(OD),分别于治疗后的0、14、28 d评价患者的营养状况和GVHD临床疗效.结果 35例胃肠道GVHD患者在治疗后14、28 d均为负氮平衡.患者的GVHD临床症状缓解率显示,TPN组大于OD组,P<0.05.结论 胃肠道GVHD患者属于营养不良状况,并且随着疾病时间的延长,营养不良状况加重,加重的程度TPN组最慢.TPN有助于抗胃肠道GVHD治疗.

  15. A glucocorticoid amplifies IL-2-induced selective expansion of CD4+CD25+FOXP3+ regulatory T cells in vivo and suppresses graft-versus-host disease after allogeneic lymphocyte transplantation

    Institute of Scientific and Technical Information of China (English)

    Yanhui Xie; Min Wu; Runhua Song; Jiexian Ma; Yi Shi; Wenming Qin; Youxin Jin

    2009-01-01

    Regulatory T (Treg) cells are a subpopulation of T cells that not only prevent autoimmunity, but also control a wide range of T cell-dependent immune responses. Glucocorticoid treatment (dexamethasone, or Dex) has been reported to amplify IL-2-mediated selective in vivo expansion of Treg cells. We simultaneously adminis-tered Dex and IL-2 to the donor in a murine allogeneic lymphocyte transplantation model to expand functional suppressive CD4+CD25+FOXP3+ T cells in the graft and to raise the regulatory T cell/effector T cell (Treg/ Teff) ratio to prevent graft-versus-host disease (GVHD). After combined treatment of the donor with Dex (5 mg/kg/day) and IL-2 (300,000 IU/mouse/day) for 3 days, grafts were subjected to flow cytometric analy-sis, and transplantation was carried out from male C57BL/6 mice to female BALB/c mice aged 8-12 weeks. Results showed that short-term simultaneous administration of Dex and IL-2 markedly expanded functional suppressive CD4+CD25+FOXP3+ T cells in the murine spleen. In this murine allogeneic transplan-tation model, the grafts from donors with Dex and IL-2 pre-treatment led to a longer survival time for the reci-pients than for the control group (median survival time> 60 day vs. 12 day, P = 0.0002). The ratio of Treg/Teff also increased remarkably (0.43 ±0.15 vs. 0.14± 0.01, P=0.01). This study demonstrated that co-stimulation with Dex and IL-2 selectively expanded functional CD4+CD25+FOXP3+ T cells in vivo, and that grafts from donors pre-treated with Dex and IL-2 led to longer survival time and greater suppression of GVHD after allogeneic transplantation. Thus, GVHD can be suppressed by the specific expansion of regulatory T cells with Dex and IL-2 in graft donors.

  16. 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 tr

  17. Role of small-dose decitabine in treatment of early recurrence and chronic graft versus host disease after allogeneic hematopoietic stem cell transplantation%小剂量地西他滨在异基因造血干细胞移植后早期复发及cGVHD治疗中的作用

    Institute of Scientific and Technical Information of China (English)

    王晓果; 陈婷; 刘焕凤; 邓天霞; 刘俊; 张诚; 张曦; 孔佩艳

    2016-01-01

    目的 分析小剂量地西他滨(decitabine/dacogen,DAC)治疗异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation,allo-HSCT)后慢性移植物抗宿主病(chronic graft versus host disease,cGVHD)患者的转归情况.方法 收集2013年6月25日至2015年7月7日我院行allo-HSCT术后早期复发及发生cGVHD,并接受小剂量DAC治疗的4例患者,包括急性髓系白血病(acute myeloid leukemia,AML)3例,骨髓增生异常综合征(myelodysplastic syndrome,MDS)1例.对其诊断、移植方式、cGVHD分型及评分、以及DAC治疗后转归进行分析.结果 4例接受小剂量DAC的患者,cGVHD症状减轻,无严重的血液学毒性.1例因严重肺部感染放弃治疗,3例目前病情稳定.结论 小剂量DAC可减轻allo-HSCT术后cGVHD症状,改善患者生存质量,并对早期复发的控制有一定的效果.

  18. The successful use of alemtuzumab for treatment of steroid-refractory acute graft-versus-host disease in pediatric patients.

    Science.gov (United States)

    Khandelwal, Pooja; Lawrence, Julia; Filipovich, Alexandra H; Davies, Stella M; Bleesing, Jacob J; Jordan, Michael B; Mehta, Parinda; Jodele, Sonata; Grimley, Michael S; Kumar, Ashish; Myers, Kasiani; Marsh, Rebecca A

    2014-02-01

    SR-aGVHD remains a significant cause of morbidity and mortality in allogeneic HCT recipients. Alemtuzumab has been used with success in adult patients but has not been studied in the pediatric setting. To estimate the effectiveness of alemtuzumab for the treatment of SR-aGVHD in pediatric patients, we retrospectively reviewed the charts of 19 patients (median age 4 yr, range 0.5-28 years) with grades II (n = 3), III (n = 10), or IV (n = 6) SR-aGVHD who received alemtuzumab treatment. Patients received a median dose of 0.9 mg/kg alemtuzumab (range 0.3-2 mg/kg) divided over 2-6 days. Eighty-nine percent of patients received additional courses. A complete response, defined as GVHD of grade 0 at four wk following the first alemtuzumab course, was observed in nine patients (47%). A partial response, defined as an improvement in grade after four wk, was observed in five patients (26%). There was no response in five patients (26%). The overall response rate at four wk was 73%. Infectious complications included bacteremia (47%), presumed or documented fungal infections (21%), adenovirus viremia (52%), EBV viremia (36%), and CMV viremia (36%). We conclude that alemtuzumab is effective for SR-aGVHD in pediatric patients with a tolerable spectrum of complications.

  19. Doença do enxerto contra hospedeiro pós-transfusional-guia para irradiação gama de hemocomponentes Transfusion-associated graft-versus-host disease-guideline on gamma irradiation of blood components

    Directory of Open Access Journals (Sweden)

    E.P. Landi

    1999-07-01

    Full Text Available A doença enxerto contra hospedeiro transfusional (DECHT é síndrome rara e geralmente fatal. É caracterizada por febre, eritema cutâneo, náuseas, vômitos, diarréia, hepatite e pancitopenia. Pode ocorrer em pacientes com imunossupressão severa e em pacientes imunocompetentes após a transfusão de hemocomponente celular de doador homozigoto para proteínas HLA às quais o receptor é heterozigoto. O diagnóstico é feito pelo quadro clínico e exame histopatológico da pele. A gamaglobulina antitimocítica associada a altas doses de corticosteróides é a terapêutica mais empregada. O desconhecimento da síndrome, o retardo no diagnóstico, o curso rápido e a ausência de resposta ao tratamento estão relacionados à má evolução dos pacientes. A melhor forma de abordagem da DECHT é a prevenção através da irradiação gama dos hemocomponentes. A dose necessária para completa inativação dos linfócitos T é de 2500 cGy. A principal alteração decorrente da irradiação é o aumento da concentração de potassio nos concentrados de hemácias. Os filtros de leucócitos não previnem o desenvolvimento da DECHT e a irradiação não previne a aloimunizaçao e as reaçoes transfusionais. Apenas hemocomponentes celulares como sangue total, concentrado de hemácias, concentrado de plaquetas e concentrado de granulócitos, necessitam ser irradiados. Devem ser irradiados os hemocomponentes para transfusão entre familiares, transfusões HLA compatíveis, pacientes submetidos a transplante de medula óssea, portadores de doença de Hodgkin, pacientes tratados com análogos da purina, transfusões intra-útero, recém nascidos pré-termo e pacientes com síndrome de imunodeficiência congênita. É recomendável a irradiação de hemocomponentes destinados a pacientes com doenças neoplásicas quando submetidos a protocolos de quimioterapia agressivos.Transfusion-associated graft-versus-host disease (TA-GVHD is a rare and usuailly fatal

  20. Experimental study of G-CSF alleviating graft-versus-host disease after mixed bone marrow transplantation in mice%粒细胞集落刺激因子减轻混合骨髓移植后移植物抗宿主病的实验研究

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective: How to reduce the incidence and severity of acute graft-versus-host disease (aGVHD) is a crucial step to improve the overall survival of allogeneic bone marrow transplantation (allo-BMT). The low incidence of severe aGVHD observed in allogeneic peripheral blood stem cell transplantation (allo-PBSCT), which may be related to modulating immune function of T lymphocytes by granulocyte colony-stimulating factor (G-CSF) primed donors. The study aimed to explore whether aGVHD could be alleviated by syngeneic bone marrow mixed with G-CSF-mobilized H-2 haploidentical marrow grafting. Methods: Female BALB/c mice and neonatal BALB/c mice were recipients and male (BALB/c × C57BL/6)F1(BCF1)mice were donor mice respectively. Donor mice were injected subcutaneously with G-CSF daily at 0.01 μg/g body weight or saline for 6 days, and splenocytes were harvested on day 6. Spleen index (SI) represented GVHD in neonatal mice after the intraperitoneal injection of mixed spleen cells. Lethally irradiated (60Co, 8.5 Gy) adult mice were transplanted with a mixture of syngeneic plus G-CSF-mobilized (control diluents) H-2 haploidentical marrow cells. Survival time and survival rate of the recipients were observed after mixed marrow transplantation (MBMT). GVHD was assessed by observing signs of weight loss, ruffled fur, diarrhea and histological change of skin, liver and small intestines. Enzyme-linked immunosorbent assay (ELISA) method was used to detect cytokines (IL-2, IL-4 and INF-Y). Fluorescence-activated cell sorting (FACS) analysis was used to detect T cells phenotype. Results: (1) The neonatal mice subject to injection of 2:1 and 1:1 mixed spleen cells and H-2 haploidentical spleen cells all suffered from aGVHD. The severity of aGVHD in recipient mice receiving G-CSF-mobilized splenocytes was dramatically reduced. (2) The aGVHD signs and histological change were observed in most mice of 2:1 and 1:1 MBMT groups. However, the survival time of G-CSF-mobilized MBMT was

  1. Tacrolimus and Mycophenolate Mofetil in Preventing Graft-Versus-Host Disease in Patients Who Have Undergone Total-Body Irradiation With or Without Fludarabine Phosphate Followed by Donor Peripheral Blood Stem Cell Transplant for Hematologic Cancer

    Science.gov (United States)

    2016-01-25

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous

  2. Effects of immature dendritic cells to express CCR7 on graft-versus-host disease in allogeneic bone marrow transplant mouse model%趋化因子受体7基因修饰的未成熟树突细胞对小鼠移植物抗宿主病的作用研究

    Institute of Scientific and Technical Information of China (English)

    李德鹏; 武家庆; 黄一虹; 宋立孝; 谷红红; 高彩玲; 李振宇; 潘秀英; 徐开林

    2013-01-01

    Objective To investigate the effects of immature dendritic cells (imDC) expressing chemokine receptor-7 (CCR7) on acute graft-versus-host disease (aGVHD)in allogeneic bone marrow transped (allo-BMT) mouse model.Methods We constructed the lentiviral vectors carrying mouse CCR7 gene and infect imDC effectively in vitro.GVHD model was established with C57BL/6(H-2b) donor mice and BALB/c (H-2d) recipient mice.After irradiation,recipients were injected with donor bone marrow and spleen cells along with CCR7-modified dendritic cells.Mice were randomized into irradiation,transplant control,pXZ9-imDC (empty vector control) and CCR7-imDC groups.Survival,GVHD score,histopathological analysis and plasma levels of inflammatory cytokines were observed.Results The mean survival in irradiation,transplantation,pXZ9-imDC and CCR7-imDC groups were (8.20± 1.48)d,(12.20± 2.78) d,(20.70 ± 6.01)d and (27.5 ± 7.55)d respectively.The survival in CCR7-imDC group was significantly improved compared with other groups (P<0.05).GVHD scores in transplantation,pXZ9-imDC and CCR7-imDC groups were (6.90± 1.66),(5.60±0.97) and (4.10± 1.79) respectively.CCR7-imDC group had significantly lower GVHD score and minor tissue damages shown by histopathological analysis than the other groups.Plasma IFN-γ level increased and reached the peak at +10 day in transplant group,while it gradually decreased in pXZ9-imDC and CCR7-imDC groups,and then reached the nadir at +20 day post-allo-BMT,with the lowest level in CCR7-imDC group (P<0.01).Plasma IL-4 decreased in transplant group,while it gradually increased in pXZ9-imDC and CCR7-imDC groups and reached the highest level at + 10 day in CCR7-imDC group (P<0.01).The 95%-100% of H-2b positive cells in recipient mice on + 30 day post-allo-BMT demonstrated the complete donor-type implantation.Conclusion Genetically modified immature DC by CCR7 gene could alleviate damages by GVHD and prolong survival of recipient mice after allo-BMT.%目的

  3. Detection of Th17/Treg Cell-Associated Cytokines in Peripheral Blood of Patients with Graft-Versus-Host Disease and Its Clinical Significance%GVHD患者外周血Th17/Treg细胞相关的细胞因子检测与临床意义

    Institute of Scientific and Technical Information of China (English)

    王静; 王兴兵; 汪健; 刘会兰; 耿良权; 丁凯阳; 孙自敏

    2011-01-01

    本研究旨在探讨急性移植物抗宿主病(aGVHD)、慢性GVHD(cGVHD)患者外周血中Th17/Treg细胞相关的细胞因子的水平与临床意义.外周血样品采集自造血干细胞移植术后患者和健康人,其中aGVHD组10例、cGVHD组13例、无GVHD组16例,健康人20名.采用酶联免疫吸附方法(ELISA)检测各组外周血血浆中细胞因子IFN-γ、IL-4、IL-6、IL-10、TGF-β1、IL-17、IL-23的表达水平.结果表明:a/cGVHD组IFN-γ、IL-4、IL-6、IL-17及IL-23水平显著高于无GVHD组和健康人(p<0.05),而IL-10、TGF-β1水平显著低于无GVHD组和健康人(p<0.05).aGVHD和cGVHD组患者治疗有效后,外周血中IL-6、IL-17及IL-23水平较治疗前明显降低;IL-10、TGF-β1水平明显升高,而IFN-γ、IL-4无明显变化.各组患者血浆中TGF-β1与IL-6、TGF-β1与IL-17、TGF-β1与IL-23水平呈负相关(r分别等于-0.36、-0.51和-0.44,p均<0.05),IL-6与IL-17、IL-6与IL-23、IL-17与IL-23水平呈正相关(r分别等于0.62、0.71和0.93,p均<0.05).结论:Th17/Treg细胞相关的细胞因子可能在aGVHD和cGVHD的发生、发展中具有重要作用,对它们的研究有助于寻找治疗a/cGVHD的新犯点.%To investigate the peripheral levels and clinical significance of Th17/Treg cell-associated cytokines in patients with acute graft versus host disease (aGVHD) or chronic GVHD ( cGVHD), blood samples were collected from 39 hematopoietic stem-cell transplantation patients and 20 healthy donors. The patients included 10 patients with aGVHD, 13 patients with cGVHD and 16 patients without evidence of GVHD. Th17/Treg cell-associated cytokines such as IFNγ, IL-4, IL-6, IL- 10, TGF-β1 , IL-17 and IL-23 were detected by ELISA. The results showed that the plasma levels of IFN-γ, IL-4, IL-6, IL-17 and IL-23 significantly increased in patients with aGVHD or cGVHD, compared with the patients without clinical signs of GVHD and the healthy donors (p < 0.05 ), while IL-10 and TGF-β1 were obviously lower than

  4. Impact of Inflammatory Cytokine Gene Polymorphisms on Developing Acute Graft-versus-Host Disease in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Riccardo Masetti

    2015-01-01

    Full Text Available Single nucleotide polymorphisms (SNPs in gene encoding pro- and anti-inflammatory factors have been associated with the occurrence of aGvHD. We retrospectively tested a wide panel of 38 polymorphisms in 19 immunoregulatory genes, aiming to first establish, in a pediatric HSCT setting, which SNPs were significantly associated with the development of aGvHD. A significant association was found between aGvHD grades II–IV and SNPs of donor IL10-1082GG, and Fas-670CC + CT and recipient IL18-607 TT + TG genotype. aGvHD grades III-IV resulted associated with donor IL10-1082GG, Fas-670CC + CT, and TLR4-3612TT as well as the use of peripheral CD34+ cells as stem cell source. The multivariate analysis confirmed the association between donor IL10-1082GG and Fas-670CC + CT and aGvHD grades II–IV and between donor IL10-1082GG and TLR4-3612TT and aGvHD grades III-IV. In conclusion we found an association between IL10, FAS, and TLR4 in the donor and IL18 in the recipient and an increased risk of developing aGvHD in transplanted children. Knowledge of the SNPs of cytokine genes associated with aGvHD represents a useful tool for an integrated pretransplantation risk assessment and could guide the physicians to an optimal and more accurate HSCT planning.

  5. Prevention of cyclosporine A combined with Cobalt protoporphyrin against murine graft-versus-host disease after allogeneic hematopoietic stem cell transplantation%环孢素A联合钴原卟啉预防小鼠HSCT后移植物抗宿主病

    Institute of Scientific and Technical Information of China (English)

    王祥民; 潘秀英; 曾令宇; 安立才; 陈伟; 张翠平; 潘彬; 徐开林

    2012-01-01

    Objective To explore prevention of cyclosporine A (CsA) combined with Cobalt protoporphyrin (CoPP) against murine graft versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods C57BL/6 (H-2Kb) mice were used as donors and BALB/c (H-2Kd) mice as recipients,which were randomly divided into 4 groups.The mice in total body irradiation group (TBI group) were lethally irradiated and injected intravenously with PBS; The mice in Allo-HSCT group (BS group) were lethally irradiated and injected intravenously with bone marrow cells and spleen cells; The mice in CsA intervention group (CsA group) were injected with CsA intraperitoneally after allo-HSCT; The mice in CsA combine with CoPP intervention group (combination group) received both CsA and CoPP intraperitoneally after alloHSCT.Recipients were monitored for condition,survival rate and weight.The liver,small intestine and skin in the recipients were gained and pathological changes of GVHD were assessed.The kidney was stained with Masson staining dye to observe the tissue fibrosis.The expression levels of renal HO-1 mRNA in the recipients were detected.Results In contrast to BS and CsA groups,GVHD degree in combination group was mild,with less reduction and quick recovery of weight.On the day 30 after HSCT,survival rate in BS group was 36.8%,and that in combination group and CsA group was 69.6% and 53.5% respectively (P<0.05).In comparison with BS and CsA groups,pathological changes in combination group were mild,cellular edema and degeneration degree of the liver,small intestine and skin were slight,and few necrosis and infiltrated inflammatory cells were observed.Tubulointerstitial fibrosis hardly occurred in combination group,but it occurred in CsA group abundantly.As compared with BS group,the expression levels of HO-1 mRNA was increased in combination group,while decreased in CsA group (P<0.05).Conclusion CsA combined with CoPP enhanced the protective effect of

  6. Establishment of a Murine Model of Chronic Graft-Versus-Host Disease After Minor Histocompatibility Antigen Mismatched Bone Marrow Transplantation%miHA不合异基因骨髓移植后慢性移植物抗宿主病小鼠模型的建立

    Institute of Scientific and Technical Information of China (English)

    黄欣; 翁建宇; 吴萍; 童嘉琦; 杜欣

    2014-01-01

    Objective To establish a murine model of chronic graft-versus-host disease (cGVHD) after major histocompatibility complex (MHC) matched and minor histocompatibility antigen (miHA) mismatched allogeneic bone marrow transplantation,and to provide in vivo research tools for cGVHD.Methods 20 recipients BALB/c (H2d) female mice were included in this study.They were divided into blank control group (n =5),irradiation control group (n =5),transplantation group (n =5) and the cGVHD group (n=5).In addition to the blank control group,the rest of the three groups of mice were irradiated with 700 cGy dose of linear accelerator.Then the irradiation control group were injected with 0.2 ml PPMI 1640; the trarsplantation group were injected with 8 × 106 bone-marrow cells,and cGVHD group were injected with bone-marrow cells and spleen cells (8× 106,1 ∶ 1) from B10.D2(Hc1 H2d H2-T18c) male mice.The observed items post-transplantation included hematopoietic reconstruction,implant,and general condition.Clinical scores were assessed every 3 days after +14 d.At + 50 d,mice were put to death for evaluation target organ pathological changes.Animal Intervention met animal ethical standard.Results Mice in transplantation groups were in hematopoietic reconstruction at +7 d,and all survived to the end point (+ 50 d).Chromosomes of recipient mice were in donor form.Clinical scores of cGVHD group have been more than 0.6 since +20 d.Pathological changes of skin,liver and lung were obviously,and pathological scores were significant higher than those of transplantation control groups (F=88.02,P< 0.05).Conclusions Irradiation dose for 700 cGy,8× 106 of bone marrow and spleen cell number infusion induce a successful cGVHD murine model,which might be an ideal study model of clinical cGVHD after bone marrow transplantation.%目的 通过主要组织相容性复合物(MHC)相合,次要组织相容性抗原(miHA)不合的异基因骨髓移植,建立慢性移植物抗宿主病(cGVHD)小鼠模型,

  7. 扁平苔藓样慢性移植物抗宿主病一例%Lichen planus-type chronic graft-versus-host disease:a case report

    Institute of Scientific and Technical Information of China (English)

    徐俊涛; 周慧; 刘菡

    2016-01-01

    患者,男,40岁。躯干泛发苔藓样皮损伴瘙痒1个月。患者1年前因“急性粒细胞白血病”行异体造血干细胞移植术。皮损组织病理示基底细胞液化变性,有嗜酸性变的角质形成细胞似胶样小体,周围淋巴细胞卫星状分布,真皮浅层淋巴细胞等呈带状浸润。诊断:扁平苔藓型慢性移植物抗宿主病。%A 40-year-old male presented with lichenoid lesions over the trunk, with itching for 1 month. The patient had a history of acute myeloid leukemia and was treated with allogeneic hematopoietic stem cell transplantation 1 year ago. Histopathology of skin lesions revealed liquefaction degeneration of basal cell, civatte bodies-like keratinocyte which surrounded by lymphocytes in satellite-like distribution and banded infiltration of lymphocytes in dermis. The diagnosis of lichen planus-type chronic graft-versus-host disease was made.

  8. Busulfan and melphalan as conditioning regimen for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia in first complete remission

    Directory of Open Access Journals (Sweden)

    Nadjanara Dorna Bueno

    2011-06-01

    Full Text Available BACKGROUND: Allogeneic hematopoietic stem cell transplantation with HLA-identical donors has been established for the treatment of acute myeloid leukemia patients for over 30 years with a cure rate of 50% to 60%. OBJECTIVES: To analyze the overall survival of patients and identify factors that influence the outcomes of this type of transplant in patients in 1st complete remission who received a busulfan and melphalan combination as conditioning regimen. METHODS: Twenty-five consecutive patients with acute myeloid leukemia were enrolled between 2003 and 2008. The median age was 34 years old (Range: 16 - 57 years. All patients received cyclosporine and methotrexate for prophylaxis against graft-versus-host disease. Median neutrophil engraftment time was 16 days (Range: 7 - 22 days and 17 days (Range: 7 - 46 days for platelets. Sinusoidal obstructive syndrome was observed in three patients, seven had grade II acute graft-versus-host disease and one extensive chronic graft-versus-host disease. RESULTS: The overall survival by the Kaplan-Meier method was 48% after 36 months with a plateau at 36 months after transplantation. Intensive consolidation with high-dose arabinoside resulted in an improved survival (p-value = 0.0001, as did grade II acute graft-versus-host disease (p-value = 0.0377 and mild chronic graft-versus-host disease (p-value < 0.0001. Thirteen patients died, five due to infection within 100 days of transplant, two due to hemorrhages, one to infection and graftversus-host disease and three relapses followed by renal failure (one and infection (two. The cause of death could not be determined for two patients. CONCLUSION: The busulfan and melphalan conditioning regimen is as good as other conditioning regimens providing an excellent survival rate.

  9. Large-scale preparation of human anti-third-party veto cytotoxic T lymphocytes depleted of graft-versus-host reactivity: a new source for graft facilitating cells in bone marrow transplantation.

    Science.gov (United States)

    Aviner, Shraga; Yao, Xin; Krauthgamer, Rita; Gan, Yehudit; Goren-Arbel, Rinat; Klein, Tirza; Tabilio, Antonio; McMannis, John D; Champlin, Richard; Martelli, Massimo F; Bachar-Lustig, Esther; Reisner, Yair

    2005-06-01

    Induction of donor type chimerism in mildly prepared hosts without graft-versus-host disease (GvHD) is a most desirable goal in bone morrow transplantation. We have recently demonstrated in a mouse model that donor veto cytotoxic T lymphocytes (CTLs) can facilitate the induction of donor type chimerism in sublethally irradiated recipients without causing GvHD if they are effectively depleted of alloreactivity against host cells by means of stimulation against a third party. We extend this approach to human cells, by preparing CTLs in two major steps: primary culture in the absence of interleukin 2, leading to death by neglect of antihost clones, and addition of interleukin 2 and subsequent dilution of antihost clones as a consequence of the expansion of the anti-third-party clones. CTLs prepared in this way specifically suppress host cytotoxic T cells directed against antigens of the donor, but not against fourth-party antigens, as demonstrated in a standard (51)Cr release assay. We conclude that human anti-third-party CTLs afford a new source of veto cells that are depleted of potential graft-versus-host-reactive clones. The cells generated by this approach could potentially be used to facilitate engraftment of allogeneic hematopoietic stem cells.

  10. Bioimaging for the monitoring of the in vivo distribution of infused mesenchymal stem cells in a mouse model of the graft-versus-host reaction.

    Science.gov (United States)

    Joo, Sun-Young; Cho, Kyung-Ah; Jung, Yun-Jae; Kim, Han-seong; Park, Seong-Yeol; Choi, Yong-Bock; Hong, Kyung-man; Woo, So-Youn; Seoh, Ju-Young; Ryu, Kyung-Ha

    2011-04-01

    Cell therapy using MSCs (mesenchymal stem cells) might be effective treatment for refractory GVHD (graft-versus-host disease). However, the fate and distribution of MSCs after transplantation remains unclear. In this study, an animal model was developed to monitor the dynamic distribution of MSCs in mice with GVHD. A GVHD mouse model was established by transplanting C57BL/6 donor bone marrow cells and C57BL/6 EGFP (enhanced green fluorescent protein) splenocytes into lethally irradiated BALB/c nude recipient mice. Donor MSCs were obtained from MHC-identical C57BL/6 RFP (red fluorescent protein) mice and infused into the recipient mice on the same transplantation day. In vivo movement of the donor splenocytes (EGFP) and MSCs (RFP) were evaluated by measuring the biofluorescence (IVIS-Xenogen system). Donor splenocytes and MSCs reached the lungs first, and then the gastrointestinal tract, lymph nodes and skin, in that order; the transit time and localization site of these cells were very similar. In the recipient mouse with GVHD, the number of detectable cells declined with time, as assessed by biofluorescence imaging and confirmed by RT (real-time)-PCR. This bioimaging system might be useful for preclinical testing and the design of therapeutic strategies for monitoring the dynamic distribution of MSCs with GVHD.

  11. 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 purest...

  12. Immunologic Diagnostic Blood Test in Predicting Side-Effects in Patients Undergoing a Donor Stem Cell Transplant for Hematologic Cancer or Other Diseases

    Science.gov (United States)

    2011-03-03

    Chronic Myeloproliferative Disorders; Graft Versus Host Disease; Infection; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic-Myeloproliferative Diseases; Neuroblastoma; Therapy-related Toxicity

  13. Allogeneic stem cell transplantation in acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    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%.

  14. 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.

  15. 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.

  16. [Prolonged acute pancreatitis after bone marrow transplantation].

    Science.gov (United States)

    De Singly, B; Simon, M; Bennani, J; Wittnebel, S; Zagadanski, A-M; Pacault, V; Gornet, J-M; Allez, M; Lémann, M

    2008-04-01

    Acute pancreatitis is not infrequent after allogenic marrow transplantation. Several causes can predispose to pancreatitis, including Graft-Versus-Host Disease (GVHD), a condition which is probably underestimated. In the literature, few description of pancreatic GVHD can be found. Pancreatic GVHD diagnosis can be difficult if pancreatic involvement occurs without other typical manifestations of GVHD. We report the case of a woman, 54 years old, suffering from prolonged, painful pancreatitis two months after allogenic bone marrow transplantation for acute myeloid leucemia. Pancreatic GVHD diagnosis was performed after five weeks on duodenal biopsies despite the absence of diarrheoa. The patient dramatically improved within few days on corticosteroids.

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

    Directory of Open Access Journals (Sweden)

    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.

  18. Disease: H00084 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available bone marrow transplant. Annu Rev Med 54:29-52 (2003) PMID:15931364 (drug) Iwasaki T. Recent advances in the treatment of graft-versus-host disease. Clin Med Res 2:243-52 (2004) ...

  19. The immunosuppressive signature of menstrual blood mesenchymal stem cells entails opposite effects on experimental arthritis and graft versus host diseases.

    Science.gov (United States)

    Luz-Crawford, Patricia; Torres, Maria J; Noël, Daniele; Fernandez, Ainoa; Toupet, Karine; Alcayaga-Miranda, Francisca; Tejedor, Gautier; Jorgensen, Christian; Illanes, Sebastian E; Figueroa, Fernando E; Djouad, Farida; Khoury, Maroun

    2016-02-01

    Recently, a noninvasive and highly proliferative stem cell population from menstrual blood called MenSCs has been identified. Despite their use in clinical studies, their immunomodulatory properties have not yet been investigated. In this context, we studied the immunosuppressive properties of MenSCs in comparison with the well-characterized bone marrow derived-MSCs (BM-MSCs). Using an in vitro proliferation assays, we showed that MenSCs displayed a lower suppressive effect on peripheral blood mononuclear cells and in particular on the proinflammatory CD4(+) IFN-γ(+) and CD8(+) IFNγ(+) cells than BM-MSCs. Moreover, compared to BM-MSCs, MenSCs activated with IFN-γ and IL-1β produced lower amounts of immunosuppressive factors such as IDO, PDL-1, PGE2, and Activin A and exhibited a substantial lower expression level of IFN-γ receptor subunits. In the collagen induced arthritis model, while BM-MSCs administration resulted in a potent therapeutic effect associated with a significant decrease of proinflammatory T cell frequency in the lymph nodes, MenSCs injection did not. In contrast, in the xeno-GVHD model, only MenSCs administration significantly increased the survival of mice. This beneficial effect mediated by MenSCs was associated with a higher capacity to migrate into the intestine and liver and not to their anti-inflammatory capacities. All together our results demonstrate for the first time that the therapeutic potential of MSC in the experimental xeno-GVHD model is independent of their immunosuppressive properties. These findings should be taken into consideration for the development of safe and effective cell therapies.

  20. [Migration and distribution of allogeneic T lymphocytes in organs of graft-versus-host disease mouse model].

    Science.gov (United States)

    Wen, Hong-Sheng; Wang, Jian-Min; Zhou, Hong; Xia, Rong; Qiu, Hui-Ying; Gao, Lei; Hu, Xiao-Xia

    2006-10-01

    This study was aimed to investigate the migration and distribution processes of allogeneic donor T lymphocytes in the organs of recipient mice. GVHD model was established by transfusion of the splenocytes of eGFP transgeneic C57BL/6 mice together with born marrow cells harvested from C57BL/6 mice into BALB/c mice underwent 8.0 Gy total body irradiation. The migration and homing of eGFP(+) cells were tracked by stereo-fluorescent microscopy or inverted fluorescent microscopy and flow cytometry. The enzyme linked immunosorbent assay (ELISA) was performed on supernatants from the tissue homogenates to detect the amount of MIP-1alpha. The results indicated that GVHD clinical manifestation and pathological changes of organs appeared on day 8 post transplantation. eGFP-positive donor T cells in recipient organs were observed by inverted fluorescence microscope in frozen section, or by stereo-fluorescence microscopy in living organs, such as liver, spleen, skin, lungs, bowels, and tongue. The highest expression of MIP-1alpha was on day 7 post transplantation in the liver (491.3 +/- 32.1 pg/ml), and day 3 post transplantation in the spleen (881.5 +/- 45.2 pg/ml), respectively (P liver, skin, bowels, as well as lungs and tongue. MIP-1alpha may be in relation with the infiltration of T lymphocytes in liver and spleen.

  1. ECZEMATOID GRAFT VERSUS HOST DISEASE IN A SEX MISMATCHED ALLOGENEIC STEM CELL TRANSPLANT REFRACTORY TO TREATMENT: A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Abhilasha

    2014-03-01

    Full Text Available A 25 years old gentleman presented with bleeding gums, purpura and fever for 2 months and severe anemia requiring 10 blood transfusions. Baseline hematological investigations and bone marrow examination confirmed aplastic anemia. He underwent allogeneic stem cell transplant as a curative option with HLA identical sister as the donor. Neutrophils engrafted on day +16. On day +115 he showed signs of dyshydrotic eczema and was initiated on local and systemic steroids and topical tacrolimus. As there were features of Cyclosporin induced MAHA, the same was stopped and oral Mycophenolate was initiated on day +129. On day +170 he presented with extensive progression of cutaneous and hepatic GVHD. Subsequent treatment with Cyclophosphamide, Sirolimus and Daclizumab did not show significant response. On day +195, he succumbed to sepsis with multiorgan failure. The diagnosis of ezcematoid GVHD was confirmed by cutaneous manifestations, biopsy, the clinical course and the presence of GVHD in other organs.

  2. [Effect of decitabine on immune regulation in patients with acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation].

    Science.gov (United States)

    Wang, Jing; Zhou, Jin; Zheng, Hui-Fei; Fu, Zheng-Zheng

    2014-10-01

    Based on the representative articles in recent years, the different mechanisms of decitabine on immune regulation in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT) are summarized. Decitabine improves the expression of WT1 gene to stimulate specific cytotoxic T cells which can enhance graft versus leukemia effect (GVL) and improve the expression of FOXP3 gene to stimulate regulatory T cells so as to inhibit the acute graft versus host disease (GVHD). Through the above-mentimed mechanisms, decitabine can improve both therapeutic effect and quality of life in the patients with AML after allogeneic HSCT.

  3. The differential diagnosis of inflammatory joint disease in maternal-fetal microchimerism

    Directory of Open Access Journals (Sweden)

    Seme Youssef Reda

    2013-12-01

    Full Text Available This study aimed at making the differential diagnosis of joint disease in a case of genetic chimerism in a female multiparous donor from the Regional Blood Bank of Guarapuava-PR (Hemocentro Regional de Guarapuava-PR, who had had three pregnancies of male fetuses. The patient showed joint pain prior to the last donation. It was possible to identify fetal cells remaining in circulation 20 years after her last pregnancy. Laboratory tests for acute phase proteins revealed possible termination of immune tolerance to circulating fetal cells. Thus, a hypothesis of graft-versus-host disease was formulated to explain the joint disease manifested by the donor.

  4. [Hemolytic anemia caused by graft-versus-host reaction in ABO-nonidentical renal transplants from blood group O donors].

    Science.gov (United States)

    Peces, R; Díaz Corte, C; Navascués, R A

    2001-01-01

    Acute hemolytic anemia is one of the side effects associated with cyclosporin and tacrolimus therapy, and three mechanisms have been described to account for hemolytic anemia in patients receiving these drugs: drug induced hemolysis, autoimmune hemolysis and alloimmune hemolysis resulting from donor lymphocytes derived from the allograft (passenger lymphocyte syndrome). We report four cases of renal transplant recipients who developed alloimmune hemolytic anemia due to minor ABO incompatibility while under treatment with cyclosporin (two) and tacrolimus (two). The anti-erythrocyte antibodies responsible for hemolysis were of the IgG isotype and showed anti-A or anti-B specificity. These findings suggest that the hemolysis could be related to alloantibodies derived from the clonal development of donor B lymphocytes in the recipients (microchimerism). In summary, hemolytic anemia due to ABO-minor incompatibility occurs infrequently after renal transplantation. Risks are higher for patients A, B or AB blood group receiving an O blood group graft under treatment with cyclosporin or tacrolimus. Follow-up of these patients is warranted for the early detection and optimal management may be achieved by reduction of immunosuppression and change to mycophenolate mofetil.

  5. Multi-state analysis illustrates treatment success after stem cell transplantation for acute myeloid leukemia followed by donor lymphocyte infusion.

    Science.gov (United States)

    Eefting, Matthias; de Wreede, Liesbeth C; Halkes, Constantijn J M; von dem Borne, Peter A; Kersting, Sabina; Marijt, Erik W A; Veelken, Hendrik; Putter, Hein; Schetelig, Johannes; Falkenburg, J H Frederik

    2016-04-01

    In the field of hematopoietic stem cell transplantation, the common approach is to focus outcome analyses on time to relapse and death, without assessing the impact of post-transplant interventions. We investigated whether a multi-state model would give insight into the events after transplantation in a cohort of patients who were transplanted using a strategy including scheduled donor lymphocyte infusions. Seventy-eight consecutive patients who underwent myeloablative T-cell depleted allogeneic stem cell transplantation for acute myeloid leukemia or myelodysplastic syndrome were studied. We constructed a multi-state model to analyze the impact of donor lymphocyte infusion and graft-versus-host disease on the probabilities of relapse and non-relapse mortality over time. Based on this model we introduced a new measure for outcome after transplantation which we called 'treatment success': being alive without relapse and immunosuppression for graft-versus-host disease. All relevant clinical events were implemented into the multi-state model and were denoted treatment success or failure (either transient or permanent). Both relapse and non-relapse mortality were causes of failure of comparable magnitude. Whereas relapse was the dominant cause of failure from the transplantation state, its rate was reduced after graft-versus-host disease, and especially after donor lymphocyte infusion. The long-term probability of treatment success was approximately 40%. This probability was increased after donor lymphocyte infusion. Our multi-state model helps to interpret the impact of post-transplantation interventions and clinical events on failure and treatment success, thus extracting more information from observational data.

  6. Drug-induced chimerism and prevention of graft-versus-host disease in lethally irradiated mice transplanted with rat bone marrow. [Gamma radiation

    Energy Technology Data Exchange (ETDEWEB)

    Pierpaoli, W.; Maestroni, G.J.M.

    1978-12-01

    L-5-hydroxytryptophan, haloperidol, and phentolamine were administered subcutaneously to groups of mice. Some groups were inoculated i.p. or i.v. with bone marrow cells. The mice were given a dose of 900 rad of whole-body gamma radiation. Observations were made on survival rate, reconstitution with rat hematopoietic tissue, and capacity to reject or accept skin grafts. Results indicate that the combination of drug-induced tolerance and a newly established preconditioning regimen that eliminated postradiation damage and mortality results in reduction in incidence or delay in onset of GVHD, successful bone marrow grafting, and induction of persistent rat chimerism. (HLW)

  7. MicroRNA-21 deficiency protects from lupus-like autoimmunity in the chronic graft-versus-host disease model of systemic lupus erythematosus.

    Science.gov (United States)

    Garchow, Barry; Kiriakidou, Marianthi

    2016-01-01

    MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression primarily at the post-transcriptional level. Emerging evidence supports a regulatory role for miRNAs in the immune response and autoimmunity. In this work, we investigated the implication of miR-21 in the experimentally inducible bm12→B6 cGVHD model of systemic lupus erythematosus (SLE). cGVHD host mice deficient in miR-21 show a 2-fold reduction in splenomegaly, significantly reduced autoantibody titers and down-regulated components of the CD40:CD40L and CD28:CD80/86 co-stimulation pathways. Furthermore, we demonstrate that miR-21-deficient hosts have reduced CD4(+) IL-17(+) cell populations and an expanded CD4(+) CD25(+) FoxP3(+) cell compartment. We propose that miR-21 has a pluripotent role, serving to link distinct lymphocyte signaling pathways and acting as a "rheostat" for signals that promote B and T cell activation in lupus. Collectively, our experiments demonstrate that miR-21 deficiency in cGVHD host mice is sufficient to protect from lupus-like autoimmunity.

  8. A radio-resistant perforin-expressing lymphoid population controls allogeneic T cell engraftment, activation, and onset of graft-versus-host disease in mice.

    Science.gov (United States)

    Davis, Joanne E; Harvey, Michael; Gherardin, Nicholas A; Koldej, Rachel; Huntington, Nicholas; Neeson, Paul; Trapani, Joseph A; Ritchie, David S

    2015-02-01

    Immunosuppressive pretransplantation conditioning is essential for donor cell engraftment in allogeneic bone marrow transplantation (BMT). The role of residual postconditioning recipient immunity in determining engraftment is poorly understood. We examined the role of recipient perforin in the kinetics of donor cell engraftment. MHC-mismatched BMT mouse models demonstrated that both the rate and proportion of donor lymphoid cell engraftment and expansion of effector memory donor T cells in both spleen and BM were significantly increased within 5 to 7 days post-BMT in perforin-deficient (pfn(-/-)) recipients, compared with wild-type. In wild-type recipients, depletion of natural killer (NK) cells before BMT enhanced donor lymphoid cell engraftment to that seen in pfn(-/-) recipients. This demonstrated that a perforin-dependent, NK-mediated, host-versus-graft (HVG) effect limits the rate of donor engraftment and T cell activation. Radiation-resistant natural killer T (NKT) cells survived in the BM of lethally irradiated mice and may drive NK cell activation, resulting in the HVG effect. Furthermore, reduced pretransplant irradiation doses in pfn(-/-) recipients permitted long-term donor lymphoid cell engraftment. These findings suggest that suppression of perforin activity or selective depletion of recipient NK cells before BMT could be used to improve donor stem cell engraftment, in turn allowing for the reduction of pretransplant conditioning.

  9. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. Diagnosis and Staging Working Group Report

    Science.gov (United States)

    2005-09-09

    keratoconjunctivitis sicca GI TRACT No symptoms Symptoms such as dysphagia , anorexia, nausea, vomiting, abdominal pain or diarrhea without...requires nutritional supplement for most calorie needs OR esophageal dilation LIVER Normal LFT Elevated Bilirubin, AP*, AST or ALT ɚ x ULN

  10. Optimal initial dose of oral cyclosporine in relation to its toxicities for graft-versus-host disease prophylaxis following reduced-intensity stem cell transplantation in Japanese patients.

    Science.gov (United States)

    Kishi, Y; Murashige, N; Kami, M; Miyakoshi, S; Shibagaki, Y; Hamaki, T; Takaue, Y; Taniguchi, S

    2005-06-01

    Since the introduction of reduced-intensity stem-cell transplantation (RIST), allogeneic stem-cell transplantation has become available for elderly patients. While pharmacokinetics of cyclosporine might differ according to age or other factors, cyclosporine is uniformly started at an oral dose of 6 mg/kg/day. We retrospectively reviewed medical records of 35 patients aged between 32 and 65 (median 52) years who had undergone RIST. Doses of cyclosporine were adjusted to the target blood trough level of 150-250 ng/ml. Cyclosporine dosages were changed in 33 patients (94%). Dose reduction was required in 32 patients because of high blood levels (n=25), renal dysfunction (n=3), hepatic dysfunction (n=2), and hypertension (n=2). Cyclosporine doses were increased in one because of the suboptimal level. The median of the achieved stable doses was 3.1 mg/kg/day (range, 1.0-7.4). Five patients sustained Grade III toxicities according to NCI-CTC version 2.0: renal dysfunction (n=4), hyperbilirubinemia (n=2), and hypertension (n=2). No patients developed grade IV toxicity. There was no statistically significant difference in the frequency and severity of cyclosporine toxicities between patients aged 50 years and above and those below 50 years. The initial oral cyclosporine dose of 6 mg/kg/day was unnecessarily high irrespective of age. The possible overdose of cyclosporine might have aggravated regimen-related toxicities.

  11. Nephrotic syndrome as a clinical manifestation of graft-versus-host disease (GVHD) in a marrow transplant recipient after cyclosporine withdrawal.

    Science.gov (United States)

    Oliveira, J S; Bahia, D; Franco, M; Balda, C; Stella, S; Kerbauy, J

    1999-01-01

    GVHD is one of the most frequent complications of BMT and recently nephrotic syndrome (NS) has been described as a manifestation of chronic GVHD. Here, we present an AA patient who developed NS 1 year after BMT when cyclosporine was stopped. Renal biopsy showed focal sclerosis associated with membranous deposits. He also had other clinical manifestations of chronic GVHD: sicca-like syndrome and colestasis. After 15 days of CsA therapy, he experienced a remarkable improvement in the NS and GVHD as a whole. We comment on immunological mechanisms that could be involved in the pathogenesis of this manifestation.

  12. Relapsing acute myeloid leukemia presenting as hypopyon uveitis

    Directory of Open Access Journals (Sweden)

    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.

  13. The Genotype of the Donor for the (GT)n 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.

    Science.gov (United States)

    Noriega, Víctor; Martínez-Laperche, Carolina; Buces, Elena; Pion, Marjorie; Sánchez-Hernández, Noemí; Martín-Antonio, Beatriz; Guillem, Vicent; Bosch-Vizcaya, Anna; Bento, Leyre; González-Rivera, Milagros; Balsalobre, Pascual; Kwon, Mi; Serrano, David; Gayoso, Jorge; de la Cámara, Rafael; Brunet, Salut; Rojas-Contreras, Rafael; Nieto, José B; Martínez, Carmen; Gónzalez, Marcos; Espigado, Ildefonso; Vallejo, Juan C; Sampol, Antonia; Jiménez-Velasco, Antonio; Urbano-Ispizua, Alvaro; Solano, Carlos; Gallardo, David; Díez-Martín, José L; Buño, Ismael

    2015-01-01

    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 (≤(GT)15) for the (GT)n 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.

  14. 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.

  15. 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

    Energy Technology Data Exchange (ETDEWEB)

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

    1980-03-01

    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.

  16. Hematopoietic stem cell transplantation for children with high-risk acute lymphoblastic leukemia in first complete remission: a report from the AIEOP registry.

    Science.gov (United States)

    Fagioli, Franca; Quarello, Paola; Zecca, Marco; Lanino, Edoardo; Rognoni, Carla; Balduzzi, Adriana; Messina, Chiara; Favre, Claudio; Foà, Roberto; Ripaldi, Mimmo; Rutella, Sergio; Basso, Giuseppe; Prete, Arcangelo; Locatelli, Franco

    2013-08-01

    Children with high-risk acute lymphoblastic leukemia in first complete remission can benefit from allogeneic hematopoietic stem cell transplantation. We analyzed the outcome of 211 children with high-risk acute lymphoblastic leukemia in first complete remission who were given an allogeneic transplant between 1990 and 2008; the outcome of patients who, despite having an indication for transplantation and a suitable donor, did not receive the allograft for different reasons in the same time period was not analyzed. Sixty-nine patients (33%) were transplanted between 1990 and 1999, 58 (27%) between 2000 and 2005, and 84 (40%) between 2005 and 2008. A matched family donor was employed in 138 patients (65%) and an unrelated donor in 73 (35%). The 10-year probabilities of overall and disease-free survival were 63.4% and 61%, respectively. The 10-year cumulative incidences of transplantation-related mortality and relapse were 15% and 24%, respectively. After 1999, no differences in either disease-free survival or transplant-related mortality were observed in patients transplanted from unrelated or matched family donors. In multivariate analysis, grade IV acute graft-versus-host disease was an independent factor associated with worse disease-free survival. By contrast, grade I acute graft-versus-host disease and age at diagnosis between 1 and 9 years were favorable prognostic variables. Our study, not intended to evaluate whether transplantation is superior to chemotherapy for children with acute lymphoblastic leukemia in first complete remission and high-risk features, shows that the allograft cured more than 60% of these patients; in the most recent period, the outcome of recipients of grafts from matched family and unrelated donors was comparable.

  17. Molecular monitoring of minimal residual disease in two patients with MLL-rearranged acute myeloid leukemia and haploidentical transplantation after relapse

    Directory of Open Access Journals (Sweden)

    Burmeister Thomas

    2012-04-01

    Full Text Available Abstract This report describes the clinical courses of two acute myeloid leukemia patients. Both had MLL translocations, the first a t(10;11(p11.2;q23 with MLL-AF10 and the second a t(11;19(q23;p13.1 with MLL-ELL fusion. They achieved a clinical remission under conventional chemotherapy but relapsed shortly after end of therapy. Both had a history of invasive mycoses (one had possible pulmonary mycosis, one systemic candidiasis. Because no HLA-identical donor was available, a haploidentical transplantation was performed in both cases. Using a specially designed PCR method for the assessment of minimal residual disease (MRD, based on the quantitative detection of the individual chromosomal breakpoint in the MLL gene, both patients achieved complete and persistent molecular remission after transplantation. The immune reconstitution after transplantation is described in terms of total CD3+/CD4+, CD3+/CD8+, CD19+, and CD16+/CD56+ cell numbers over time. The KIR and HLA genotypes of donors and recipients are reported and the possibility of a KIR-mediated alloreactivity is discussed. This report illustrates that haploidentical transplantation may offer a chance of cure without chronic graft-versus-host disease in situations where no suitable HLA-identical donor is available even in a high-risk setting and shows the value of MRD monitoring in the pre- and posttransplant setting.

  18. Successful Pregnancy and Delivery After Radiation With Ovarian Shielding for Acute Lymphocytic Leukemia Before Menarche.

    Science.gov (United States)

    Ishibashi, Naoya; Maebayashi, Toshiya; Aizawa, Takuya; Sakaguchi, Masakuni; Abe, Osamu; Saito, Tsutomu; Tanaka, Yoshiaki; Chin, Motoaki; Mugishima, Hideo

    2015-07-01

    Total body irradiation is performed as a preconditioning regimen to inhibit graft-versus-host disease after bone marrow transplantation and to eradicate remaining tumor cells. However, these regimens result in delayed secondary sex characteristics and failure of ovarian function recovery, leading to amenorrhea and infertility. Herein, we report a case of an 11-year-old girl diagnosed with acute lymphocytic leukemia who received induction chemotherapy and prophylactic cranial irradiation. For bone marrow transplantation, she received total body irradiation of 12 Gy with uterine and ovarian shielding at 13 years of age. The patient remained in remission and menarche began at 14 years of age. At 23, she became pregnant and delivered a baby naturally with no abnormalities.

  19. Mycophenolate mofetil toxicity mimicking acute cellular rejection in a small intestinal transplant

    Science.gov (United States)

    Apostolov, Ross; Asadi, Khashayar; Lokan, Julie; Kam, Ning; Testro, Adam

    2017-01-01

    Mycophenolate mofetil (MMF) is an important medication used for maintenance immunosuppression in solid organ transplants. A common gastrointestinal (GI) side effect of MMF is enterocolitis, which has been associated with multiple histological features. There is little data in the literature describing the histological effects of MMF in small intestinal transplant (SIT) recipients. We present a case of MMF toxicity in a SIT recipient, with histological changes in the donor ileum mimicking persistent acute cellular rejection (ACR). Concurrent biopsies of the patient’s native colon showed similar changes to those from the donor small bowel, suggesting a non-graft specific process, raising suspicion for MMF toxicity. The MMF was discontinued and complete resolution of these changes occurred over three weeks. MMF toxicity should therefore be considered as a differential diagnosis for ACR and graft-versus-host disease in SITs. PMID:28280702

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

    Energy Technology Data Exchange (ETDEWEB)

    Lucarelli, G.; Izzi, T.; Porcellini, A.; Delfini, C.; Galimberti, M.; Moretti, L.; Polchi, P.; Agostinelli, F.; Andreani, M.; Manna, M. (Haematological Department, Pesaro Hospital, Pesaro, Italy)

    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.

  1. [Mucocutaneous diseases and murine models with death of keratinocytes induced by lichenoid tissue reaction/interface dermatitis].

    Science.gov (United States)

    Okiyama, Naoko

    2015-01-01

    A set of histopathological elements with death of epidermal basal cell layer keratinocytes along with inflammatory cell infiltration distinguishes lichenoid tissue reaction (LTR)/interface dermatitis (IFD) from other inflammatory mucocutaneous diseases. The LTR/IFD can be seen in skin disorders like as lichen planus, acute graft-versus-host disease, lupus erythematosus, dermatomyositis, and toxic epidermal necrolysis/Stevesn-Johnson syndrome. Clinical and basic researches suggested that cytotoxic CD8 T cells producing interferon-γ and FasL are final effector cells to cause apoptosis of keratinocyte. Some murine models of LTR/IFD have been established, for example, LTR/IFD reactions of keratinocyte-specific ovalbumin (OVA)-transgenic mice after OVA-specific T-cell-receptor(+)CD8 T cells. By analysis of the murine model, a new class of immunosuppressant, a JAK inhibitor, has been suggested as a new candidate for treatment of LTR/IFD.

  2. Matching for the non-conventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

    NARCIS (Netherlands)

    Carapito, Raphael; Jung, Nicolas; Kwemou, Marius; Untrau, Meiggie; Michel, Sandra; Pichot, Angélique; Giacometti, Gaëlle; Macquin, Cécile; Ilias, Wassila; Morlon, Aurore; Kotova, Irina; Apostolova, Petya; Schmitt-Graeff, Annette; Cesbron, Anne; Gagne, Katia; Oudshoorn, Machteld; van der Holt, Bronno; Labalette, Myriam; Spierings, Eric; Picard, Christophe; Loiseau, Pascale; Tamouza, Ryad; Toubert, Antoine; Parissiadis, Anne; Dubois, Valérie; Lafarge, Xavier; Maumy-Bertrand, Myriam; Bertrand, Frédéric; Vago, Luca; Ciceri, Fabio; Paillard, Catherine; Querol, Sergi; Sierra, Jorge; Fleischhauer, Katharina; Nagler, Arnon; Labopin, Myriam; Inoko, Hidetoshi; von dem Borne, Peter A; Kuball, Jürgen H E; Ota, Masao; Katsuyama, Yoshihiko; Michallet, Mauricette; Lioure, Bruno; Peffault de Latour, Régis; Blaise, Didier; Cornelissen, Jan J; Yakoub-Agha, Ibrahim; Claas, Frans; Moreau, Philippe; Milpied, Noël; Charron, Dominique; Mohty, Mohamad; Zeiser, Robert; Socié, Gérard; Bahram, Seiamak

    2016-01-01

    Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic "MHC class I chain-related gene A", MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the i

  3. Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

    NARCIS (Netherlands)

    Carapito, R. (Raphael); Jung, N. (Nicolas); Kwemou, M. (Marius); Untrau, M. (Meiggie); Michel, S. (Sandra); Pichot, A. (Angélique); Giacometti, G. (Gaëlle); Macquin, C. (Cécile); Ilias, W. (Wassila); Morlon, A. (Aurore); Kotova, I. (Irina); Apostolova, P. (Petya); Schmitt-Graeff, A. (Annette); Cesbron, A. (Anne); K. Gagne (Katia); M. Oudshoorn (Machteld); B. van der Holt (Bronno); Labalette, M. (Myriam); E. Spierings (E.); Picard, C. (Christophe); P. Loiseau (Pascale); Tamouza, R. (Ryad); Toubert, A. (Antoine); Parissiadis, A. (Anne); V. Dubois (Valerie); Lafarge, X. (Xavier); Maumy-Bertrand, M. (Myriam); Bertrand, F. (Frédéric); Vago, L. (Luca); F. Ciceri (Fabio); Paillard, C. (Catherine); Querol, S. (Sergi); J. Sierra (Jorge); Fleischhauer, K. (Katharina); A. Nagler (Arnon); M. Labopin (Myriam); H. Inoko (Hidetoshi); P.A. von dem Borne (P. A.); J. Kuball (Jürgen); Ota, M. (Masao); Katsuyama, Y. (Yoshihiko); M. Michallet (M.); B. Lioure; De Latour, R.P. (Régis Peffault); D. Blaise (Didier); J.J. Cornelissen (Jan); I. Yakoub-Agha (Ibrahim); F.H.J. Claas (Frans); P. Moreau; N. Milpied; Charron, D. (Dominique); M. Mohty (Mohamad); Zeiser, R. (Robert); G. Socie (Gerard); Bahram, S. (Seiamak)

    2016-01-01

    textabstractGraft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain-related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts

  4. 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.

    Science.gov (United States)

    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.

  5. Autologous Peripheral Blood Stem Cell Transplantation in Patients With Life Threatening Autoimmune Diseases

    Science.gov (United States)

    2005-06-23

    Purpura, Schoenlein-Henoch; Graft Versus Host Disease; Anemia, Hemolytic, Autoimmune; Rheumatoid Arthritis; Churg-Strauss Syndrome; Hypersensitivity Vasculitis; Wegener's Granulomatosis; Systemic Lupus Erythematosus; Giant Cell Arteritis; Pure Red Cell Aplasia; Juvenile Rheumatoid Arthritis; Polyarteritis Nodosa; Autoimmune Thrombocytopenic Purpura; Takayasu Arteritis

  6. 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.)

  7. Autologous stem cell transplantation versus alternative allogeneic donor transplants in adult acute leukemias.

    Science.gov (United States)

    Claude Gorin, Norbert

    2016-04-01

    The availability of alternative sources of stem cells including most recently T-replete haploidentical marrow or peripheral blood, and the increasing use of reduced-intensity conditioning (RIC), renders feasible an allogeneic transplant to almost all patients with acute leukemia up to 70 years of age. Autologous stem cell transplantation (ASCT) for consolidation of complete remission (CR), however, offers in some circumstances an alternative option. Although associated with a higher relapse rate, autologous transplant benefits from a lower non-relapse mortality, the absence of graft-versus-host disease (GVHD), and a better quality of life for long-term survivors. The recent use of intravenous busulfan (IVBU) with high-dose melphalan, better monitoring of minimal residual disease (MRD), and maintenance therapy post autografting bring new interest. Few retrospective studies compared the outcome following alternative donor versus autologous transplants for remission consolidation. Genoidentical and phenoidentical allogeneic stem cell transplantations are undisputed gold standards, but there are no data showing the superiority of alternative allogeneic donor over autologous transplantation, at the time of undetectable MRD, in patients with good- and intermediate-1 risk acute myelocytic leukemia (AML) in first complete remission (CR1), acute promyelocytic leukemia in second complete remission (CR2), and Philadelphia chromosome-positive (Ph(+)) acute lymphocytic leukemia (ALL).

  8. Effects of KIR ligand incompatibility on clinical outcomes of umbilical cord blood transplantation without ATG for acute leukemia in complete remission.

    Science.gov (United States)

    Tanaka, J; Morishima, Y; Takahashi, Y; Yabe, T; Oba, K; Takahashi, S; Taniguchi, S; Ogawa, H; Onishi, Y; Miyamura, K; Kanamori, H; Aotsuka, N; Kato, K; Kato, S; Atsuta, Y; Kanda, Y

    2013-11-29

    To clarify the effect of killer cell immunoglobulin-like receptor (KIR) ligand incompatibility on outcomes of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients in complete remission after single cord blood transplantation (CBT), we assessed the outcomes of CBT registered in the Japan Society for Hematopoietic Cell Transplantation (JSHCT) database. A total of 643 acute leukemia (357 AML and 286 ALL) patient and donor pairs were categorized according to their KIR ligand incompatibility by determining whether or not they expressed HLA-C, Bw4 or A3/A11 by DNA typing. A total of 128 patient-donor pairs were KIR ligand-incompatible in the graft-versus-host (GVH) direction and 139 patient-donor pairs were incompatible in the host-versus-graft (HVG) direction. Univariate and multivariate analyses showed no significant differences between the KIR ligand-incompatible and compatible groups in the GVH direction for both AML and ALL patients of overall survival, disease-free survival, relapse incidence, non-relapse mortality and acute GVH disease. However, KIR incompatibility in the HVG direction ameliorated engraftment in ALL patients (hazard ratio 0.66, 95% confidence interval 0.47-0.91, P=0.013). Therefore, there were no effects of KIR ligand incompatibility in the GVH direction on single CBT outcomes for acute leukemia patients without anti-thymocyte globulin use. However, it is necessary to pay attention to KIR incompatibility in the HVG direction for engraftment.

  9. 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.

  10. KEGG DISEASE / Acute encephalitis [KEGG DISEASE

    Lifescience Database Archive (English)

    Full Text Available DISEASE: H01417 Entry H01417Disease Name Acute encephalitis Description Acute encep...ns Infections caused by dsDNA viruses H01417Acute encephalitis Human diseases in ICD-10 classification [BR:b...of the central nervous system G04Encephalitis, myelitis and encephalomyelitis H01417Acute encephalitis Patho...elines for management. Journal Eur J Neurol 12:331-43 (2005) KEGG DISEASE / Acute encephalitis ...

  11. CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia.

    Science.gov (United States)

    Green, Margaret L; Leisenring, Wendy M; Xie, Hu; Walter, Roland B; Mielcarek, Marco; Sandmaier, Brenda M; Riddell, Stanley R; Boeckh, Michael

    2013-08-15

    The association between cytomegalovirus (CMV) reactivation and relapse was evaluated in a large cohort of patients with acute myeloid leukemia (AML) (n = 761), acute lymphoblastic leukemia (ALL) (n = 322), chronic myeloid leukemia (CML) (n = 646), lymphoma (n = 254), and myelodysplastic syndrome (MDS) (n = 371) who underwent allogeneic hematopoietic cell transplantation (HCT) between 1995 and 2005. In multivariable models, CMV pp65 antigenemia was associated with a decreased risk of relapse by day 100 among patients with AML (hazard ratio [HR] = 0.56; 95% confidence interval [CI], 0.3-0.9) but not in patients with ALL, lymphoma, CML, or MDS. The effect appeared to be independent of CMV viral load, acute graft-versus-host disease, or ganciclovir-associated neutropenia. At 1 year after HCT, early CMV reactivation was associated with reduced risk of relapse in all patients, but this did not reach significance for any disease subgroup. Furthermore, CMV reactivation was associated with increased nonrelapse mortality (HR = 1.31; 95% CI, 1.1-1.6) and no difference in overall mortality (HR = 1.05; 95% CI, 0.9-1.3). This report demonstrates a modest reduction in early relapse risk after HCT associated with CMV reactivation in a large cohort of patients without a benefit in overall survival.

  12. Graft-versus-host disease and membranous nephropathy in post-allogeneic haematopoietic stem cell transplantation%移植物抗宿主反应与造血干细胞移植术后膜性肾病

    Institute of Scientific and Technical Information of China (English)

    黄湘华; 秦卫松; 张明超; 郑春霞; 曾彩虹; 刘志红

    2010-01-01

    目的:分析异基因造血干细胞移植术后膜性肾病(MN)的临床病理特征,并探讨其与慢性移植物抗宿主反应(GVHD)之间的关系. 方法:选取在我科经活检证实的5例异基因造血干细胞移植(Allo-HSCT)术后MN为研究对象,分析5例患者的临床表现,实验室结果以及肾脏病理形态学、免疫荧光及电镜的病理特点,并行IgG亚型免疫荧光染色,观察不同IgG亚型在肾小球分布的特点及与nephrin分布的关系.此外,利用Western印迹的方法,我们检测了患者血清中是否存在抗M型磷脂酶A2受体(PLA2R)自身抗体. 结果:5例患者的临床病理特征如下:(1)移植前无肾脏病史及肾脏病家族史;(2)所有患者在出现蛋白尿的时候均合并存在慢性GVHD(cGVHD)的表现,R4例患者既往有急性GVHD(aGVHD)的病史,经过有效的抗GVHD治疗后,患者的蛋白尿也随之好转;(3)部分患者自身抗体检测阳性,肾组织伴有CA及Clq的沉积,提示体内存在自身免疫现象;(4)肾组织沉积的IgG以IgG4为主,其分布与nephri一致;(5)抗PLA2R自身抗体的检测结果显示5例患者中仅有1例阳性,阳性率远低于特发性膜性肾病(IMN)的检测结果. 结论:我们认为Allo-HSCT术后的MN也是cGVHD的一种表现形式,其发病机制可能与移植入的免疫细胞产生了抗宿主足细胞的抗体有关,且抗体的类型不同于IMN的抗PLA2R自身抗体.

  13. Bone marrow transplantation: graft versus host disease and oral changes = Transplante de medula óssea: doença enxerto versus hospedeiro e alterações orais

    Directory of Open Access Journals (Sweden)

    Lima, Emeline das Neves de Araújo

    2012-01-01

    Conclusão: Diante da prevalência de alterações orais relativamente alta associada à DEVH em pacientes submetidos ao TMO, o presente estudo confirma a necessidade de se considerar a odontologia no exame, diagnóstico, tratamento e prognóstico de possíveis complicações após o transplante de medula óssea

  14. Allogeneic stem-cell transplantation in patients with refractory acute leukemia: a long-term follow-up.

    Science.gov (United States)

    Oyekunle, A A; Kröger, N; Zabelina, T; Ayuk, F; Schieder, H; Renges, H; Fehse, N; Waschke, O; Fehse, B; Kabisch, H; Zander, A R

    2006-01-01

    We examined retrospectively 44 patients with refractory acute leukemia (acute myeloid leukemia (AML)/acute lymphoblastic leukemia=25/19) who underwent allogeneic transplantation at our center between 11/1990 and 04/2004. The median leukemic blasts was 25% and age 28 years (range, 3-56). Twenty-one patients had untreated relapse, 13 failed reinduction, eight in partial remission and two aplastic. Conditioning was myeloablative using cyclophosphamide, busulfan, total-body irradiation and etoposide (Bu/Cy/VP, n=22; TBI/Cy/VP, n=17; others, n=5) followed by marrow or peripheral blood transplant (n=23/21) from unrelated or related donors (n=28/16). All patients had graft-versus-host disease (GVHD) prophylaxis with cyclosporin and methotrexate. One patient experienced late graft failure. Severe acute-GVHD and chronic-GVHD appeared in eight and 14 patients, respectively. Thirteen patients (30%) remain alive after a median of 25.3 months (range, 2.4-134.1); with 31 deaths, mostly from relapse (n=15) and infections (n=12). Overall survival (OS) and progression-free survival (PFS) at 5 years was 28 and 26%, respectively. OS and PFS were significantly better with blasts < or =20% and time to transplant < or =1 year while transplant-related mortality was less with the use of TBI. We conclude that patients with refractory leukemia can benefit from allogeneic BMT, especially with < or =20% marrow blast.

  15. A phase 3 randomized trial comparing inolimomab vs usual care in steroid-resistant acute GVHD.

    Science.gov (United States)

    Socié, Gérard; Vigouroux, Stéphane; Yakoub-Agha, Ibrahim; Bay, Jacques-Olivier; Fürst, Sabine; Bilger, Karin; Suarez, Felipe; Michallet, Mauricette; Bron, Dominique; Gard, Philippe; Medeghri, Zakaria; Lehert, Philippe; Lai, Chinglin; Corn, Tim; Vernant, Jean-Paul

    2017-02-02

    Treatment of steroid-resistant acute graft-versus-host disease (GVHD) remains an unmet clinical need. Inolimomab, a monoclonal antibody to CD25, has shown encouraging results in phase 2 trials. This phase 3 randomized, open-label, multicenter trial compared inolimomab vs usual care in adult patients with steroid-refractory acute GVHD. Patients were randomly selected to receive treatment with inolimomab or usual care (the control group was treated with antithymocyte globulin [ATG]). The primary objective was to evaluate overall survival at 1 year without changing baseline allocated therapy. A total of 100 patients were randomly placed: 49 patients in the inolimomab arm and 51 patients in the ATG arm. The primary criteria were reached by 14 patients (28.5%) in the inolimomab and 11 patients (21.5%) in the ATG arms, with a hazard ratio of 0.874 (P = .28). With a minimum follow-up of 1 year, 26 (53%) and 31 (60%) patients died in the inolimomab and ATG arms, respectively. Adverse events were similar in the 2 arms, with fewer viral infections in the inolimomab arm compared with the ATG arm. The primary end point of this randomized phase 3 trial was not achieved. The lack of a statistically significant effect confirms the need for development of more effective treatments for acute GVHD. This trial is registered to https://www.clinicaltrialsregister.eu/ctr-search/search as EUDRACT 2007-005009-24.

  16. KEGG DISEASE / Acute alcohol sensitivity [KEGG DISEASE

    Lifescience Database Archive (English)

    Full Text Available DISEASE: H01071 Entry H01071Disease Name Acute alcohol sensitivity Description Alde...bolism Congenital disorders of carbohydrate metabolism H01071Acute alcohol sensit...eases. Journal Cardiovasc Res 88:51-7 (2010) KEGG DISEASE / Acute alcohol sensitivity ...

  17. Steroid-Refractory Acute GVHD: Predictors and Outcomes

    Directory of Open Access Journals (Sweden)

    Jason R. Westin

    2011-01-01

    Full Text Available Patients with steroid-resistant acute graft versus host disease (aGVHD have a dismal prognosis, with mortality rates in excess of 90%. We sought to identify a subgroup of patients less likely to benefit from initial therapy with corticosteroids as well as the impact of response on day 14 on outcome. Retrospective evaluation was performed of patients with biopsy-proven aGVHD treated with corticosteroids after allogeneic HSCT at M.D. Anderson Cancer Center from 1998 through 2002 (=287. Overall response to first-line therapy on day 14 was 56%. Grade III-IV aGVHD and hyperacute GVHD were the most significant factors predicting failure. Patients who fail to respond to steroids by day 14 should be considered for clinical trials. Severity of aGVHD, hyperacute GVHD, and sex mismatch could be integrated into prognostic scoring systems which may allow for pretreatment identification of patients unlikely to benefit from standard therapy with corticosteroids.

  18. The Sequence of Cyclophosphamide and Myeloablative Total Body Irradiation in Hematopoietic Cell Transplantation for Patients with Acute Leukemia.

    Science.gov (United States)

    Holter-Chakrabarty, Jennifer L; Pierson, Namali; Zhang, Mei-Jie; Zhu, Xiaochun; Akpek, Görgün; Aljurf, Mahmoud D; Artz, Andrew S; Baron, Frédéric; Bredeson, Christopher N; Dvorak, Christopher C; Epstein, Robert B; Lazarus, Hillard M; Olsson, Richard F; Selby, George B; Williams, Kirsten M; Cooke, Kenneth R; Pasquini, Marcelo C; McCarthy, Philip L

    2015-07-01

    Limited clinical data are available to assess whether the sequencing of cyclophosphamide (Cy) and total body irradiation (TBI) changes outcomes. We evaluated the sequence in 1769 (CyTBI, n = 948; TBICy, n = 821) recipients of related or unrelated hematopoietic cell transplantation who received TBI (1200 to 1500 cGY) for acute leukemia from 2003 to 2010. The 2 cohorts were comparable for median age, performance score, type of leukemia, first complete remission, Philadelphia chromosome-positive acute lymphoblastic leukemia, HLA-matched siblings, stem cell source, antithymocyte globulin use, TBI dose, and type of graft-versus-host disease (GVHD) prophylaxis. The sequence of TBI did not significantly affect transplantation-related mortality (24% versus 23% at 3 years, P = .67; relative risk, 1.01; P = .91), leukemia relapse (27% versus 29% at 3 years, P = .34; relative risk, .89, P = .18), leukemia-free survival (49% versus 48% at 3 years, P = .27; relative risk, .93; P = .29), chronic GVHD (45% versus 47% at 1 year, P = .39; relative risk, .9; P = .11), or overall survival (53% versus 52% at 3 years, P = .62; relative risk, .96; P = .57) for CyTBI and TBICy, respectively. Corresponding cumulative incidences of sinusoidal obstruction syndrome were 4% and 6% at 100 days (P = .08), respectively. This study demonstrates that the sequence of Cy and TBI does not impact transplantation outcomes and complications in patients with acute leukemia undergoing hematopoietic cell transplantation with myeloablative conditioning.

  19. Reduced-intensity stem-cell transplantation for adult acute lymphoblastic leukemia: a retrospective study of 33 patients.

    Science.gov (United States)

    Hamaki, T; Kami, M; Kanda, Y; Yuji, K; Inamoto, Y; Kishi, Y; Nakai, K; Nakayama, I; Murashige, N; Abe, Y; Ueda, Y; Hino, M; Inoue, T; Ago, H; Hidaka, M; Hayashi, T; Yamane, T; Uoshima, N; Miyakoshi, S; Taniguchi, S

    2005-03-01

    Efficacy of reduced-intensity stem-cell transplantation (RIST) for acute lymphoblastic leukemia (ALL) was investigated in 33 patients (median age, 55 years). RIST sources comprised 20 HLA-identical related donors, five HLA-mismatched related, and eight unrelated donors. Six patients had undergone previous transplantation. Disease status at RIST was first remission (n=13), second remission (n=6), and induction failure or relapse (n=14). All patients tolerated preparatory regimens and achieved neutrophil engraftment (median, day 12.5). Acute and chronic graft-versus-host disease (GVHD) developed in 45 and 64%, respectively. Six patients received donor lymphocyte infusion (DLI), for prophylaxis (n=1) or treatment of recurrent ALL (n=5). Nine patients died of transplant-related mortality, with six deaths due to GVHD. The median follow-up of surviving patients was 11.6 months (range, 3.5-37.3 months). The 1-year relapse-free and overall survival rates were 29.8 and 39.6%, respectively. Of the 14 patients transplanted in relapse, five remained relapse free for longer than 6 months. Cumulative rates of progression and progression-free mortality at 3 years were 50.9 and 30.4%, respectively. These findings suggest the presence of a graft-versus-leukemia effect for ALL. RIST for ALL is worth considering for further evaluation.

  20. 以全身照射为预处理方案的急性白血病患者造血干细胞移植后间质性肺炎相关因素分析%Analysis on Factors Related to Interstitial Pneumonia in Patients with Acute Leukemia and with Total Body Irradiation as Conditioning Regimen

    Institute of Scientific and Technical Information of China (English)

    赵奇; 周菊英; 秦颂兵; 郭建

    2015-01-01

    Objective To analyze factors related to interstitial pneumonia (IP) in patients with acute leukemia after hematopoietic stem cell transplantation (HSCT) and had received total body irradiation (TBI) as conditioning regimen.Methods 139 cases with acute leukemia after HSCT with TBI as conditioning regimen were studied retrospectively. Univariate and multivariate analysis were conducted of clinical factors that may affect the occurrence of IP such as remission before transplantation, acute graft-versus-host disease, transplantation way, age, sex, and TBI program parameters such as irradiation scheme, dose rate and the whole body dose uniformity. Results Remission before transplantation (χ2=5.213,P=0.022), acute graft-versus-host disease (aGVHD) (χ2=5.829,P=0.016), irradiation scheme (χ2=4.281,P=0.039) were statistically signifi cant factors by univariate analysis; irradiation scheme (P=0.042), aGVHD (P=0.016), remission before transplantation (P=0.020) were signifi cantly correlated factors by Logistic regression model analysis.Conclusion Occurrence of IP after HSCT is the result of the combined effects of multiple factors. Great importance should be attached to the risk of IP in patients with non-fi rst complete remission, single total body irradiation and occurrence of aGVHD.%目的:分析预处理方案中含全身照射(total body irradiation, TBI)的急性白血病患者造血干细胞移植(hematopoietic stem cell transplantation, HSCT)后发生间质性肺炎(interstitial pneumonia, IP)的相关因素。方法对139例HSCT预处理方案中含TBI的急性白血病患者资料进行回顾性研究,对可能影响IP发生的临床因素如移植前缓解状态、急性移植物抗宿主病(acute graft-versus-host disease, aGVHD)、移植方式、年龄、性别以及TBI参数如照射方案、剂量率、全身剂量均匀度采用单因素和多因素分析。结果单因素分析差异有统计学意义的相关因素

  1. Treosulfan-Based Conditioning and Hematopoietic Cell Transplantation for Nonmalignant Diseases: A Prospective Multi-Center Trial

    Science.gov (United States)

    Burroughs, Lauri M.; Nemecek, Eneida R.; Torgerson, Troy R.; Storer, Barry E.; Talano, Julie-An; Domm, Jennifer; Giller, Roger H.; Shimamura, Akiko; Delaney, Colleen; Skoda-Smith, Suzanne; Thakar, Monica S.; Baker, K. Scott; Rawlings, David J.; Englund, Janet A.; Flowers, Mary E. D.; Deeg, H. Joachim; Storb, Rainer; Woolfrey, Ann E.

    2015-01-01

    Hematopoietic cell transplantation (HCT) is effective in the treatment of patients with nonmalignant diseases and for many is the only known cure. Conventional myeloablative regimens have been associated with unacceptably high early transplant-related mortality (TRM) particularly in patients with co-morbid conditions. This prospective multicenter trial was designed to determine the safety and engraftment efficacy of treosulfan-based conditioning in patients with nonmalignant diseases. Thirty-one patients received HLA-matched related (n=4) or unrelated (n=27) grafts following conditioning with treosulfan (total dose: 42 g/m2), fludarabine (total dose: 150 mg/m2), ± thymoglobulin (6 mg/kg; n=22). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. All patients engrafted. Day-100 TRM was 0%. With a median follow-up of 2 years, the 2-year survival was 90%. Three patients died of GVHD, recurrent hemophagocytic lymphohistiocytosis, and a surgical complication, respectively. The cumulative incidences of grades II–IV and III–IV acute GVHD at day 100 and chronic GVHD at 2 years were 62%, 10% and 21%, respectively. Patients who received thymoglobulin had a significantly lower incidence of grade III-IV acute GVHD (0% versus 33%; P = 0.005). These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with low toxicity and improved survival in patients with nonmalignant diseases, and support the need for future disease-specific clinical trials. PMID:25196857

  2. Concurrent acute myeloid leukemia and T lymphoblastic lymphoma in a patient with rearranged PDGFRB genes

    Directory of Open Access Journals (Sweden)

    Chang Hung

    2012-02-01

    Full Text Available Abstract Concurrent hematologic malignancies are relatively rare. We encountered a case of concurrent acute myeloid leukemia (AML and T lymphoblastic lymphoma. The bone marrow chromosome analysis showed the karyotype 46, XY, t(5;12(q33;p13, which indicated presence of PDGFRB gene translocations. Therefore, this disease belongs to the new WHO category of myeloid and lymphoid neoplasms with abnormalities in PDGFRA, PDGFRB and FGFR1 genes. Although such genetic mutations are prone to multi-lineage differentiation, the present case is in fact the first report of concurrent AML and T lymphoblastic lymphoma involving PDGFRB mutations. The patient was treated with cytarabine and daunomycin in combination with high dose dexamethasone. Allogeneic stem cell transplantation was performed after successful remission induction for both entities. The patient eventually died of chronic graft-versus-host-disease related infection. Based on such an experience, we suggest the decision of stem cell transplantation should be weighed carefully against the risks, especially when tyrosine kinase inhibitors are safe and potentially effective in dealing with such entities.

  3. MHC Class I Chain-Related Gene A (MICA) Donor-Recipient Mismatches and MICA-129 Polymorphism in Unrelated Donor Hematopoietic Cell Transplantations Has No Impact on Outcomes in Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, or Myelodysplastic Syndrome: A Center for International Blood and Marrow Transplant Research Study.

    Science.gov (United States)

    Askar, Medhat; Sobecks, Ronald; Wang, Tao; Haagenson, Mike; Majhail, Navneet; Madbouly, Abeer; Thomas, Dawn; Zhang, Aiwen; Fleischhauer, Katharina; Hsu, Katharine; Verneris, Michael; Lee, Stephanie J; Spellman, Stephen R; Fernández-Viña, Marcelo

    2017-03-01

    Single-center studies have previously reported associations of MHC Class I Chain-Related Gene A (MICA) polymorphisms and donor-recipient MICA mismatching with graft-versus-host disease (GVHD) after unrelated donor hematopoietic cell transplantation (HCT). In this study, we investigated the association of MICA polymorphism (MICA-129, MM versus MV versus VV) and MICA mismatches after HCT with 10/10 HLA-matched (n = 552) or 9/10 (n = 161) unrelated donors. Included were adult patients with a first unrelated bone marrow or peripheral blood HCT for acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome that were reported to the Center for International Blood and Marrow Transplant Research between 1999 and 2011. Our results showed that neither MICA mismatch nor MICA-129 polymorphism were associated with any transplantation outcome (P acute GVHD grades II to IV (HR, 1.4; P = .013) There were no significant interactions between MICA mismatches and HLA matching (9/10 versus 10/10). In conclusion, the findings in this cohort did not confirm prior studies reporting that MICA polymorphism and MICA mismatches were associated with HCT outcomes.

  4. Research progress of CD4+CD25+ regulatory T cell in bone marrow hematopoietic system diseases%CD4+CD25+调节性T细胞在骨髓造血系统疾病中的研究进展

    Institute of Scientific and Technical Information of China (English)

    刘增慧; 李勇华

    2011-01-01

    CD4 + CD25 + regulatory T cell is a unique T-cell subsets with immune regulation function. Natural CD4+CD25 + regulatory T cell originates from the thymus and acquired CD4+CD25 + regulatory T cell can be induced from CD4* CD25 - T cells in peripheral blood. A specific transcription inhibicory factor-foxp3 , can be expressed in its molecule surface, besides, it also can express other membrane molecules, such as CD4, CD25, CTLA-4 ( CD152), GITR, CD103, CD62L, CD69, CD134, CD71, CD54, CD45RA , TGF-β1 , IL-10, glactin-1 , neuropilin-1 , etc. Its main function is immunosuppression and immune anergy. Recent research finds that it overexpresses in acute myeloid leukemia, chronic lymphocytic leukemia and high-risk myelodysplastic syndrome. However, in aplastic anemia its expression is much lower than normal. Other researchers believe that it has much to do with acute graft versus host disease, in its occurrence and development. In this article, we will review the recent research results of CD4 + CD25 + regulatory T cell in bone marrow hematopoietic system diseases, specifically, in leukemia, acute graft versus host disease, aplastic anemia, myelodysplastic syndrome and multiple myeloma.%CD4+CD25+调节性T细胞(regulatory T cell, Treg)是具有独特免疫调节功能的T细胞亚群. 天然CD4+CD25+ Treg起源于胸腺,外周血中CD4+CD25-T细胞亦可诱导产生.其分子表面表达特异性的转录抑制因子Foxp3,还表达CD4、CD25、CTLA-4(CD152))、GITR、CD103、CD62L、CD69、CD134、CD71、CD54、CD45RA、TGF-β1、IL-10、半乳糖结合蛋白(glactin)-1、神经菌毛素(neuropilin)-1等膜分子,具有免疫抑制和免疫无能作用.近年来研究发现,急性髓细胞白血病(acute myeloid leukemia,AML)、慢性淋巴细胞白血病(chronic lymphocytic leukemia,CLL)、高危骨髓异常增生综合征(myelodysplastic syndrome, MDS)患者Treg表达异常增高,而在再生障碍性贫血(aplastic anemia,AA)患者表达明显降低,其异常表达

  5. Initial fluconazole prophylaxis may not be required in adults with acute leukemia or myelodysplastic/myeloproliferative disorders after reduced intensity conditioning peripheral blood stem cell allogeneic transplantation.

    Science.gov (United States)

    Brissot, Eolia; Cahu, Xavier; Guillaume, Thierry; Delaunay, Jacques; Ayari, Sameh; Peterlin, Pierre; Le Bourgeois, Amandine; Harousseau, Jean-Luc; Milpied, Noel; Bene, Marie-Christine; Moreau, Philippe; Mohty, Mohamad; Chevallier, Patrice

    2015-04-01

    In the myeloablative transplant setting, the early use of fluconazole prophylaxis provides a benefit in overall survival. Recent changes in transplantation practices, including the use of peripheral blood stem cells (PBSC) and/or reduced intensity conditioning (RIC) regimen may have favorably impacted the epidemiology of invasive fungal infections (IFI) after allogeneic stem cell transplantation (allo-SCT). Yet, the impact of removing fluconazole prophylaxis after RIC PBSC allotransplant is ill known. Here, a retrospective analysis was performed comparing patients who received fluconazole as antifungal prophylaxis (n = 53) or not (n = 56) after allo-SCT for acute leukemia or myelodysplastic/myeloproliferative syndrome. Sixteen IFI were documented (14 %) at a median time of 103 days after transplantation, including eight before day +100, at a similar rate, whether the patients received fluconazole prophylaxis (13 %) or not (16 %). IFI were due mainly to Aspergillus species (87 %), and only two Candida-related IFI (13 %) were documented in the non-fluconazole group before day +100. The incidences of IFI (overall, before or after day +100) as well as 3-year overall and disease-free survival, non-relapse mortality, or acute and chronic graft-versus-host disease (GVHD) were similar between both groups. In conclusion, this study suggests that fluconazole may not be required at the initial phase of RIC allo-SCT using PBSC. This result has to be confirmed prospectively while Aspergillus prophylaxis should be discussed in this particular setting.

  6. Reduced-toxicity conditioning with treosulfan, fludarabine and ATG as preparative regimen for allogeneic stem cell transplantation (alloSCT) in elderly patients with secondary acute myeloid leukemia (sAML) or myelodysplastic syndrome (MDS).

    Science.gov (United States)

    Kröger, N; Shimoni, A; Zabelina, T; Schieder, H; Panse, J; Ayuk, F; Wolschke, C; Renges, H; Dahlke, J; Atanackovic, D; Nagler, A; Zander, A

    2006-02-01

    We investigated a dose-reduced conditioning regimen consisting of treosulfan and fludarabine followed by allogeneic stem cell transplantation (SCT) in 26 patients with secondary AML or MDS. Twenty patients were transplanted from matched or mismatched unrelated donors and six from HLA-identical sibling donors. The median age of the patients was 60 years (range, 44-70). None of the patients was eligible for a standard myeloablative preparative regimen. No graft-failure was observed, and leukocyte and platelet engraftment were observed after a median of 16 and 17 days, respectively. Acute graft-versus-host disease (GvHD) grade II-IV was seen in 23% and severe grade III GvHD in 12% of the patients. No patients experienced grade IV acute GvHD. Chronic GvHD was noted in 36% of the patients, which was extensive disease in 18%. The 2-year cumulative incidence of relapse was 21%. The relapse rate was higher in patients beyond CR1 or with intermediate two or high risk MDS (P = 0.02). The treatment-related mortality at day 100 was 28%. The 2-year estimated overall and disease-free survival was 36-34%, respectively. No difference in survival was seen between unrelated and related SCT.

  7. Allogeneic stem cell transplant for adults with myelodysplastic syndromes: relevance of pre-transplant disease status.

    Science.gov (United States)

    Busca, Alessandro; Pecoraro, Clara; Giaccone, Luisa; Bruno, Benedetto; Allione, Bernardino; Corsetti, Maria Teresa; Pini, Massimo; Marmont, Filippo; Audisio, Ernesta; D'Ardia, Stefano; Frairia, Chiara; Castiglione, Anna; Ciccone, Giovannino; Levis, Alessandro; Vitolo, Umberto; Falda, Michele

    2014-04-01

    The aim of the present study was to investigate the outcome of 94 adult patients with myelodysplasia (MDS) who received an allogeneic stem cell transplant between January 1995 and September 2010 in two Italian hematology centers. At the time of transplant, 53 patients (56%) had relapsed/refractory disease. The cumulative incidence of grades II-IV acute graft-versus-host disease (GVHD) and chronic GVHD was 33% (95% confidence interval [CI] 21-45%) and 78% (95% CI 66-90%), respectively. The cumulative incidence of transplant-related mortality (TRM) at 100 days was 13% (95% CI 6-21%). The 2-year progression free survival (PFS) and overall survival (OS) were 41% (95% CI 31-51%) and 49% (95% CI 38-59%), respectively. On multivariate analysis, advanced disease stage at transplant was the major independent variable associated with an inferior 2-year PFS (HR 3.66, 95% CI 1.98-6.76) and OS (HR 3.68, 95% CI 1.95-6.93). Use of an alternative donor was an independent variable associated with TRM (HR 3.18, 95% CI 1.31-7.72). In conclusion, our data suggest that disease status at the time of transplant is the major predictor for improved PFS and OS, and treatments required to reach this goal may have value in leading to an improved outcome.

  8. Reduced-Intensity Conditioning Combined with (188)Rhenium Radioimmunotherapy before Allogeneic Hematopoietic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia: The Role of In Vivo T Cell Depletion.

    Science.gov (United States)

    Schneider, Sebastian; Strumpf, Annette; Schetelig, Johannes; Wunderlich, Gerd; Ehninger, Gerhard; Kotzerke, Jörg; Bornhäuser, Martin

    2015-10-01

    The combination of reduced-intensity conditioning, (188)rhenium anti-CD66 radioimmunotherapy, and in vivo T cell depletion was successfully applied in elderly patients with acute myeloid leukemia or myelodysplastic syndrome. Within a prospective phase II protocol, we investigated whether a dose reduction of alemtuzumab (from 75 mg to 50 mg MabCampath) would improve leukemia-free survival by reducing the incidence of relapse. Fifty-eight patients (median age, 67 years; range, 54 to 76) received radioimmunotherapy followed by fludarabine 150 mg/m(2) and busulfan 8 mg/kg combined with either 75 mg (n = 26) or 50 mg (n = 32) alemtuzumab. Although we observed a trend towards a shorter duration of neutropenia in the 50 mg group (median, 19 versus 21 days; P = .07), the time from transplantation to neutrophil and platelet engraftment as well as the overall incidence of engraftment did not differ. The incidence of severe acute graft-versus-host disease tended to be higher after the lower alemtuzumab dose (17% versus 4%; P = .15). No significant differences in the cumulative incidences of relapse (38% versus 35%; P = .81) or nonrelapse mortality (46% versus 27%; P = .31) were observed. Accordingly, disease-free and overall survival were not significantly different between groups. Although the feasibility of radioimmunotherapy plus reduced-intensity conditioning could be demonstrated in elderly patients, the dose reduction of alemtuzumab had no positive impact on overall outcome.

  9. 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.

  10. Interferon α: the salvage therapy for patients with unsatisfactory response to minimal residual disease-directed modified donor lymphocyte infusion

    Institute of Scientific and Technical Information of China (English)

    Mo Xiaodong; Zhao Xiangyu; Xu Lanping; Liu Daihong; Zhang Xiaohui; Chen Huan; Wang Yu

    2014-01-01

    Background Minimal residual disease (MRD)-directedmodified donor lymphocyte infusion (mDLI) is used to treat relapse after hematopoietic stem cell transplantation (HSCT).For patients who experience an unsatisfactory response tomDLI,relapse is usually inevitable.Therefore,we sought to evaluate the efficacy ofinterferon α therapy in these patients.Methods Regular MRD monitoring was carried out after the HSCT.The patients who were MRD-positive underwent mDLI.Patients with an unsatisfactory response to mDLI received interferon α therapy (3 million units,twice weekly) with regular monitoring of MRD.To ensure the immunomodulatory effects of interferon α,immunosuppressant treatment would be stopped before interferon α treatment.Results Five patients with an unsatisfactory response to mDLI treatment received interferon α (3 had t(8;21) chromosomal translocation acute myeloid leukemia,and 2 had common acute leukemia).They had significantly reduced or resolved MRD.Four patients developed chronic graft-versus-host disease.Two of the 5 patients reported transient fevers,and no significant bone marrow suppression was observed.All of them were in continuous complete remission after interferon α treatment.The median survival time was 469 days (range 368-948 days).Conclusions In patients with an unsatisfactory response to MRD-directed mDLI,interferon α may directly or indirectly induce the graft-versus-leukemia effect to improve mDLI efficacy and clear MRD.

  11. Invasive fungal infection following reduced-intensity cord blood transplantation for adult patients with hematologic diseases.

    Science.gov (United States)

    Miyakoshi, Shigesaburo; Kusumi, Eiji; Matsumura, Tomoko; Hori, Akiko; Murashige, Naoko; Hamaki, Tamae; Yuji, Koichiro; Uchida, Naoyuki; Masuoka, Kazuhiro; Wake, Atsushi; Kanda, Yoshinobu; Kami, Masahiro; Tanaka, Yuji; Taniguchi, Shuichi

    2007-07-01

    Invasive fungal infection (IFI) is a significant complication after allogeneic hematopoietic stem cell transplantation (HSCT); however, we have little information on its clinical features after reduced intensity cord blood transplantation (RICBT) for adults. We reviewed medical records of 128 patients who underwent RICBT at Toranomon Hospital between March 2002 and November 2005. Most of the patients received purine-analogbased preparative regimens. Graft-versus-host disease (GVHD) prophylaxis was a continuous infusion of either tacrolimus 0.03 mg/kg or cyclosporine 3 mg/kg. IFI was diagnosed according to the established EORTC/NIH-MSG criteria. IFI was diagnosed in 14 patients. Thirteen of the 14 had probable invasive pulmonary aspergillosis and the other had fungemia resulting from Trichosporon spp. Median onset of IFI was day 20 (range: 1-82), and no patients developed IFI after day 100. Three-year cumulative incidence of IA was 10.2%. Four of the 13 patients with invasive aspergillosis (IA) developed grade II-IV acute GVHD, and their IA was diagnosed before the onset of acute GVHD. The mortality rate of IFI was 86%. Multivariate analysis revealed that the use of prednisolone >0.2 mg/kg (relative risk 7.97, 95% confidence interval 2.24-28.4, P = .0014) was a significant risk factor for IA. This study suggests that IFI is an important cause of deaths after RICBT, and effective strategies are warranted to prevent IFI.

  12. 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.

  13. 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).

  14. Impact of Graft-Recipient ABO Compatibility on Outcomes after Umbilical Cord Blood Transplant for Nonmalignant Disease.

    Science.gov (United States)

    Kudek, Matthew R; Shanley, Ryan; Zantek, Nicole D; McKenna, David H; Smith, Angela R; Miller, Weston P

    2016-11-01

    Existing literature shows mixed conclusions regarding the impact of ABO incompatibility on outcomes after hematopoietic stem cell transplantation. Because the future for umbilical cord blood (UCB) expansion technologies is bright, we assessed whether this typically overlooked graft characteristic impacted various outcomes after UCB transplantation (UCBT) for nonmalignant disorders (NMDs). A prospectively maintained institutional blood and marrow transplant program database was queried for all patients undergoing first UCBT for NMDs. UCB and recipient ABO compatibility was considered as matched, major mismatched, minor mismatched, or bidirectional mismatched. The impact of ABO incompatibility was assessed on overall survival, graft failure, acute and chronic graft-versus-host disease (GVHD), time to neutrophil and platelet recovery, day 0 to day 100 RBC transfusion burden, and donor hematopoietic chimerism. Through December 2014, 270 patients have undergone first UCBT for various NMDs. In both univariable and multivariable analyses, ABO compatibility status did not appear to impact any outcomes assessed, although a trend toward increased grades III to IV acute GVHD was seen in recipients of major mismatched units. When considering UCBT for treatment of NMDs, ABO compatibility between the donor unit and intended recipient does not appear to be an important consideration in the UCB unit choice.

  15. 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.

  16. 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.

  17. Low CD34 dose is associated with poor survival after reduced-intensity conditioning allogeneic transplantation for acute myeloid leukemia and myelodysplastic syndrome.

    Science.gov (United States)

    Törlén, Johan; Ringdén, Olle; Le Rademacher, Jennifer; Batiwalla, Minoo; Chen, Junfang; Erkers, Tom; Ho, Vincent; Kebriaei, Partow; Keever-Taylor, Carolyn; Kindwall-Keller, Tamila; Lazarus, Hillard M; Laughlin, Mary J; Lill, Michael; O'Brien, Tracey; Perales, Miguel-Angel; Rocha, Vanderson; Savani, Bipin N; Szwajcer, David; Valcarcel, David; Eapen, Mary

    2014-09-01

    Reduced-intensity conditioning/nonmyeloablative conditioning regimens are increasingly used in allogeneic hematopoietic cell transplantation (HCT). Reports have shown CD34(+) dose to be important for transplantation outcome using myeloablative conditioning. The role of CD34(+) dose of peripheral blood progenitor cells (PBPC) has not been previously analyzed in a large population undergoing reduced-intensity conditioning/nonmyeloablative HCT. We studied 1054 patients, ages 45 to 75 years, with acute myeloid leukemia or myelodysplastic syndrome who underwent transplantation between 2002 and 2011. Results of multivariate analysis showed that PBPC from HLA-matched siblings containing after myeloablative HCT, CD34(+) dose did not affect relapse or graft-versus-host disease with either donor type. An upper cell dose limit was not associated with adverse outcomes. These data suggest that PBPC CD34(+) doses >4 × 10(6) CD34(+)/kg and >6 × 10(6) CD34(+)/kg are optimal for HLA-matched sibling and unrelated donor HCT, respectively.

  18. [Bone marrow transplantation in Mexico. Report of the 1st successful case in acute myeloblastic leukemia. Grupo de Trasplante Medular Oseo del INNSZ].

    Science.gov (United States)

    León, E; Sosa, R

    1992-01-01

    The first case of allogeneic bone marrow transplantation in acute myelogenous leukemia (AML) done in Mexico is reported. The patient was a 26 year old Mexican woman who in October 1987 was diagnosed of having AML of the M2 subtype. After three cycles of the TADOP regimen (6-thioguanine, cytosine-arabinoside, doxorubicin, vincristine & prednisone), the patient entered complete remission. Unfortunately, after a seven month period of remission she suffered a relapse which was refractory to a new chemotherapy cycle. On 9/14/88 an allogeneic BMT from her HLA identical brother was performed. The conditioning regimen consisted of busulfan and cyclophosphamide. Prophylaxis for GVHD consisted of cyclosporine and methylprednisolone. The posttransplantation course was satisfactory, reaching > 500 neutrophils x 10(9)/L on day 14 and > 50,000 platelets x 10(9)/L without support on day 23 posttransplant. The patient developed fever of unknown etiology, which was satisfactorily resolved with ceftazidime, vancomycin and metronidazole. She also presented a grade II oral and esophageal mucositis. As a late complication, on day 90 posttransplant, she developed a bilateral pneumonia which was resolved with sulfamethoxazole-trimethoprim administration. Up to the time of this report (40 months posttransplant) the patient is completely asymptomatic, is under no immunosuppression, and shows no evidence of graft versus host disease or recurrent leukemia.

  19. A summary about dendritic cells in skin diseases

    Institute of Scientific and Technical Information of China (English)

    Jianguo Huang; Robert Gniadecki

    2005-01-01

    Dendritic cellls (DCs) comprise an essential component of the immune system, are crucial in the initiation of antigen specific immune responses. In this summary we focus on summarizing on the central role of DCs in skin diseases: Bullous dermatoses,Dermatitis, Psoriasis, Lichen Planus , Graft-versus-host disease, Connect Tissue Diseases, Virus Diseases, Fungi Diseases, HIV, Urticaria, Urticaria pigmentosa, Mastocytosis, Tumour, Solar dermatoses. Moreover, in this summary we review the distribution and phenotype of DCs in human skin. Markers and phenotyps ' s study have provided strong support for a concept in which DCs play an important role in the pothogenesis of some skin diseases.

  20. Skin biopsy: Biopsy issues in specific diseases.

    Science.gov (United States)

    Elston, Dirk M; Stratman, Erik J; Miller, Stanley J

    2016-01-01

    Misdiagnosis may result from biopsy site selection, technique, or choice of transport media. Important potential sources of error include false-negative direct immunofluorescence results based on poor site selection, uninformative biopsy specimens based on both site selection and technique, and spurious interpretations of pigmented lesions and nonmelanoma skin cancer based on biopsy technique. Part I of this 2-part continuing medical education article addresses common pitfalls involving site selection and biopsy technique in the diagnosis of bullous diseases, vasculitis, panniculitis, connective tissue diseases, drug eruptions, graft-versus-host disease, staphylococcal scalded skin syndrome, hair disorders, and neoplastic disorders. Understanding these potential pitfalls can result in improved diagnostic yield and patient outcomes.

  1. Cord blood transplantation for the treatment of acute leukemia

    Institute of Scientific and Technical Information of China (English)

    Meerim Park; Young-ho Lee

    2013-01-01

    Objective This review discussed the available data on treatment outcomes of cord blood transplantation (CBT) for acute leukemia.Data sources The data cited in this review were obtained from articles listed in Medline and Pubmed.Study selection We reviewed the articles of clinical results from various registries and institutions,as well as our experiences with CBT in children,adolescents and adults.Results This research has clearly shown that cord blood (CB) has several unique characteristics resulting in distinct advantage and disadvantages when compared to transplantation with unrelated donor bone marrow or peripheral blood stem cells.The field of CBT has advanced from investigating its safety and feasibility to addressing more specific issues such as accelerating engraftment,extending access,and examining outcomes in specific subgroups of patients.Many approaches have been investigated in the attempt to improve engraftment and survival.Variable factors have been identified,such as factors related to donor choice (human leukocyte antigen (HLA) compatibility,cell dose,and others) and transplantation (conditioning and graft-versus-host disease prophylaxis regimen).Data support that CB should be considered a reasonable option in those that do not have HLA matched sibling donor and for those in whom the time to transplant is critical.Conclusions CB is a reasonable alternative to unrelated donor bone marrow or peripheral blood progenitor cells for transplantation.Recently developed strategies aimed at improving hematopoietic recovery and reducing early transplantation-related mortality could further improve treatment outcomes of CBT for patients with acute leukemia.

  2. Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome.

    Science.gov (United States)

    Pusic, Iskra; Choi, Jaebok; Fiala, Mark A; Gao, Feng; Holt, Matthew; Cashen, Amanda F; Vij, Ravi; Abboud, Camille N; Stockerl-Goldstein, Keith E; Jacoby, Meghan A; Uy, Geoffrey L; Westervelt, Peter; DiPersio, John F

    2015-10-01

    Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I, inducing leukemic differentiation and re-expression of epigenetically silenced putative tumor antigens. We assessed safety and efficacy of decitabine maintenance after allogeneic transplantation for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Decitabine maintenance may help eradicate minimal residual disease, decrease the incidence of graft-versus-host disease (GVHD), and facilitate a graft-versus-leukemia effect by enhancing the effect of T regulatory lymphocytes. Patients with AML/MDS in complete remission (CR) after allotransplantation started decitabine between day +50 and +100. We investigated 4 decitabine doses in cohorts of 4 patients: 5, 7.5, 10, and 15 mg/m(2)/day × 5 days every 6 weeks, for a maximum 8 cycles. The maximum tolerated dose (MTD) was defined as the maximum dose at which ≤ 25% of people experience dose-limiting toxicities during the first cycle of treatment. Twenty-four patients were enrolled and 22 were evaluable. All 4 dose levels were completed and no MTD was reached. Overall, decitabine maintenance was well tolerated. Grade 3 and 4 hematological toxicities were experienced by 75% of patients, including all patients treated at the highest dose level. Nine patients completed all 8 cycles and 8 of them remain in CR. Nine patients died from relapse (n = 4), infectious complications (n = 3), and GVHD (n = 2). Most occurrences of acute GVHD were mild and resolved without interruption of treatment; 1 patient died of acute gut GVHD. Decitabine maintenance did not clearly impact the rate of chronic GVHD. Although there was a trend of increased FOXP3 expression, results were not statistically significant. In conclusion, decitabine maintenance is associated with acceptable toxicities when given in the post-allotransplantation setting. Although the MTD was not reached, the dose of 10 mg/m(2) for 5 days every 6 weeks appeared to be the

  3. Nonmyeloablative Stem Cell Transplantation with Alemtuzumab/Low-Dose Irradiation to Cure and Improve the Quality of Life of Adults with Sickle Cell Disease.

    Science.gov (United States)

    Saraf, Santosh L; Oh, Annie L; Patel, Pritesh R; Jalundhwala, Yash; Sweiss, Karen; Koshy, Matthew; Campbell-Lee, Sally; Gowhari, Michel; Hassan, Johara; Peace, David; Quigley, John G; Khan, Irum; Molokie, Robert E; Hsu, Lewis L; Mahmud, Nadim; Levinson, Dennis J; Pickard, A Simon; Garcia, Joe G N; Gordeuk, Victor R; Rondelli, Damiano

    2016-03-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is rarely performed in adult patients with sickle cell disease (SCD). We utilized the chemotherapy-free, alemtuzumab/total body irradiation 300 cGy regimen with sirolimus as post-transplantation immunosuppression in 13 high-risk SCD adult patients between November 2011 and June 2014. Patients received matched related donor (MRD) granulocyte colony-stimulating factor-mobilized peripheral blood stem cells, including 2 cases that were ABO incompatible. Quality-of-life (QoL) measurements were performed at different time points after HSCT. All 13 patients initially engrafted. A stable mixed donor/recipient chimerism was maintained in 12 patients (92%), whereas 1 patient not compliant with sirolimus experienced secondary graft failure. With a median follow-up of 22 months (range, 12 to 44 months) there was no mortality, no acute or chronic graft-versus-host disease (GVHD), and no grades 3 or 4 extramedullary toxicities. At 1 year after transplantation, patients with stable donor chimerism have normalized hemoglobin concentrations and improved cardiopulmonary and QoL parameters including bodily pain, general health, and vitality. In 4 patients, sirolimus was stopped without rejection or SCD-related complications. These results underscore the successful use of a chemotherapy-free regimen in MRD HSCT for high-risk adult SCD patients and demonstrates a high cure rate, absence of GVHD or mortality, and improvement in QoL including the applicability of this regimen in ABO mismatched cases (NCT number 01499888).

  4. Cytoreductive treatment with clofarabine/ara-C combined with reduced-intensity conditioning and allogeneic stem cell transplantation in patients with high-risk, relapsed, or refractory acute myeloid leukemia and advanced myelodysplastic syndrome.

    Science.gov (United States)

    Buchholz, Stefanie; Dammann, Elke; Stadler, Michael; Krauter, Juergen; Beutel, Gernot; Trummer, Arne; Eder, Matthias; Ganser, Arnold

    2012-01-01

    The combination of cytoreductive chemotherapy with reduced-intensity conditioning (RIC) is a highly effective antileukemic therapy. Purpose of this retrospective analysis was to evaluate the antileukemic efficacy and toxicity of clofarabine-based chemotherapy followed by RIC and allogeneic stem cell transplantation (SCT) for high-risk, relapsed, or refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). From May 2007 until October 2009, a total of 27 patients underwent allogeneic SCT after treatment with clofarabine and ara-C for 5d and RIC (4Gy TBI/cyclophosphamide/ATG). Prophylaxis of graft-versus-host disease (GvHD) consisted of cyclosporine and mycophenolate mofetil. Unmanipulated G-CSF mobilized PBSC (n=26) or bone marrow cells (n=1) were transplanted from unrelated (n=21) or matched related (n=6) donors. Non-hematological toxicities of this regimen mainly affected liver and skin and were all reversible. Seven patients relapsed within a median time of 5.7 months. The overall survival (OS) and relapse-free survival rates were 56% and 52% at 2 yr, respectively. In this cohort of patients, cytoreduction with clofarabine/ara-C (ClAraC) followed by RIC allogeneic SCT was well tolerated and showed good antileukemic efficacy even in patients with high-risk AML or MDS, with engraftment and GvHD-incidence comparable to other RIC regimens.

  5. Alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following alemtuzumab, fludarabine, and melphalan RIC HCT.

    Science.gov (United States)

    Marsh, Rebecca A; Lane, Adam; Mehta, Parinda A; Neumeier, Lisa; Jodele, Sonata; Davies, Stella M; Filipovich, Alexandra H

    2016-01-28

    Reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) with alemtuzumab, fludarabine, and melphalan is an effective approach for patients with nonmalignant disorders. Mixed chimerism and graft-versus-host-disease (GVHD) remain limitations on success. We hypothesized that higher levels of alemtuzumab at day 0 would result in a low risk of acute GVHD, a higher risk of mixed chimerism, and delayed early lymphocyte recovery and that alemtuzumab level thresholds for increased risks of these outcomes would be definable. We collected data from 105 patients to examine the influence of peritransplant alemtuzumab levels on acute GVHD, mixed chimerism, and lymphocyte recovery. The cumulative incidences of initial grades I-IV, II-IV, and III-IV acute GVHD in patients with alemtuzumab levels ≤0.15 vs ≥0.16 μg/mL were 68% vs 18% (P alemtuzumab level ≤0.15 μg/mL was 21%, vs 42% with levels of 0.16 to 4.35 μg/mL, and 100% with levels >4.35 μg/mL (P = .003). Patients with alemtuzumab levels ≤0.15 or 0.16 to 0.56 μg/mL had higher lymphocyte counts at day +30 and higher T-cell counts at day +100 compared with patients with levels ≥0.57 μg/mL (all P alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following RIC HCT with alemtuzumab, fludarabine, and melphalan. Precision dosing trials are warranted. We recommend a day 0 therapeutic range of 0.2 to 0.4 μg/mL.

  6. 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.

  7. Anti-CD19 chimeric antigen receptor T-cell therapy for adult Philadelphia chromosome-positive acute lymphoblastic leukemia

    Science.gov (United States)

    Zhu, Yang-min; Wu, Zhao; Tan, You-ping; Du, Yuan-yuan; Liu, Zhi; Ou, Rui-ming; Liu, Shuang; Pu, Cheng-fei; Jiang, Jing; Wang, Jin-ping; Xiao, Lei; Zhang, Qing

    2016-01-01

    Abstract Rationale: The presence of the Philadelphia chromosome (Ph) in acute lymphoblastic leukemia (ALL) has been associated with a high risk of disease relapse and a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment for adults with Ph-positive ALL, but relapse remains the primary cause of treatment failure, and is associated with an extremely poor prognosis. The emergence of resistance to tyrosine kinase inhibitors (TKIs) poses a challenge for patients with disease relapses after initial treatment with TKI-containing regimens. Patient concerns: Two patients with TKI-resistant recurrent Ph-positive ALL. Diagnoses: Ph-positive ALL. Interventions: Anti-CD19 CAR T-cell infusion. Outcomes: One patient's bone marrow blasts decreased significantly, and the other reached negative minimal residual disease (MRD). However, we first recorded the development of new-onset acute graft-versus-host disease (aGVHD) after anti-CD19 CAR T-cell infusion in a patient who received allogeneic HSCT. Our 2 case reports also demonstrate the efficacy of anti-CD19 CAR T-cell therapy in the treatment of TKI-resistant Ph-positive ALL. Lessons: Our report suggests that anti-CD19 CAR T-cell therapy may be a promising option for the treatment of relapsed Ph-positive ALL after conventional chemotherapy or allogeneic HSCT. However, caution is due given the possibility of the adverse effects of cytokine release syndrome (CRS)-induced aGVHD for patients receiving allogeneic HSCT. PMID:28002337

  8. Minimal change nephrotic syndrome after stem cell transplantation: a case report and literature review

    Directory of Open Access Journals (Sweden)

    Silva Sandra

    2007-10-01

    Full Text Available Abstract Graft-versus-host disease is one of the most frequent complications occurring after haematopoietic stem cell transplantation. Recently, renal involvement has been described as a manifestation of chronic graft-versus-host disease. Immunosuppression seems to play a major role: clinical disease is triggered by its tapering and resolution is achieved with the resumption of the immunosuppressive therapy. Prognosis is apparently favourable, but long term follow up data are lacking. We report a case of a 53-year-old man who developed nephrotic syndrome 142 days after allogeneic stem cell transplantation for acute myeloid leukaemia. Onset of nephrotic syndrome occurred after reduction of immunosuppressants and was accompanied by manifestations of chronic graft-versus-host disease. Histological examination of the kidney was consistent with Minimal Change Disease. After treatment with prednisolone and mycophenolate mofetil he had complete remission of proteinuria and improvement of graft-versus-host disease. Eighteen months after transplantation the patient keeps haematological remission and normal renal function, without proteinuria. Since patients with chronic graft-versus-host disease might be considered at risk for development of nephrotic syndrome, careful monitoring of renal parameters, namely proteinuria, is advisable.

  9. Minimal change nephrotic syndrome after stem cell transplantation: a case report and literature review.

    Science.gov (United States)

    Silva, Sandra; Maximino, José; Henrique, Rui; Paiva, Ana; Baldaia, Jorge; Campilho, Fernando; Pimentel, Pedro; Loureiro, Alfredo

    2007-10-30

    Graft-versus-host disease is one of the most frequent complications occurring after haematopoietic stem cell transplantation. Recently, renal involvement has been described as a manifestation of chronic graft-versus-host disease. Immunosuppression seems to play a major role: clinical disease is triggered by its tapering and resolution is achieved with the resumption of the immunosuppressive therapy. Prognosis is apparently favourable, but long term follow up data are lacking.We report a case of a 53-year-old man who developed nephrotic syndrome 142 days after allogeneic stem cell transplantation for acute myeloid leukaemia. Onset of nephrotic syndrome occurred after reduction of immunosuppressants and was accompanied by manifestations of chronic graft-versus-host disease. Histological examination of the kidney was consistent with Minimal Change Disease. After treatment with prednisolone and mycophenolate mofetil he had complete remission of proteinuria and improvement of graft-versus-host disease. Eighteen months after transplantation the patient keeps haematological remission and normal renal function, without proteinuria.Since patients with chronic graft-versus-host disease might be considered at risk for development of nephrotic syndrome, careful monitoring of renal parameters, namely proteinuria, is advisable.

  10. Outcomes of patients with acute leukaemia who relapsed after reduced-intensity stem cell transplantation from HLA-identical or one antigen-mismatched related donors.

    Science.gov (United States)

    Kobayashi, Kazuhiko; Kami, Masahiro; Murashige, Naoko; Kusumi, Eiji; Kishi, Yukiko; Hamaki, Tamae; Hori, Akiko; Matsumura, Tomoko; Yuji, Koichiro; Masuo, Shigeru; Mori, Shinichiro; Miyakoshi, Shigesaburo; Tanosaki, Ryuji; Mitamura, Tadayuki; Takaue, Yoichi; Taniguchi, Shuichi

    2005-06-01

    The characteristics of relapse following reduced-intensity stem-cell transplantation (RIST) remain to be clarified. We reviewed the medical records of 19 patients with acute leukaemia [acute myeloid leukaemia (AML), 16; acute lymphoblastic leukaemia (ALL), 3] who relapsed after RIST from related donors using purine-analogue-based regimens. Their median age was 55 years (range, 29-65 years). Median interval between RIST and relapse was 4.9 months (range, 1.8-24.9 months). Three chose not to receive interventions. The remaining 16 patients received withdrawal of immunosuppression (n = 3), chemotherapy (n = 2), donor lymphocyte infusion (n = 10) and second transplantation (n = 7), alone (n = 9) or in combination (n = 7). Four are alive with a median follow-up of 27.6 months (range, 16.0-28.9 months); three in remission and one in relapse. The 2-year overall survival after relapse was 28.9%. Causes of death in 15 patients included progressive disease (n = 7), graft-versus-host disease (n = 5) and infections (n = 3). Cumulative incidences of relapse-related and non-relapse-related deaths at 2 years after relapse were 37% and 32% respectively. Two prognostic factors were identified on univariate analysis: age [P = 0.017; hazard ratio (HR), 1.16; 95% confidence interval (CI), 1.03-1.32], and ALL as underlying disease (P = 0.011; HR, 10.4; 95% CI, 1.73-62.4). Some AML patients who relapse after RIST achieve durable remission with allogeneic immunotherapy-based interventions; however they carry a significant risk of non-relapse mortality.

  11. 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.

  12. Rat acute GvHD is Th1-driven and characterized by predominant donor CD4(+) T cell infiltration of skin and gut.

    Science.gov (United States)

    Boieri, Margherita; Shah, Pranali; Jalapothu, Dasaradha; Zaitseva, Olena; Walter, Lutz; Rolstad, Bent; Naper, Christian; Dressel, Ralf; Inngjerdingen, Marit

    2017-02-23

    Acute graft-versus-host disease (aGvHD) remains a significant hurdle to successful treatment of many hematological disorders. The disease is caused by infiltration of allo-activated donor T cells primarily into the gastrointestinal tract and skin. While cytotoxic T cells mediate direct cellular damage, T helper (Th) cells differentially secrete immunoregulatory cytokines. Acute GvHD is thought to be primarily initiated by Th1 cells but a consensus is still lacking regarding the role of Th2 and Th17 cells. The aim of this study was to determine the contribution of distinct T cell subsets to aGvHD in the rat. Acute GvHD was induced by transplanting irradiated rats with T-cell depleted MHC-mismatched bone marrow, followed two weeks later by donor lymphocyte infusion. Near complete donor T cell chimerism was achieved in the blood and lymphatic tissues, in contrast to mixed chimerism in the skin and gut. Skin and gut donor T cells were predominantly CD4(+), in contrast to T cells in blood and lymphatic tissues. Genes associated with Th1 cells were up-regulated in gut, liver, lung, and skin tissues affected by aGvHD. Increased serum levels of CXCL10 and IL-18 preceded symptoms of aGvHD, accompanied by increased responsiveness to CXCL10 by blood CD4(+) T cells. No changes in expression of Th2- or Th17-associated genes were observed, indicating that aGvHD in this rat model is mainly Th1-driven. The rat model of aGvHD could be instrumental for further investigations of donor T cell subsets in the skin and gut, and for exploring therapeutic options to ameliorate symptoms of aGvHD.

  13. Early and late-onset acute GvHD following hematopoietic cell transplantation: CT features of gastrointestinal involvement with clinical and pathological correlation

    Energy Technology Data Exchange (ETDEWEB)

    Brodoefel, H. [Department of Diagnostic Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, 72076 Tuebingen (Germany)], E-mail: h.brodoefel@t-online.de; Bethge, W. [Department of Internal Medicine II, Oncology/Haematology, Eberhard-Karls-University, Otfried-Mueller-Str. 10, 72076 Tuebingen (Germany); Vogel, M.; Fenchel, M. [Department of Diagnostic Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, 72076 Tuebingen (Germany); Faul, C. [Department of Internal Medicine II, Oncology/Haematology, Eberhard-Karls-University, Otfried-Mueller-Str. 10, 72076 Tuebingen (Germany); Wehrmann, M. [Department of Pathology, Eberhard-Karls-University, Liebermeister-Str. 8, 72076, Tuebingen (Germany); Claussen, C.; Horger, M. [Department of Diagnostic Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, 72076 Tuebingen (Germany)

    2010-03-15

    Objective: With the introduction of non-myeloablative hematopoietic cell transplantation, acute graft-versus-host-disease (GvHD) is frequently observed beyond the traditional 100 days cut-off. The aim of this study was to describe and compare CT features of gastrointestinal early and late-onset GvHD and to correlate findings with clinical and pathology grading. Subjects and methods: Abdominal CT scans were obtained in 20 patients with early and 15 with late-onset GvHD. Examinations were assessed for intestinal and extraintestinal abnormalities and findings compared between the two subgroups of GvHD. Distinct CT abnormalities as well as a CT-score integrating multiple pathologies were correlated with gut, clinical or pathology grading. Results: Frequent intestinal abnormalities included wall thickening, abnormal enhancement, and excessive fluid-filling (94%, 89%, and 94%). 86% of patients showed concomitant small and large bowel involvement. A discontinuous distribution was observed in 54%. Bile tract abnormality was the most common extra-intestinal finding (74%). The distribution of pathologies was equal between subgroups of early or late-onset disease. Wall thickening and mucosal attenuation in non-enhanced scans were significantly related to clinical and pathology scores (P {<=} 0.018). Number of abnormal segments, small bowel dilatation, engorgement of the vasa recta, mesenteric fat stranding and ascites were linked to clinical grading (P {<=} 0.019). A CT-score integrating multiple abnormalities was correlated to gut, overall clinical and pathology grading (r = 0.64, 0.57, 0.50). Conclusion: CT morphology of acute GvHD is independent of its time of onset and, thus, facilitates differential diagnosis of late-onset acute GvHD. Correlation of CT morphology with clinical and pathological grading is important in terms of prognosis and may help guiding the therapeutic approach.

  14. Incidence and outcome of invasive fungal diseases after allogeneic stem cell transplantation: a prospective study of the Gruppo Italiano Trapianto Midollo Osseo (GITMO).

    Science.gov (United States)

    Girmenia, Corrado; Raiola, Anna Maria; Piciocchi, Alfonso; Algarotti, Alessandra; Stanzani, Marta; Cudillo, Laura; Pecoraro, Clara; Guidi, Stefano; Iori, Anna Paola; Montante, Barbara; Chiusolo, Patrizia; Lanino, Edoardo; Carella, Angelo Michele; Zucchetti, Elisa; Bruno, Benedetto; Irrera, Giuseppe; Patriarca, Francesca; Baronciani, Donatella; Musso, Maurizio; Prete, Arcangelo; Risitano, Antonio Maria; Russo, Domenico; Mordini, Nicola; Pastore, Domenico; Vacca, Adriana; Onida, Francesco; Falcioni, Sadia; Pisapia, Giovanni; Milone, Giuseppe; Vallisa, Daniele; Olivieri, Attilio; Bonini, Alessandro; Castagnola, Elio; Sica, Simona; Majolino, Ignazio; Bosi, Alberto; Busca, Alessandro; Arcese, William; Bandini, Giuseppe; Bacigalupo, Andrea; Rambaldi, Alessandro; Locasciulli, Anna

    2014-06-01

    Epidemiologic investigation of invasive fungal diseases (IFDs) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be useful to identify subpopulations who might benefit from targeted treatment strategies. The Gruppo Italiano Trapianto Midollo Osseo (GITMO) prospectively registered data on 1858 consecutive patients undergoing allo-HSCT between 2008 and 2010. Logistic regression analysis was performed to identify risk factors for proven/probable IFD (PP-IFD) during the early (days 0 to 40), late (days 41 to 100), and very late (days 101 to 365) phases after allo-HSCT and to evaluate the impact of PP-IFDs on 1-year overall survival. The cumulative incidence of PP-IFDs was 5.1% at 40 days, 6.7% at 100 days, and 8.8% at 12 months post-transplantation. Multivariate analysis identified the following variables as associated with PP-IFDs: transplant from an unrelated volunteer donor or cord blood, active acute leukemia at the time of transplantation, and an IFD before transplantation in the early phase; transplant from an unrelated volunteer donor or cord blood and grade II-IV acute graft-versus-host disease (GVHD) in the late phase; and grade II-IV acute GVHD and extensive chronic GVHD in the very late phase. The risk for PP-IFD was significantly higher when acute GVHD was followed by chronic GVHD and when acute GVHD occurred in patients undergoing transplantation with grafts from other than matched related donors. The presence of PP-IFD was an independent factor in long-term survival (hazard ratio, 2.90; 95% confidence interval, 2.32 to 3.62; P < .0001). Our findings indicate that tailored prevention strategies may be useful in subpopulations at differing levels of risk for PP-IFDs.

  15. 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

  16. Allogeneic stem cell transplantation in adult patients with acute myeloid leukaemia and 17p abnormalities in first complete remission: a study from the Acute Leukemia Working Party (ALWP of the European Society for Blood and Marrow Transplantation (EBMT

    Directory of Open Access Journals (Sweden)

    Xavier Poiré

    2017-01-01

    Full Text Available Abstract Background Acute myeloid leukaemia (AML with 17p abnormalities (abn(17p carries a very poor prognosis due to high refractoriness to conventional chemotherapy, and allogeneic stem cell transplantation (allo-SCT appears as the only potential curative option. Methods To address outcomes after allo-SCT in patients with abn(17p, we retrospectively analysed de novo or secondary AML undergoing SCT between 2000 and 2013 from the EBMT registry. Results One hundred thirty-nine patients with confirmed abn(17p have been selected. At the time of transplant, one hundred twenty-five were in first remission (CR1. Median age was 54 years old. Abn(17p was associated with a monosomal karyotype in 83% of patients, complex karyotype in 91%, monosomy 5 or 5q deletion (-5/5q- in 55%, monosomy 7 (-7 in 39% and both -5/5q and -7 in 27%. Seventy-three patients (59% had a reduced-intensity conditioning regimen. The 2-year overall survival (OS and leukaemia-free survival (LFS were 28 and 24%, respectively. The 2-year non-relapse mortality (NRM was 15%, and 2-year relapse incidence (RI was 61%. The cumulative incidence of grade II to IV acute graft-versus-host disease (GvHD was 24% and that of chronic GvHD was 21%. In multivariate analysis, the presence of a -5/5q- in addition to abn(17p was significantly and independently associated with worse OS, LFS and higher RI. Age and donor types did not correlate with outcome. Conditioning intensity was not statistically associated with OS, LFS and NRM when adjusted for patients’ age. Conclusions In contrast to the dismal prognosis reported for AML patients harbouring abn(17p undergoing conventional chemotherapy, allogeneic SCT provides responses in about 25% of those patients transplanted in CR1.

  17. 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.

  18. KEGG DISEASE / Acute myeloid leukemia (AML) [KEGG DISEASE

    Lifescience Database Archive (English)

    Full Text Available DISEASE: H00003 Entry H00003Disease Name Acute myeloid leukemia (AML) Description Acute.... Category Cancer Brite Human diseases [BR:br08402] Cancers Cancers of haematopoietic and lymphoid tissues H00003Acute...atopoietic and related tissue C92Myeloid leukaemia H00003Acute myeloid leukemia (AML) Cancer-accociated carb...ohydrates [br08441.html] H00003 Pathway hsa05221Acute myeloid leukemiahsa05202Transcriptional misregulation ... or t(16; 16)(p13, q22), (CBF-beta/MYH11) ICD-O: 9866/3, Tumor type: Acute promyelocytic leukaemia (AML with

  19. Acute kidney injury in patients with systemic sclerosis participating in hematopoietic cell transplantation trials in the United States.

    Science.gov (United States)

    Hosing, Chitra; Nash, Richard; McSweeney, Peter; Mineishi, Shin; Seibold, James; Griffith, Linda M; Shulman, Howard; Goldmuntz, Ellen; Mayes, Maureen; Parikh, Chirag R; Crofford, Leslie; Keyes-Elstein, Lynette; Furst, Daniel; Steen, Virginia; Sullivan, Keith M

    2011-05-01

    Recipients of hematopoietic cell transplantation may be at risk for developing acute kidney injury (AKI), and this risk may be increased in patients who undergo transplantation for severe systemic sclerosis (SSc) due to underlying scleroderma renal disease. AKI after transplantation can increase treatment-related mortality. To better define these risks, we analyzed 91 patients with SSc who were enrolled in 3 clinical trials in the United States of autologous or allogeneic hematopoietic cell transplantation (HCT). Eleven (12%) of the 91 patients with SSc in these studies (8 undergoing autologous HCT, 1 undergoing allogeneic HCT, 1 pretransplantation, 1 given i.v. cyclophosphamide on a transplantation trial) experienced AKI, of whom 8 required dialysis and/or therapeutic plasma exchange. AKI injury in the 9 HCT recipients developed a median of 35 days (range, 0-90 days) after transplantation. Ten of 11 patients with AKI received angiotensin-converting enzyme inhibitor (ACE-I) therapy. The etiology of AKI was attributed to scleroderma renal crisis in 6 patients (including 2 with normotensive renal crisis), to AKI of uncertain etiology in 2 patients, and to AKI superimposed on scleroderma kidney disease in 3 patients. Eight of the 11 patients died, one each because of progression of SSc, multiorgan failure, gastrointestinal and pulmonary bleeding, pericardial tamponade and pulmonary complications, diffuse alveolar hemorrhage, pulmonary embolism, graft-versus-host disease, and malignancy. Limiting nephrotoxins, cautious use of corticosteroids, renal shielding during total body irradiation, strict control of blood pressure, and aggressive use of ACE-Is may be of importance in preventing renal complications after HCT for SSc.

  20. Focus on acute diarrhoeal disease

    Institute of Scientific and Technical Information of China (English)

    Fabio Baldi; Maria Antonia Bianco; Gerardo Nardone; Alberto Pilotto; Emanuela Zamparo

    2009-01-01

    Diarrhoea is an alteration of normal bowel movement characterized by an increase in the water content,volume, or frequency of stools. Diarrhoea needs to be classified according to the trends over time (acute or chronic) and to the characteristics of the stools (watery, fatty, inflammatory). Secretory diarrhoeas,mostly acute and of viral aetiology in more than 70% of cases, are by far the most important subtype of diarrhoeas in terms of frequency, incidence and mortality (over 2.5 million deaths/year in developing countries). Natural and synthetic opiates such as morphine, codeine, and loperamide which react with endogenous opiates (enkephalins, beta-endorphins,dynorphins) mainly act on intestinal motility and slow down transit. An antidiarrhoeal drug developed in recent years, racecadotril, acts as an enkephalinase inhibitor.Clinical studies have shown that it is just as effective as loperamide in resolving acute diarrhoea but with greater reduction in pain and abdominal distension.Some studies have explored the prevalence of diarrhoea in old age. An epidemiological study carried out in Italy by 133 General Practitioners on 5515 elderly outpatients reported a prevalence of diarrhoea, defined according to the Rome criteria, of 9.1%. Infectious diseases (19%) and drug use (16%) were the most commoncauses of diarrhoea in old age. Regardless of the cause,the treatment of elderly patients with diarrhoea must include rehydration and nutritional support. Every year,more than 50 million tourists travel from industrialized countries to places where hygiene levels are poor. At least 75% of those travelling for short periods mention health problems, and in particular traveller's diarrhoea.

  1. 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.

  2. Is acute recurrent pancreatitis a chronic disease?

    OpenAIRE

    Mariani, Alberto; Testoni, Pier Alberto

    2008-01-01

    Whether acute recurrent pancreatitis is a chronic disease is still debated and a consensus is not still reached as demonstrated by differences in the classification of acute recurrent pancreatitis. There is major evidence for considering alcoholic pancreatitis as a chronic disease ab initio while chronic pancreatitis lesions detectable in biliary acute recurrent pancreatitis (ARP) seem a casual association. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation, hereditary a...

  3. Granulocyte Colony-stimulating Factor-primed Bone Marrow: An Excellent Stem-cell Source for Transplantation in Acute Myelocytic Leukemia and Chronic Myelocytic Leukemia

    Institute of Scientific and Technical Information of China (English)

    Yuhang Li; Min Jiang; Chen Xu; Jianlin Chen; Botao Li; Jun Wang; Jiangwei Hu

    2015-01-01

    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).Incidence of grade Ⅲ-Ⅳ acute GVHD and extensive chronic GVHD (cGVHD) was lower than seen with SS-BM (P < 0.05) and similar to G-PBSC.Although the incidence of cGVHD in the G-BM group was similar to SS-BM,both were lower than G-PBSC (P < 0.05).G-BM and G-PBSC exhibited similar survival,LFS,and TRM,but were significantly different from SS-BM (P < 0.05).There were no significant differences in leukemia relapse rates among the groups (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.

  4. NKAML: A Pilot Study to Determine the Safety and Feasibility of Haploidentical Natural Killer Cell Transplantation in Childhood Acute Myeloid Leukemia

    Science.gov (United States)

    Rubnitz, Jeffrey E.; Inaba, Hiroto; Ribeiro, Raul C.; Pounds, Stanley; Rooney, Barbara; Bell, Teresa; Pui, Ching-Hon; Leung, Wing

    2010-01-01

    Purpose To conduct a pilot study to determine the safety, feasibility, and engraftment of haploidentical natural killer (NK) cell infusions after an immunosuppressive regimen in children with acute myeloid leukemia (AML). Patients and Methods Ten patients (0.7 to 21 years old) who had completed chemotherapy and were in first complete remission of AML were enrolled on the Pilot Study of Haploidentical Natural Killer Cell Transplantation for Acute Myeloid Leukemia (NKAML) study. They received cyclophosphamide (60 mg/kg on day −7) and fludarabine (25 mg/m2/d on days −6 through −2), followed by killer immunoglobulin-like receptor–human leukocyte antigen (KIR-HLA) mismatched NK cells (median, 29 × 106/kg NK cells) and six doses of interleukin-2 (1 million U/m2). NK cell chimerism, phenotyping, and functional assays were performed on days 2, 7, 14, 21, and 28 after transplantation. Results All patients had transient engraftment for a median of 10 days (range, 2 to 189 days) and a significant expansion of KIR-mismatched NK cells (median, 5,800/mL of blood on day 14). Nonhematologic toxicity was limited, with no graft-versus-host disease. Median length of hospitalization was 2 days. With a median follow-up time of 964 days (range, 569 to 1,162 days), all patients remain in remission. The 2-year event-free survival estimate was 100% (95% CI, 63.1% to 100%). Conclusion Low-dose immunosuppression followed by donor-recipient inhibitory KIR-HLA mismatched NK cells is well tolerated by patients and results in successful engraftment. We propose to further investigate the efficacy of KIR-mismatched NK cells in a phase II trial as consolidation therapy to decrease relapse without increasing mortality in children with AML. PMID:20085940

  5. 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

  6. The predictive value of selected serum microRNAs for acute GVHD by TaqMan MicroRNA arrays.

    Science.gov (United States)

    Zhang, Chunyan; Bai, Nan; Huang, Wenrong; Zhang, Pengjun; Luo, Yuan; Men, Shasha; Wen, Ting; Tong, Hongli; Wang, Shuhong; Tian, Ya-Ping

    2016-10-01

    Currently, the diagnosis of acute graft-versus-host disease (aGVHD) is mainly based on clinical symptoms and biopsy results. This study was designed to further explore new no noninvasive biomarkers for aGVHD prediction/diagnosis. We profiled miRNAs in serum pools from patients with aGVHD (grades II-IV) (n = 9) and non-aGVHD controls (n = 9) by real-time qPCR-based TaqMan MicroRNA arrays. Then, predictive models were established using related miRNAs (n = 38) and verified by a double-blind trial (n = 54). We found that miR-411 was significantly down regulated when aGVHD developed and recovered when aGVHD was controlled, which demonstrated that miR-411 has potential as an indicator for aGVHD monitoring. We developed and validated a predictive model and a diagnostic model for aGVHD. The predictive model included two miRNAs (miR-26b and miR-374a), which could predict an increased risk for aGVHD 1 or 2 weeks in advance, with an AUC, Positive Predictive Value (PPV), and Negative Predictive Value (NPV) of 0.722, 76.19 %, and 69.70 %, respectively. The diagnostic model included three miRNAs (miR-28-5p, miR-489, and miR-671-3p) with an AUC, PPV, and NPV of 0.841, 85.71 % and 83.33 %, respectively. Our results show that circulating miRNAs (miR-26b and miR-374a, miR-28-5p, miR-489 and miR-671-3p) may serve as biomarkers for the prediction and diagnosis of grades II-IV aGVHD.

  7. Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD.

    Science.gov (United States)

    Carapito, Raphael; Jung, Nicolas; Kwemou, Marius; Untrau, Meiggie; Michel, Sandra; Pichot, Angélique; Giacometti, Gaëlle; Macquin, Cécile; Ilias, Wassila; Morlon, Aurore; Kotova, Irina; Apostolova, Petya; Schmitt-Graeff, Annette; Cesbron, Anne; Gagne, Katia; Oudshoorn, Machteld; van der Holt, Bronno; Labalette, Myriam; Spierings, Eric; Picard, Christophe; Loiseau, Pascale; Tamouza, Ryad; Toubert, Antoine; Parissiadis, Anne; Dubois, Valérie; Lafarge, Xavier; Maumy-Bertrand, Myriam; Bertrand, Frédéric; Vago, Luca; Ciceri, Fabio; Paillard, Catherine; Querol, Sergi; Sierra, Jorge; Fleischhauer, Katharina; Nagler, Arnon; Labopin, Myriam; Inoko, Hidetoshi; von dem Borne, Peter A; Kuball, Jürgen; Ota, Masao; Katsuyama, Yoshihiko; Michallet, Mauricette; Lioure, Bruno; Peffault de Latour, Régis; Blaise, Didier; Cornelissen, Jan J; Yakoub-Agha, Ibrahim; Claas, Frans; Moreau, Philippe; Milpied, Noël; Charron, Dominique; Mohty, Mohamad; Zeiser, Robert; Socié, Gérard; Bahram, Seiamak

    2016-10-13

    Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain-related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice.

  8. Prognostic Limitations of Donor T Cell Chimerism after Myeloablative Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes.

    Science.gov (United States)

    Wong, Eric; Mason, Kate; Collins, Jenny; Hockridge, Barbara; Boyd, Janis; Gorelik, Alexandra; Szer, Jeffrey; Ritchie, David S

    2017-02-06

    Donor T cell chimerism is associated with relapse outcomes after allogeneic stem cell transplantation (alloSCT) for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, measures of statistical association do not adequately assess the performance of a prognostic biomarker, which is best characterized by its sensitivity and specificity for the chosen outcome. We analyzed donor T cell chimerism results at day 100 (D100chim) after myeloablative alloSCT for AML or MDS in 103 patients and determined its sensitivity and specificity for relapse-free survival at 6 months (RFS6) and 12 months (RFS12) post-alloSCT. The area under the receiver operating characteristic curve for RFS6 was .68, demonstrating only modest utility as a predictive biomarker, although this was greater than RFS12 at .62. Using a D100chim threshold of 65%, the specificity for RFS6 was 96.6%; however, sensitivity was poor at 26.7%. This equated to a negative predictive value of 88.5% and positive predictive value of 57.1%. Changing the threshold for D100chim to 75% or 85% modestly improved the sensitivity of D100chim for RFS6; however, this was at the expense of specificity. D100chim is specific but lacks sensitivity as a prognostic biomarker of early RFS after myeloablative alloSCT for AML or MDS. Caution is required when using D100chim to guide treatment decisions including immunologic manipulation, which may expose patients to unwarranted graft-versus-host disease.

  9. Acute exacerbations of fibrotic interstitial lung disease.

    Science.gov (United States)

    Churg, Andrew; Wright, Joanne L; Tazelaar, Henry D

    2011-03-01

    An acute exacerbation is the development of acute lung injury, usually resulting in acute respiratory distress syndrome, in a patient with a pre-existing fibrosing interstitial pneumonia. By definition, acute exacerbations are not caused by infection, heart failure, aspiration or drug reaction. Most patients with acute exacerbations have underlying usual interstitial pneumonia, either idiopathic or in association with a connective tissue disease, but the same process has been reported in patients with fibrotic non-specific interstitial pneumonia, fibrotic hypersensitivity pneumonitis, desquamative interstitial pneumonia and asbestosis. Occasionally an acute exacerbation is the initial manifestation of underlying interstitial lung disease. On biopsy, acute exacerbations appear as diffuse alveolar damage or bronchiolitis obliterans organizing pneumonia (BOOP) superimposed upon the fibrosing interstitial pneumonia. Biopsies may be extremely confusing, because the acute injury pattern can completely obscure the underlying disease; a useful clue is that diffuse alveolar damage and organizing pneumonia should not be associated with old dense fibrosis and peripheral honeycomb change. Consultation with radiology can also be extremely helpful, because the fibrosing disease may be evident on old or concurrent computed tomography scans. The aetiology of acute exacerbations is unknown, and the prognosis is poor; however, some patients survive with high-dose steroid therapy.

  10. Comparison of Outcomes for Pediatric Patients With Acute Myeloid Leukemia in Remission and Undergoing Allogeneic Hematopoietic Cell Transplantation With Myeloablative Conditioning Regimens Based on Either Intravenous Busulfan or Total Body Irradiation: A Report From the Japanese Society for Hematopoietic Cell Transplantation.

    Science.gov (United States)

    Ishida, Hiroyuki; Kato, Motohiro; Kudo, Kazuko; Taga, Takashi; Tomizawa, Daisuke; Miyamura, Takako; Goto, Hiroaki; Inagaki, Jiro; Koh, Katsuyoshi; Terui, Kiminori; Ogawa, Atsushi; Kawano, Yoshifumi; Inoue, Masami; Sawada, Akihisa; Kato, Koji; Atsuta, Yoshiko; Yamashita, Takuya; Adachi, Souichi

    2015-12-01

    Pediatric patients with acute myeloid leukemia (AML) mainly receive myeloablative conditioning regimens based on busulfan (BU) or total body irradiation (TBI) before allogeneic hematopoietic cell transplantation (allo-HCT); however, the optimal conditioning regimen remains unclear. To identify which of these regimens is better for pediatric patients, we performed a retrospective analysis of nationwide registration data collected in Japan between 2006 and 2011 to assess the outcomes of patients receiving these regimens before a first allo-HCT. Myeloablative conditioning regimens based on i.v. BU (i.v. BU-MAC) (n = 69) or TBI (TBI-MAC) (n = 151) were compared in pediatric AML patients in first or second complete remission (CR1/CR2). The incidences of sinusoid obstruction syndrome, acute and chronic graft-versus-host disease, and early nonrelapse mortality (NRM) before day 100 were similar for both conditioning groups; however, the incidence of bacterial infection during the acute period was higher in the TBI-MAC group (P = .008). Both groups showed a similar incidence of NRM, and there was no significant difference in the incidence of relapse between the groups. Univariate and multivariate analyses revealed no significant differences in the 2-year relapse-free survival rates for the i.v. BU-MAC and TBI-MAC groups in the CR1/CR2 setting (71% versus 67%, P = .36; hazard ratio, .73; 95% CI, .43 to 1.24, respectively). TBI-MAC was no better than i.v. BU-MAC for pediatric AML patients in remission. Although this retrospective registry-based analysis has several limitations, i.v. BU-MAC warrants further evaluation in a prospective trial.

  11. Acute Ischemic Stroke and Acute on Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Raja Ahsan Aftab

    2016-06-01

    Full Text Available Ischemic stroke is due to either local thrombus formation or emboli that occlude a cerebral artery, together with chronic kidney disease represent major mortality and morbidity. Here wer present a case of 53 years old Malay man, admitted to a hospital in Malaysia complaining of sudden onset of weakness on right sided upper and lower limb associated with slurred speech. Patient was also suffering from uncontrolled hypertension, hyperlipidemia, chronic kidney disease stage 4, and diabetes mellitus(un controlled. He was diagnosed with acute ischemic stroke with cranial nerve 7 palsy (with right hemiparesis, acute on chronic kidney disease precipitated by dehydration and ACE inhibitor, and hyperkalemia. Patients with ischemic disease and chronic kidney disaese require constant monitering and carefull selected pharmacotherapy. Patient was placed under observation and was prescribed multiple pharamacotherpay to stabalise detoriating condition. Keywords: ischemic disease; chronic kidney disease; uncontrolled hypertension. | PubMed

  12. Is acute recurrent pancreatitis a chronic disease?

    Institute of Scientific and Technical Information of China (English)

    Alberto Mariani; Pier Alberto Testoni

    2008-01-01

    Whether acute recurrent pancreaUtis is a chronic disease is still debated and a consensus is not still reached as demonstrated by differences in the classification of acute recurrent pancreatitis.There is major evidence for considering alcoholic pancreatitis as a chronic disease ab initio while chronic pancreatitis lesions detectable in biliary acute recurrent pancreatitis (ARP) seem a casual association.Cystic fibrosis transmembrane con ductance regulator (CFTR) gene mutation,hereditary and obstructive pancreatitis seem an acute disease that progress to chronic pancreatitis,likely as a consequence of the activation and proliferation of pancreatic stellate cells that produce and activate collagen and therefore fibrosis.From the diagnostic point of view,in patients with acute recurrent pancreatitis Endoscopic ultrasound (EUS) seems the more reliable technique for an accurate evaluation and follow-up of some ductal and parenchymal abnormalities suspected for early chronic pancreatitis.

  13. Polymorphism in the interleukin-7 receptor-alpha and outcome after allogeneic hematopoietic cell transplantation with matched unrelated donor

    DEFF Research Database (Denmark)

    Shamim, Z; Spellman, S; Haagenson, M;

    2013-01-01

    and increased treatment-related mortality (TRM) (rs1494555G) and acute graft versus host disease (aGvHD) (rs1494555G and rs1494558T) after hematopoietic cell transplantation (HCT). Some studies have confirmed an association between rs6897932C and multiple sclerosis. In this study, we evaluated the prognostic...

  14. Oral cyclosporine A treatment is feasible after myeloablative conditioning in allogeneic hematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Nygaard, M; Hovgaard, D; Schjødt, I M;

    2015-01-01

    underwent myeloablative hematopoietic stem cell transplantation. Twenty-one patients (44%) tolerated CsA orally throughout the transplantation period without increased incidence of acute graft versus host disease(aGVHD). Low concentration of CsA in week 2 was associated with increased incidence of a...

  15. Hepatic injury following reduced intensity unrelated cord blood transplantation for adult patients with hematological diseases.

    Science.gov (United States)

    Kusumi, Eiji; Kami, Masahiro; Kanda, Yoshinobu; Murashige, Naoko; Seki, Kunihiko; Fujiwara, Masayo; Koyama, Rikako; Komatsu, Tsunehiko; Hori, Akiko; Tanaka, Yuji; Yuji, Koichiro; Matsumura, Tomoko; Masuoka, Kazuhiro; Wake, Atsushi; Miyakoshi, Shigesaburo; Taniguchi, Shuichi

    2006-12-01

    Liver injury is a common complication in allogeneic hematopoietic stem cell transplantation. Its major causes comprise graft-versus-host disease (GVHD), infection, and toxicities of preparative regimens and immunosuppressants; however, we have little information on liver injuries after reduced intensity cord blood transplantation (RICBT). We reviewed medical records of 104 recipients who underwent RICBT between March 2002 and May 2004 at Toranomon Hospital. Preparative regimen and GVHD prophylaxis comprised fludarabine/melphalan/total body irradiation and cyclosporine or tacrolimus. We assessed the etiology of liver injuries based on the clinical presentation, laboratory results, comorbid events, and imaging studies in 85 patients who achieved primary engraftment. The severity of liver dysfunction was assessed according to the National Cancer Institute Common Toxicity Criteria version 2.0. Hyperbilirubinemia was graded according to a report by Hogan et al (Blood. 2004;103:78-84). Moderate to very severe liver injuries were observed in 36 patients. Their causes included cholestatic liver disease (CLD) related to GVHD or sepsis (n = 15), GVHD (n = 7), cholangitis lenta (n = 5), and others (n = 9). Median onsets of CLD, GVHD, and cholangitis lenta were days 37, 40, and 22, respectively. Frequencies of grade 3-4 alanine aminotransferase elevation were comparable across the 3 types of hepatic injuries. Serum gamma-glutamil transpeptidase was not elevated in any patients with cholangitis lenta, whereas 27% and 40% of patients with CLD and GVHD, respectively, developed grade 3-4 gamma-glutamil transpeptidase elevation. Multivariate analysis identified 2 risk factors for hyperbilirubinemia; grade II-IV acute GVHD (relative risk, 2.23; 95% confidential interval, 1.11-4.47; P = .024) and blood stream infection (relative risk, 3.77; 95% confidential interval, 1.91-7.44; P = .00013). In conclusion, the present study has demonstrated that the hepatic injuries are significant

  16. Adoptive Transfer of Treg Cells Combined with Mesenchymal Stem Cells Facilitates Repopulation of Endogenous Treg Cells in a Murine Acute GVHD Model.

    Science.gov (United States)

    Lee, Eun-Sol; Lim, Jung-Yeon; Im, Keon-Il; Kim, Nayoun; Nam, Young-Sun; Jeon, Young-Woo; Cho, Seok-Goo

    2015-01-01

    Therapeutic effects of combined cell therapy with mesenchymal stem cells (MSCs) and regulatory T cells (Treg cells) have recently been studied in acute graft-versus-host-disease (aGVHD) models. However, the underlying, seemingly synergistic mechanism behind combined cell therapy has not been determined. We investigated the origin of Foxp3+ Treg cells and interleukin 17 (IL-17+) cells in recipients following allogeneic bone marrow transplantation (allo-BMT) to identify the immunological effects of combined cell therapy. Treg cells were generated from eGFP-expressing C57BL/6 mice (Tregegfp cells) to distinguish the transferred Treg cells; recipients were then examined at different time points after BMT. Systemic infusion of MSCs and Treg cells improved survival and GVHD scores, effectively downregulating pro-inflammatory Th×and Th17 cells. These therapeutic effects of combined cell therapy resulted in an increased Foxp3+ Treg cell population. Compared to single cell therapy, adoptively transferred Tregegfp cells only showed prolonged survival in the combined cell therapy group on day 21 after allogeneic BMT. In addition, Foxp3+ Treg cells, generated endogenously from recipients, significantly increased. Significantly higher levels of Tregegfp cells were also detected in aGVHD target organs in the combined cell therapy group compared to the Treg cells group. Thus, our data indicate that MSCs may induce the long-term survival of transferred Treg cells, particularly in aGVHD target organs, and may increase the repopulation of endogenous Treg cells in recipients after BMT. Together, these results support the potential of combined cell therapy using MSCs and Treg cells for preventing aGVHD.

  17. Thrombolysis in Acute Cerebrovascular Disease

    Institute of Scientific and Technical Information of China (English)

    刘泽霖

    2003-01-01

    @@ Large-scale trials have shown that thrombolytic therapy reduces mortality and preserves left ventricular function in patients with acute myocardial infarction (AMI). That's a rationale for the use of thrombolytic agents in the management of ischemic stroke.

  18. Establishment and Pathophysiology Study of Allogeneic Bone Marrow Transplantation Model for Graft-Versus-Host Disease%同种异基因骨髓移植GVHD动物模型的建立及其病理生理学机制初探

    Institute of Scientific and Technical Information of China (English)

    刘杰; 王永安; 钱远宇; 孟庆义

    2009-01-01

    目的:建立稳定的异基因骨髓移植GVHD(移植物抗宿主病)动物模型,并初步了解其病理生理学机制.方法:以BALB/c(H-2d)雌性小鼠为受者,接受8 Gy致死剂量的60Co.全身照射后,输注雄性C57BL/6(H-2b)供鼠的脾细胞和骨髓细胞.观察受鼠的体征、造血功能恢复及生存时问的变化,并进行病理学、嵌合体和T细胞亚群及相关细胞因子的检查.结果:模型组小鼠在移植后出现了典型的GVHD症状;肠、肝、脾、皮肤的病理学分析均属于Ⅳ度GVHD;嵌合体植入成功;以7、14和21 d为检测时间点,发现模型组鼠体内T细胞亚群移植后较移植前CD3+CD4+T细胞数量减少,CD3+CD8+T细胞显著升高,CD4+和CD8+T细胞比例严重倒置,随着时间变化比值会逐渐升高,但仍然处于较显著的倒置水平;血清中IFN-y、TNF-a在移植后+7 d表达显著增高,尤其是IFN-V的表达在+7 d达峰值;IL-4和IL-10的水平在移植前后几乎没有变化.结论:建立了稳定的GVHD动物模型;此模型发病过程中,CD8+T细胞介导的CTL细胞毒性作用可能要大于CD4+Th介导的细胞因子效应;IFN-y、TNF-a炎症因子在GVHD的早期发挥重要作用;IL-4、IL-10的低水平分泌与急性GVHD的高发病率有关.

  19. Efficacy of cyclosporine A combined with mycophenolate mofetil on graft-versus-host disease after allogeneic hematopoietic stem cell transplantation%环孢素联合吗替麦考酚酯预防异基因造血干细胞移植后移植物抗宿主病43例分析

    Institute of Scientific and Technical Information of China (English)

    陈纯; 方建培; 黄绍良; 周敦华; 黄科; 徐宏贵; 夏焱; 薛红漫

    2008-01-01

    目的 探讨环孢素(CSA)联合吗替麦考酚酯(MMF)在异基因造血干细胞移植预防移植物抗宿主病(GVHD)的效果.方法 回顾性分析2001年1月至2006年12月于中山大学附属二院进行异基因造血干细胞移植后发生GVHD的43例患儿的临床资料,其中28例应用CSA联合MMF为主的方案预防急性GVHD(称为MMF预防组),15例未使用MMF(称为无MMF预防组).结果 异基因外周血造血干细胞移植造血重建较脐血移植组快(P<0.05),与使用MMF与否无关.28例MMF预防组中.急性GVHD和慢性GVHD的发生率分别为50.0%(14/28)和14.29%(4/28);15例无MMF预防组中,急性GVHD和慢性GVHD的发生率为80.0%(12/15)和66.7%(10/15).13例使用MMF的非血缘相关脐血移植患儿中,5例发生急性GVHD,仅1例发生慢性GvHD.另4例非血缘相关脐血移植和5例血缘相关脐血移植患儿未使用MMF,8例发生急性GVHD,5例发生了慢性GVHD.21例异基因外周血干细胞移植患儿,15例使用MMF患儿,其中4例发生急性GVHD,仅3例发生慢性GVHD.发生率为20.0%(3/15),而6例无使用MMF患儿,4例发生了急性GVHD,5例发生了慢性GVHD(83.3%).慢性GVHD的发生与移植类型关系不明显,但使用MMF组发生慢性GVHD比无使用MMF组少(P<0.05).结论 CSA联合MMF在减少异基因造血干细胞移植后慢性GVHD的发生方面作用明显.

  20. Diarrheal Diseases - Acute and Chronic

    Science.gov (United States)

    ... acute, watery diarrhea are caused by viruses (viral gastroenteritis). The most common ones in children are rotavirus and in adults are norovirus (this is sometimes called “cruise ship diarrhea” due to well publicized epidemics). Bacteria are a common cause of traveler’s diarrhea. Causes – ...

  1. Stem cell therapy in treatment of different diseases.

    Science.gov (United States)

    Larijani, Bagher; Esfahani, Ensieh Nasli; Amini, Peyvand; Nikbin, Behrouz; Alimoghaddam, Kamran; Amiri, Somayeh; Malekzadeh, Reza; Yazdi, Nika Mojahed; Ghodsi, Maryam; Dowlati, Yahya; Sahraian, Mohammad Ali; Ghavamzadeh, Ardeshir

    2012-01-01

    Stem cells are undifferentiated cells with the ability of proliferation, regeneration, conversion to differentiated cells and producing various tissues. Stem cells are divided into two categories of embryonic and adult. In another categorization stem cells are divided to Totipotent, Multipotent and Unipotent cells.So far usage of stem cells in treatment of various blood diseases has been studied (such as lymphoblastic leukemia, myeloid leukemia, thalassemia, multiple myeloma and cycle cell anemia). In this paper the goal is evaluation of cell therapy in treatment of Parkinson's disease, Amyotrophic lateral sclerosis, Alzheimer, Stroke, Spinal Cord Injury, Multiple Sclerosis, Radiation Induced Intestinal Injury, Inflammatory Bowel Disease, Liver Disease, Duchenne Muscular Dystrophy, Diabetes, Heart Disease, Bone Disease, Renal Disease, Chronic Wounds, Graft-Versus-Host Disease, Sepsis and Respiratory diseases. It should be mentioned that some disease that are the target of cell therapy are discussed in this article.

  2. Stem Cell Therapy in Treatment of Different Diseases

    Directory of Open Access Journals (Sweden)

    Mohammad Ali Sahraian

    2012-02-01

    Full Text Available Stem cells are undifferentiated cells with the ability of proliferation, regeneration, conversion to differentiated cells and producing various tissues. Stem cells are divided into two categories of embryonic and adult. In another categorization stem cells are divided to Totipotent, Multipotent and Unipotent cells.So far usage of stem cells in treatment of various blood diseases has been studied (such as lymphoblastic leukemia, myeloid leukemia, thalassemia, multiple myeloma and cycle cell anemia. In this paper the goal is evaluation of cell therapy in treatment of Parkinsons disease, Amyotrophic lateral sclerosis, Alzheimer, Stroke, Spinal Cord Injury, Multiple Sclerosis, Radiation Induced Intestinal Injury, Inflammatory Bowel Disease, Liver Disease, Duchenne Muscular Dystrophy, Diabetes, Heart Disease, Bone Disease, Renal Disease, Chronic Wounds, Graft-Versus-Host Disease, Sepsis and Respiratory diseases. It should be mentioned that some disease that are the target of cell therapy are discussed in this article.

  3. Effects of priming with recombinant human granulocyte colony-stimulating factor on conditioning regimen for high-risk acute myeloid leukemia patients undergoing human leukocyte antigen-haploidentical hematopoietic stem cell transplantation: a multicenter randomized controlled study in southwest China.

    Science.gov (United States)

    Gao, Lei; Wen, Qin; Chen, Xinghua; Liu, Yao; Zhang, Cheng; Gao, Li; Kong, Peiyan; Zhang, Yanqi; Li, Yunlong; Liu, Jia; Wang, Qingyu; Su, Yi; Wang, Chunsen; Wang, Sanbin; Zeng, Yun; Sun, Aihua; Du, Xin; Zeng, Dongfeng; Liu, Hong; Peng, Xiangui; Zhang, Xi

    2014-12-01

    HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an effective and immediate treatment for high-risk acute myeloid leukemia (HR-AML) patients lacking matched donors. Relapse remains the leading cause of death for HR-AML patients after haplo-HSCT. Accordingly, the prevention of relapse remains a challenge in the treatment of HR-AML. In a multicenter randomized controlled trial in southwestern China, 178 HR-AML patients received haplo-HSCT with conditioning regimens involving recombinant human granulocyte colony-stimulating factor (rhG-CSF) or non-rhG-CSF. The cumulative incidences of relapse and graft-versus-host disease (GVHD), 2-year leukemia-free survival (LFS), and overall survival (OS) were evaluated. HR-AML patients who underwent the priming conditioning regimen with rhG-CSF had a lower relapse rate than those who were treated with non-rhG-CSF (38.2%; 95% confidence interval [CI], 28.1% to 48.3% versus 60.7%, 95% CI, 50.5% to 70.8%; P priming group and 31 patients in the non-rhG-CSF-priming group were still alive at the median follow-up time of 42 months (range, 24 to 80 months). The 2-year probabilities of LFS and OS in the rhG-CSF-priming and non-rhG-CSF-priming groups were 55.1% (95% CI, 44.7% to 65.4%) versus 32.6% (95% CI, 22.8% to 42.3%) (P priming group (67.4%; 95% CI, 53.8% to 80.9% versus 41.9%; 95% CI, 27.1% to 56.6%; P priming conditioning regimen is an acceptable choice for HR-AML patients, especially for the patients with no M4/M5/M6 subtype who achieved CR before transplantation.

  4. Precursor T-cell acute lymphoblastic leukemia presenting with bone marrow necrosis: a case report

    Directory of Open Access Journals (Sweden)

    Khoshnaw Najmaddin SH

    2012-10-01

    Full Text Available Abstract Introduction Bone marrow necrosis is a clinicopathological condition diagnosed most often at postmortem examination, but it is also seen during the course of malignancy and is not always associated with a poor prognosis. The morphological features of bone marrow necrosis are disruption of the normal marrow architecture and necrosis of myeloid tissue and medullary stroma. Non-malignant conditions associated with bone marrow necrosis are sickle cell anemia, infections, drugs (sulfasalazine, interferon α, all-trans retinoic acid, granulocyte colony-stimulating factor and fludarabine, disseminated intravascular coagulation, antiphospholipid antibody syndrome and acute graft versus host diseases. The malignant causes are leukemia, lymphoma and metastatic carcinomas. Herein we report the case of a patient with precursor T-cell acute lymphoblastic leukemia and bone marrow necrosis at initial presentation. Case presentation A 10-year-old Kurdish boy was presented with generalized bone pain and fever of 1 month’s duration which was associated with sweating, easy fatigability, nose bleeding, breathlessness and severe weight loss. On examination, we observed pallor, tachypnea, tachycardia, low blood pressure, fever, petechial hemorrhage, ecchymoses, tortuous dilated veins over the chest and upper part of abdomen, multiple small cervical lymph node enlargements, mildly enlarged spleen, palpable liver and gross abdominal distention. Blood analysis revealed pancytopenia and elevated lactate dehydrogenase and erythrocyte sedimentation rate. Imaging results showed mediastinal widening on a planar chest X-ray and diffuse focal infiltration of the axial bone marrow on magnetic resonance imaging of the lumbosacral vertebrae. Bone marrow aspiration and biopsy examination showed extensive bone marrow necrosis. Immunophenotyping analysis of the bone marrow biopsy confirmed T-cell acute lymphoblastic leukemia, as CD3 and terminal deoxynucleotidyl

  5. Correlation of HLA-G expression with graft-versus-host reaction following HSCT%造血干细胞移植后HLA-G表达与移植物抗宿主反应的相关性研究

    Institute of Scientific and Technical Information of China (English)

    尹建平; 张义成; 刘胜洪; 游泳; 江梦天

    2012-01-01

    Background Due to the scarcity of hematopoietic stem cell transplantation (HSGT) and organs for transplantation, and due to the several mechanisms that contribute to graft rejection,much effort has been devoted to understanding the mechanisms associated with graft rejection and survival. Since the discovery in the 1990s that HLA-G played a relevant physiological role in the induction of maternal-fetal tolerance, the idea of investigating the role of HLA-G in allografting has taken hold. Several studies have been reported demonstrating that the presence of HLA-G in the allograft or the increase of soluble HLA-G serum/plasma levels are associated with better graft acceptance, increased graft survival or both. Objective To determine the correlation of human leukocyte antigen-G (HLA-G) expression on mononuclear cells after hematopoietic stem cell transplantation (HSCT). Methods A total of 225 first-time HSCT recipients in one transplantation center were divided into acute GVHR group and chronic group according to whether they had active GVHR. mHLA-Gl expression on leukocytes was analyzed by flow cytometry. The concentrations of soluble HLA-G5 were detected using ELISA. The sHLA-G5 cutoff levels by ROC curve was employed to predict the active GVRH. The expression of sHLA-G5 mRNA and protein in leukocytes was analyzed by using RT PCR and Western blotting respectively. Immunohistochemical staining was used to detect the HLA-G expression in marrow biopsies of 12 cases. Results The expression of mHLA-G1 in peripheral blood was low in both acute and chronic group. In acute reaction, the proportion of CD14+ mHLA-G1+ cells (45. 53 ± 17. 32)% in peripheral blood was increased as compared with that in chronic group (10. 22 ± 5. 78)%. The expression of sHLA-G5 was increased significantly in acute group. The optimal cutoff value of sHLA-G5 predicting the active GVHR was 253. 9 μg/L,with high diagnostic accuracy. HLA-G was positive in the marrow of 10 patients out of 12 patients

  6. An Acute Hemorrhagic Infectious Disease:Ebola Virus Disease

    Institute of Scientific and Technical Information of China (English)

    JIAO Lei; XU An-hua; FENG Chao; QIU Qian-qian; TANG Qi-ling; LIU Xiao-huan

    2014-01-01

    Ebola virus disease (EVD) is an acute hemorrhagic infectious disease caused by ebola virus, with high infectivity and fatality rate. At present, it mainly occurs in areas of Central Africa and West Africa and no effective vaccine and antiviral drugs are available for the clinical treatment.

  7. Clinical analysis of allogeneic hematopoietic stem cells transplantation for treatment of 15 children with malignant hematological diseases%异基因造血干细胞移植治疗儿童恶性血液病15例临床分析

    Institute of Scientific and Technical Information of China (English)

    王娴静; 董秀娟; 陈蕾; 马红霞; 焦雪丽; 吴书一; 刘文刚; 赵晓武

    2014-01-01

    目的 观察异基因造血干细胞移植(allo-HSCT)治疗儿童恶性血液病的疗效和相关并发症,探讨allo-HSCT治疗儿童恶性血液病的适应证.方法 回顾性分析15例接受allo-HSCT治疗的儿童恶性血液病患者的临床资料,其中13例为急性白血病,1例为慢性粒细胞白血病(加速期),1例为骨髓增生异常综合征(MDS-REBT);8例为亲缘供者,7例为非亲缘供者;11例行外周血造血干细胞移植治疗,4例行脐血造血干细胞移植治疗;6例为HLA配型全相合,9例为HLA配型不全相合.结果 15例患儿中生存7例,生存期为5个月~6年;5例因复发或重症感染放弃治疗;3例死亡.6例发生急性移植物抗宿主病(GVHD),包括Ⅰ度3例,Ⅱ、Ⅲ、Ⅳ度各1例,其中发生Ⅳ度急性GVHD患儿死亡.2例发生广泛性慢性GVHD,其中1例死亡,另1例生活质量严重受影响.结论 allo-HSCT是治疗儿童恶性血液病的重要方法,其并发症多、风险大,在防治并发症的同时,应严格把握allo-HSCT治疗儿童恶性血液病的适应证.%Objective To observe the therapeutic efficiency and associated complications of allogeneic hematopoietic stem cells transplantation (allo-HSCT) for treatment of children with malignant hematological disease.Methods Fifteen children with malignant hematological disease were subjected to allo-HSCT from Jan 2007 to Jan 2013.Among those 15 patients,13 cases were diagnosed as acute leukemia (AL),1 case as chronic myeloid leukemia (CML),and 1 case as myelodysplastic syndrome (MDS-RAEB).The clinical characters of all cases after transplantation were analyzed retrospectively.Results Seven cases survived from 5 months to 6 years after transplantation.Five cases abandoned treatment because of relapse or severe infections.Three cases developed grade Ⅰ acute graft-versus-host disease (aGVHD),three cases developed grade Ⅱ,Ⅲ and Ⅳ aGVHD respectively,and one case died of Ⅳ aGVHD.Two patients experienced extensive chronic graft-versus-host

  8. Interleukin-22: a likely target for treatment of autoimmune diseases

    Science.gov (United States)

    Yang, Xuyan; Zheng, Song Guo

    2014-01-01

    Interleukin -22 (IL-22) is a member of IL-10 family cytokines that is produced by many different types of lymphocytes including both those of the innate and adaptive immune system. This includes activated T cells, most notably Th17 and Th22 cells, and NK cells, γδ T cells, LTi cells and LTi-like cells. IL-22 mediates its effects via the IL-22-IL-22R complex and subsequent Janus Kinase-signal transduces and activators transcription (JAK-STAT) signaling pathway. Recently accumulated evidence has indicated that IL-22 also plays an important role in the pathogenesis of many autoimmune diseases. In this review, we discuss the recent findings and advancement of the role for IL-22 in several autoimmune diseases, such as psoriasis, rheumatoid arthritis (RA), hepatitis, graft versus host disease (GHVD) and allergic diseases, implicating that target IL-22 may have a therapeutic potential in those autoimmune diseases. PMID:24418299

  9. Long-term Survival and Late Effects among 1-year Survivors of Second Allogeneic Hematopoietic Cell Transplantation for Relapsed Acute Leukemia and Myelodysplastic Syndromes

    Science.gov (United States)

    Duncan, Christine N.; Majhail, Navneet S.; Brazauskas, Ruta; Wang, Zhiwei; Cahn, Jean-Yves; Frangoul, Haydar A.; Hayashi, Robert J.; Hsu, Jack W.; Kamble, Rammurti T.; Kasow, Kimberly A.; Khera, Nandita; Lazarus, Hillard M.; Loren, Alison W.; Marks, David I.; Maziarz, Richard T.; Mehta, Paulette; Myers, Kasiani C.; Norkin, Maxim; Pidala, Joseph A.; Porter, David L.; Reddy, Vijay; Saber, Wael; Savani, Bipin N.; Schouten, Harry C.; Steinberg, Amir; Wall, Donna A.; Warwick, Anne B.; Wood, William A.; Yu, Lolie C.; Jacobsohn, David A.; Sorror, Mohamed L.

    2014-01-01

    We analyzed the outcomes of patients who survived disease-free for 1-year or more following second allogeneic hematopoietic cell transplantation (HCT) for relapsed acute leukemia or myelodysplastic syndromes between 1980 and 2009. A total of 1285 patients received a second allogeneic transplant following disease relapse; among these 325 survived relapse-free at 1-year after the second HCT. The median time from first to second HCT was 17 and 24 months for children and adults, respectively. A myeloablative preparative regimen was used in the second transplant in 62% of children and 45% of adult patients. The overall 10-year conditional survival rates after second transplantation in this cohort of patients who had survived disease-free for at least one year were 55% in children and 39% in adults. Relapse was the leading cause of mortality (77% and 54% of deaths in children and adults, respectively). In multivariate analyses, only disease status prior to second HCT was significantly associated with higher risk for overall mortality (HR 1.71 for patients with disease not in complete remission prior to second HCT, P<0.01). Chronic graft-versus-host disease (GVHD) developed in 43% and 75% of children and adults following second transplant. Chronic GVHD was the leading cause of non-relapse mortality followed by organ failure and infection. The cumulative incidence of developing at least one of the studied late effects at 10-years after second HCT was 63% in children and 55% in adults. The most frequent late effects in children were growth disturbance (10-year cumulative incidence 22%) and cataracts (20%), and in adults were cataracts (20%) and avascular necrosis (13%). Among patients with acute leukemia and myelodysplastic syndromes who receive a second allogeneic HCT for relapse and survive disease-free for at least 1-year, many can be expected to survive long term. However, they continue to be at risk for relapse and non-relapse morbidity and mortality. Novel approaches

  10. Long-term survival and late effects among one-year survivors of second allogeneic hematopoietic cell transplantation for relapsed acute leukemia and myelodysplastic syndromes.

    Science.gov (United States)

    Duncan, Christine N; Majhail, Navneet S; Brazauskas, Ruta; Wang, Zhiwei; Cahn, Jean-Yves; Frangoul, Haydar A; Hayashi, Robert J; Hsu, Jack W; Kamble, Rammurti T; Kasow, Kimberly A; Khera, Nandita; Lazarus, Hillard M; Loren, Alison W; Marks, David I; Maziarz, Richard T; Mehta, Paulette; Myers, Kasiani C; Norkin, Maxim; Pidala, Joseph A; Porter, David L; Reddy, Vijay; Saber, Wael; Savani, Bipin N; Schouten, Harry C; Steinberg, Amir; Wall, Donna A; Warwick, Anne B; Wood, William A; Yu, Lolie C; Jacobsohn, David A; Sorror, Mohamed L

    2015-01-01

    We analyzed the outcomes of patients who survived disease-free for 1 year or more after a second allogeneic hematopoietic cell transplantation (HCT) for relapsed acute leukemia or myelodysplastic syndromes between 1980 and 2009. A total of 1285 patients received a second allogeneic transplant after disease relapse; among these, 325 were relapse free at 1 year after the second HCT. The median time from first to second HCT was 17 and 24 months for children and adults, respectively. A myeloablative preparative regimen was used in the second transplantation in 62% of children and 45% of adult patients. The overall 10-year conditional survival rates after second transplantation in this cohort of patients who had survived disease-free for at least 1 year was 55% in children and 39% in adults. Relapse was the leading cause of mortality (77% and 54% of deaths in children and adults, respectively). In multivariate analyses, only disease status before second HCT was significantly associated with higher risk for overall mortality (hazard ratio, 1.71 for patients with disease not in complete remission before second HCT, P < .01). Chronic graft-versus-host disease (GVHD) developed in 43% and 75% of children and adults after second transplantation. Chronic GVHD was the leading cause of nonrelapse mortality, followed by organ failure and infection. The cumulative incidence of developing at least 1 of the studied late effects within 10 years after second HCT was 63% in children and 55% in adults. The most frequent late effects in children were growth disturbance (10-year cumulative incidence, 22%) and cataracts (20%); in adults they were cataracts (20%) and avascular necrosis (13%). Among patients with acute leukemia and myelodysplastic syndromes who receive a second allogeneic HCT for relapse and survive disease free for at least 1 year, many can be expected to survive long term. However, they continue to be at risk for relapse and nonrelapse morbidity and mortality. Novel

  11. Treatment of Acute Pelvic Inflammatory Disease

    Directory of Open Access Journals (Sweden)

    Richard L. Sweet

    2011-01-01

    Full Text Available Pelvic inflammatory disease (PID, one of the most common infections in nonpregnant women of reproductive age, remains an important public health problem. It is associated with major long-term sequelae, including tubal factor infertility, ectopic pregnancy, and chronic pelvic pain. In addition, treatment of acute PID and its complications incurs substantial health care costs. Prevention of these long-term sequelae is dependent upon development of treatment strategies based on knowledge of the microbiologic etiology of acute PID. It is well accepted that acute PID is a polymicrobic infection. The sexually transmitted organisms, Neisseria gonorrhoeae and Chlamydia trachomatis, are present in many cases, and microorganisms comprising the endogenous vaginal and cervical flora are frequently associated with PID. This includes anaerobic and facultative bacteria, similar to those associated with bacterial vaginosis. Genital tract mycoplasmas, most importantly Mycoplasma genitalium, have recently also been implicated as a cause of acute PID. As a consequence, treatment regimens for acute PID should provide broad spectrum coverage that is effective against these microorganisms.

  12. Chagas' Disease: an acute transfusional case report

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    Dalva Marli Valério Wanderley

    1988-12-01

    Full Text Available Report of a case of acute transfusional Chagas'disease in a four-year-old child with a previous diagnosis of acute lymphocytic leukemia, transmitted in São Paulo, the Capital of São Paulo State, Brazil. Epidemiological investigation disclosed the donor's serological positivity and his previous residence in an area where Chagas' disease is endemic. The importance of adequate sorological screening in blood donors is evident. It should be stressed that this is the first case notified to the Superintendência de Controle de Endemias (SUCEN (Superintendency for the Endemy Control of the State Secretariat of Health, São Paulo, for the last five years.

  13. Acute recurrent pancreatitis: An autoimmune disease?

    Institute of Scientific and Technical Information of China (English)

    Raffaele Pezzilli

    2008-01-01

    In this review article,we will briefly describe the main characteristics of autoimmune pancreatitis and then we will concentrate on our aim,namely,evaluating the clinical characteristics of patients having recurrence of pain from the disease.In fact,the open question is to evaluate the possible presence of autoimmune pancreatitis in patients with an undefined etiology of acute pancreatitis and for this reason we carried out a search in the literature in order to explore this issue.In cases of recurrent attacks of pain in patients with "idiopathic"pancreatitis,we need to keep in mind the possibility that our patients may have autoimmune pancreatitis.Even though the frequency of this disease seems to be quite low,we believe that in the future,by increasing our knowledge on the subject,we will be able to diagnose an ever-increasing number of patients having acute recurrence of pain from autoimmune pancreatitis.

  14. Fatal acute Chagas Disease in a Chimpanzee

    Science.gov (United States)

    2009-08-01

    protozoan parasite belonging to the order Kinetoplastida, family Trypanosomatidae. Arthropod vectors (Reduviidae, assassin bugs or cone nosed bugs or...Laranja FS. Experimental Chagas’ disease in rhesus monkeys. I. Clinical, parasitological , hematological and anatomo- pathological studies in the acute...of infection and immunity from mother to young. Parasitology . 1972; 65:1–9. [PubMed: 4626452] 21. Miles MA, Marsden PD, Pettitt LE, Draper CC, Watson

  15. 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.

  16. Crohn's disease and acute pancreatitis. A review of literature.

    Science.gov (United States)

    Jasdanwala, Sarfaraz; Babyatsky, Mark

    2015-03-01

    Crohn's disease, a transmural inflammatory bowel disease, has many well-known extra-intestinal manifestations and complications. Although acute pancreatitis has a higher incidence in patients with Crohn's disease as compared to the general population, acute pancreatitis is still relatively uncommon in patients with Crohn's disease. Patients with Crohn's disease are at an approximately fourfold higher risk than the general population to develop acute pancreatitis. The risk of developing acute pancreatitis is higher in females as compared to males. Acute pancreatitis can occur at any age with higher incidence reported in patients in their 20s and between 40-50 years of age. The severity and prognosis of acute pancreatitis in patients with Crohn's disease is the same as in general population. Acute pancreatitis can occur before onset of intestinal Crohn's disease, this presentation being more common in children than adults. It can also occur as the presenting symptom. However, most commonly it occurs after intestinal symptoms have manifest with a mean time interval between the initial presentation and development of acute pancreatitis being 2 years. There are several etiological factors contributing to acute pancreatitis in patients with Crohn's disease. It is not clear whether acute pancreatitis is a direct extra-intestinal manifestation of Crohn's disease; however, majority of the cases of acute pancreatitis in patients with Crohn's disease are due to GS and medications. Drugs used for the treatment of Crohn's disease that have been reported to cause acute pancreatitis include 5-ASA agents, azathioprine and 6 mercaptopurine, metornidazole and corticosteroids. Recent evidence has emerged correlating both type 1 and 2 autoimmune pancreatitis with Crohn's disease. Understanding the association between the two disease entities is key to effectively manage patients with Crohn's disease and acute pancreatitis.

  17. Clarithromycin-induced acute interstitial nephritis and minimal change disease

    OpenAIRE

    Russell, Wendy; Smith, William

    2009-01-01

    Drug associated acute interstitial nephritis and minimal change disease has been well documented but the simultaneous presentation of both is rare and has not been reported with clarithromycin. We describe a case of simultaneous acute tubulointerstitial nephritis and minimal change disease induced by clarithromycin. The patient had acute kidney injury, nephrotic syndrome, eosinophilic pneumonitis and a maculopapular skin rash. The role of steroid therapy in acute interstitial nephritis is con...

  18. Hematopoietic stem cell transplantation for primary immunodeficiency diseases.

    Science.gov (United States)

    Slatter, Mary A; Cant, Andrew J

    2011-11-01

    Hematopoietic stem cell transplantation (HSCT) is now highly successfully curing a widening range of primary immunodeficiencies (PIDs). Better tissue typing, matching of donors, less toxic chemotherapy, better virus detection and treatment, improved supportive care, and graft-versus-host disease prophylaxis mean up to a 90% cure for severe combined immunodeficiency patients and a 70-80% cure for other PIDs given a matched unrelated donor, and rising to 95% for young patients with specific PIDs, such as Wiskott-Aldrich syndrome. Precise molecular diagnosis, detailed data on prognosis, and careful pre-HSCT assessment of infective lung and liver damage will ensure an informed benefit analysis of HSCT and the best outcome. It is now recognized that the best treatment option for chronic granulomatous disease is HSCT, which can also be curative for CD40 ligand deficiency and complex immune dysregulation disorders.

  19. Survival Advantage and Comparable Toxicity in Reduced-Toxicity Treosulfan-Based versus Reduced-Intensity Busulfan-Based Conditioning Regimen in Myelodysplastic Syndrome and Acute Myeloid Leukemia Patients after Allogeneic Hematopoietic Cell Transplantation.

    Science.gov (United States)

    Sakellari, Ioanna; Mallouri, Despina; Gavriilaki, Eleni; Batsis, Ioannis; Kaliou, Maria; Constantinou, Varnavas; Papalexandri, Apostolia; Lalayanni, Chrysavgi; Vadikolia, Chrysanthi; Athanasiadou, Anastasia; Yannaki, Evangelia; Sotiropoulos, Damianos; Smias, Christos; Anagnostopoulos, Achilles

    2017-03-01

    Treosulfan has been incorporated in conditioning regimens for sustained remission without substantial toxicity and treatment-related mortality (TRM). We aimed to analyze the safety and efficacy of a fludarabine 150 mg/m(2) and treosulfan 42 g/m(2) (FluTreo) conditioning regimen in medically infirm patients. Outcomes were compared with those of a similar historical group treated with fludarabine 150 mg/m(2) to 180 mg/m(2), busulfan 6.4 mg/kg, and antithymocyte globulin (ATG) 5 mg/kg to 7.5 mg/kg (FluBuATG). Thirty-one consecutive patients with acute myeloid leukemia (AML; n = 21), myelodysplastic syndrome (MDS; n = 6), or treatment-related AML (n = 4) received FluTreo conditioning. The historical group consisted of 26 consecutive patients treated with FluBuATG. In the FluTreo group, engraftment was prompt in all patients and 74% achieved >99% donor chimerism by day +30. No grades III or IV organ toxicities were noted. One-year cumulative incidences (CI) of acute and chronic graft-versus-host disease (GVHD) were 19.4% and 58.4%. The groups were similar for age, disease risk, lines of treatment, hematopoietic cell transplantation-specific comorbidity index, and acute or chronic GVHD incidence, except that there were more matched unrelated donor recipients in the FluTreo group (P < .001). With 20 (range, 2 to 36) months follow-up for FluTreo and 14 (range, 2 to 136) for FluBuATG, the 1-year cumulative overall survival (OS) probability was 76% versus 57%, respectively (P = .026); 1-year disease-free survival (DFS) was 79% versus 38% (P < .001). In multivariate analysis, the only significantly favorable factor for OS and DFS was FluTreo (P = .010 and P = .012). The CI of relapse mortality was markedly decreased in FluTreo versus FluBuATG (7.4% versus 42.3%, P < .001). In conclusion, the treosulfan-based regimen resulted in favorable OS and DFS with acceptable toxicity and low relapse rates compared with busulfan-based conditioning.

  20. Related and unrelated nonmyeloablative hematopoietic stem cell transplantation for malignant diseases.

    Science.gov (United States)

    Georges, George E; Maris, Michael; Sandmaier, Brenda M; Malone, David G; Feinstein, Lyle; Niederweiser, Dietger; Shizuru, Judith A; McSweeney, Peter A; Chauncey, Thomas R; Agura, Edward; Little, Marie-Trse; Sahebi, Firoozeh; Hegenbart, Ute; Pulsipher, Michael A; Bruno, Benedetto; Forman, Stephen; Woolfrey, Ann E; Radich, Jerald P; Blume, Karl G; Storb, Rainer

    2002-08-01

    Patients with advanced hematological malignancies ineligible for conventional myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) due to advanced age or medical contraindications were enrolled in multi-center study to investigate the safety and efficacy of nonmyeloablative HSCT using a 2 Gy total body irradi ation (TBI)-based regimen. A total of 192 patients (median age 55) were treated with HLA-matched sibling peripheral blood stem cell (PBSC) grafts, and 63 patients (median age 53) received a 10 of 10 HLA-antigen matched unrelated donor (URD) HSCT (PBSC graft, n = 48; marrow graft, n = 15). Diagnoses included multiple myeloma (n = 61), myelodysplastic syndrome (n = 55), chronic myeloid leukemia (n = 31), non-Hodgkin lymphoma (n = 31), acute myeloid leukemia (n = 28), chronic lymphocytic leukemia (n = 24), Hodgkin Disease (n = 14). The conditioning regimen was fludarabine 30 mg/m2/d x 3 days and 2 Gy TBI. Ninety-five related HSCT patients received 2 Gy TBI without fludarabine. Postgrafting immunosuppression was combined mycophenolate mofetil an cyclosporine. Transplants were well tolerated with a median of 0 days of hospitalization in the first 60 days for eligible patients. For related HSCT recipients, median follow-up was 289 (100-1,188) days. Nonfatal graft rejection occurred in 6.8%. Of those with sustained engraftment, graft-versus-host disease (GVHD) occurred in 49% (33% grade II, 11% grade III, 5% grade IV). Day-100 non-relapse mortality was 6%. Overall, 59% (114/192) of patients were alive. The relapse/disease progression mortality was 18%, and non-relapse mortality was 22%. The projecte 2-year survival and progression-free survival were 50% and 40%. For the URD HSCT recipients, median follow-up was 190 (100-468) days. Graft rejection occurred in 27% (17/63) of patients, mostly in recipients of marrow grafts (9/15). Acute GVHD occurred in 63% (50% grade II, 13% grade III) of 46 engrafted patients. Chronic GVHD requiring therapy occurred

  1. A case of acute viral hepatitis interfering with acute fatty liver disease of pregnancy

    Directory of Open Access Journals (Sweden)

    Abdulkadir Turgut

    2013-03-01

    Full Text Available Acute hepatitis A is a rarely seen infection during pregnancy.In terms of clinical and laboratory findings, it can beinterfere with acute fatty liver disease which can be quitemortal during pregnancy. Since liver function tests are elevatedin both conditions, hepatitis A infection should alsobe kept in mind in differential diagnosis. We present a 30year-old pregnant woman with 35 weeks of gestation whopresented to our clinic with a suspection of acute fattyliver disease but finally diagnosed as acute hepatitis A infection.J Clin Exp Invest 2013; 4 (1: 123-125Key words: Hepatitis A, pregnancy, acute fatty liver disease

  2. Acute renal dysfunction in liver diseases

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Renal dysfunction is common in liver diseases, either as part of multiorgan involvement in acute illness or secondary to advanced liver disease. The presence of renal impairment in both groups is a poor prognostic indicator. Renal failure is often multifactorial and can present as pre-renal or intrinsic renal dysfunction. Obstructive or post renal dysfunction only rarely complicates liver disease. Hepatorenal syndrome (MRS) is a unique form of renal failure associated with advanced liver disease or cirrhosis, and is characterized by functional renal impairment without significant changes in renal histology. Irrespective of the type of renal failure, renal hypoperfusion is the central pathogenetic mechanism, due either to reduced perfusion pressure or increased renal vascular resistance. Volume expansion, avoidance of precipitating factors and treatment of underlying liver disease constitute the mainstay of therapy to prevent and reverse renal impairment. Splanchnic vasoconstrictor agents, such as terlipressin, along with volume expansion, and early placement of transjugular intrahepatic portosystemic shunt (TIPS) may be effective in improving renal function in HRS. Continuous renal replacement therapy (CRRT) and molecular absorbent recirculating system (MARS) in selected patients may be life saving while awaiting liver transplantation.

  3. Monoclonal antibodies in human organ transplantation and auto-immune diseases.

    Science.gov (United States)

    Wijdenes, J; Roy, C; Morel-Fourrier, B; Racadot, E

    1992-01-01

    The usefulness of monoclonal antibodies (mAbs) in the transplantation field has become evident over the last couple of years. Different mAbs have been used as a prophylactic treatment after transplantation, in a therapeutic way against acute organ rejection and new diagnostic tools to predict clinical rejection immerge. One can even hope that with humanised mAbs or human mAbs obtained by repertoire cloning the formation of human anti-mouse antibodies will be solved although on the one hand this appeared not to be a big problem and on the other hand anti-idiotypic antibodies can still be expected. However, the most puzzling question is how the mAbs modulates the immuno-response and this not only in organ rejection but also in auto-immune diseases. Only one out of many CD25 mAbs with seemingly similar epitope recognition can be used in therapeutical treatment of acute Graft versus Host Disease. The same mAb is not, however, very efficient in the prophylactic treatment of kidney transplantation without association of suboptimal doses of cyclosporin A. Another example is a CD4 mAb which is efficient in the treatment of polyarthritis with no side effects but which provokes transient but clear side effects when used in psoriasis or multiple sclerosis patients. A second CD4 mAb with high inhibitory activity in several bioassays compared to the first CD4 mAb has no beneficial effect at all on polyarthritis. Also the question why there is a percentage of "no response" patients among apparently identical "good response" patients remains unanswered. However it becomes clear from these experiences that: 1) mAbs recognizing a similar epitope and being of the same isotype will not automatically have the same effect in therapy. 2) side effects may be depending of the disease treated. 3) the activities of mAbs in bioassays and even animal models very often do not reflect the in vivo situation in human. 4) efficiency of the treatment with mAbs can be increased by a better

  4. Acute rheumatic fever and rheumatic heart disease.

    Science.gov (United States)

    Carapetis, Jonathan R; Beaton, Andrea; Cunningham, Madeleine W; Guilherme, Luiza; Karthikeyan, Ganesan; Mayosi, Bongani M; Sable, Craig; Steer, Andrew; Wilson, Nigel; Wyber, Rosemary; Zühlke, Liesl

    2016-01-14

    Acute rheumatic fever (ARF) is the result of an autoimmune response to pharyngitis caused by infection with group A Streptococcus. The long-term damage to cardiac valves caused by ARF, which can result from a single severe episode or from multiple recurrent episodes of the illness, is known as rheumatic heart disease (RHD) and is a notable cause of morbidity and mortality in resource-poor settings around the world. Although our understanding of disease pathogenesis has advanced in recent years, this has not led to dramatic improvements in diagnostic approaches, which are still reliant on clinical features using the Jones Criteria, or treatment practices. Indeed, penicillin has been the mainstay of treatment for decades and there is no other treatment that has been proven to alter the likelihood or the severity of RHD after an episode of ARF. Recent advances - including the use of echocardiographic diagnosis in those with ARF and in screening for early detection of RHD, progress in developing group A streptococcal vaccines and an increased focus on the lived experience of those with RHD and the need to improve quality of life - give cause for optimism that progress will be made in coming years against this neglected disease that affects populations around the world, but is a particular issue for those living in poverty.

  5. Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts From HLA-Matched Related and Unrelated Donors in Preventing GVHD

    Science.gov (United States)

    2016-07-08

    Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Acute Biphenotypic Leukemia; Acute Leukemia of Ambiguous Lineage; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Blastic Plasmacytoid Dendritic Cell Neoplasm; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Graft Versus Host Disease; Lymphoblastic Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Anemia With Excess Blasts

  6. Impact of in vivo T cell depletion in HLA-identical allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission conditioned with a fludarabine iv-busulfan myeloablative regimen: a report from the EBMT Acute Leukemia Working Party

    Directory of Open Access Journals (Sweden)

    Marie Thérèse Rubio

    2017-01-01

    Full Text Available Abstract Background The impact of the use of anti-thymocyte globulin (ATG in allogeneic stem cell transplantation performed with HLA-identical sibling donors following fludarabine and 4 days intravenous busulfan myeloablative conditioning regimen has been poorly explored. Methods We retrospectively analyzed 566 patients who underwent a first HLA-identical allogeneic stem cell transplantation with this conditioning regimen for acute myeloid leukemia in first complete remission between 2006 and 2013 and compared the outcomes of 145 (25.6% patients who received ATG (ATG group to 421 (74.4% who did not (no-ATG group. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. Results Patients in the ATG group were older, received more frequently peripheral blood stem cell grafts from older donors, and were transplanted more recently. With a median follow-up of 19 months, patients in the ATG group had reduced 2-year cumulative incidence of chronic graft-versus-host disease (GVHD (31 vs. 52%, p = 0.0002 and of its extensive form (8 vs. 26%, p < 0.0001 but similar relapse incidence (22 vs. 27%, p = 0.23 leading to improved GVHD and relapse-free survival (GRFS (60 vs. 40%, p = 0.0001. In multivariate analyses, the addition of ATG was independently associated with lower chronic GVHD (HR = 0.46, p = 0.0001, improved leukemia-free survival (HR = 0.67, p = 0.027, overall survival (HR = 0.65, p = 0.027, and GRFS (HR = 0.51, p = 4 × 10−5. Recipient age above 50 years was the only other factor associated with worse survivals. Conclusions These results suggest that the use of ATG with fludarabine and 4 days intravenous busulfan followed by HLA-identical sibling donor allogeneic stem cell transplantation for acute myeloid leukemia improves overall transplant outcomes due to reduced incidence of chronic GVHD without increased

  7. Clarithromycin-induced acute interstitial nephritis and minimal change disease.

    Science.gov (United States)

    Russell, Wendy; Smith, William

    2009-10-01

    Drug associated acute interstitial nephritis and minimal change disease has been well documented but the simultaneous presentation of both is rare and has not been reported with clarithromycin. We describe a case of simultaneous acute tubulointerstitial nephritis and minimal change disease induced by clarithromycin. The patient had acute kidney injury, nephrotic syndrome, eosinophilic pneumonitis and a maculopapular skin rash. The role of steroid therapy in acute interstitial nephritis is controversial but is accepted as beneficial in minimal change nephrotic syndrome. Steroid therapy in our patient resulted in complete clinical resolution.

  8. Human bone marrow-derived mesenchymal stem cells

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    Lopez M

    2007-01-01

    Full Text Available Mesenchymal stem cells (MSCs have elicited a great clinical interest, particularly in the areas of regenerative medicine and induction of tolerance in allogeneic transplantation. Previous reports demonstrated the feasibility of transplanting MSCs, which generates new prospects in cellular therapy. Recently, injection of MSCs induced remission of steroid-resistant acute graft-versus-host disease (GVHD. This review summarizes the knowledge and possible future clinical uses of MSCs.

  9. 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.

  10. Total body irradiation and cyclophosphamide plus antithymocyte globulin regimen is well tolerated and promotes stable engraftment as a preparative regimen before T cell-replete haploidentical transplantation for acute leukemia.

    Science.gov (United States)

    Fu, Haixia; Xu, Lanping; Liu, Daihong; Liu, Kaiyan; Zhang, Xiaohui; Chen, Huan; Chen, Yuhong; Han, Wei; Wang, Yu; Wang, Jingzhi; Wang, Fengrong; Huang, Xiaojun

    2014-08-01

    We compared total body irradiation (TBI, 700 cGy)/cyclophosphamide (Cy, 3.6 g/m(2))/simustine (250 mg/m(2)) plus antithymocyte globulin (ATG) (TBI/Cy plus ATG) with cytarabine (8 g/m(2))/i.v. busulfan (Bu, 9.6 mg/kg)/Cy (3.6 g/m(2))/simustine (250 mg/m(2)) plus ATG (modified Bu/Cy plus ATG) as preparative therapy in T cell-replete haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for acute leukemia. From August 2009 to August 2013, 38 consecutive patients using TBI/Cy plus ATG regimen for T cell-replete haplo-HSCT (TBI group) at our center were eligible, which contained 28 high-risk and 10 standard-risk patients. A nested case-control study was designed. Seventy-seven patients using modified Bu/Cy plus ATG regimen (Bu group) were randomly selected in a 1 to 3:1 ratio matching for age, disease and status, year of HSCT (±2 years), and length of follow-up. Only 1 graft failure occurred in the TBI group. The incidence and time of neutrophil and platelet engraftment were comparable between the 2 groups. Severe grades III/IV graft-versus-host disease was observed in 13.4% of Bu group and only 2.6% of TBI group (P = .083). More toxicity of the liver (37.7% versus 10.5%; P = .002) and more hemorrhagic cystitis occurred in the Bu group (49.3% versus 23.7%, P = .008). Diarrhea was more common in the TBI group (44.7% versus 22.1%; P = .031). No significant differences were found in the 2-year incidences of relapse (26.5% for TBI group versus 32.3% for Bu group, P = .742), 1-year transplant-related mortality (12.6% versus 16.2%, P = .862), 2-year overall survival (60.2% versus 57.0%, P = .937), and 2-year incidence of disease-free survival (57.9% versus 56.6%, P = .845) between the 2 groups. We conclude that the TBI/Cy plus ATG regimen seems to be feasible in T cell-replete haplo-HSCT, which promotes stable engraftment and a lower incidence of liver toxicity and hemorrhagic cystitis. However, longer follow-up is necessary to

  11. Managing Acute Complications Of Sickle Cell Disease In Pediatric Patients.

    Science.gov (United States)

    Subramaniam, Sathyaseelan; Chao, Jennifer H

    2016-11-01

    Sickle cell disease is a chronic hematologic disease with a variety of acute, and often recurring, complications. Vaso-occlusive crisis, a unique but common presentation in sickle cell disease, can be challenging to manage. Acute chest syndrome is the leading cause of death in patients with sickle cell disease, occurring in more than half of patients who are hospitalized with a vaso-occlusive crisis. Uncommon diagnoses in children, such as stroke, priapism, and transient red cell aplasia, occur more frequently in patients with sickle cell disease and necessitate a degree of familiarity with the disease process and its management. Patients with sickle cell trait generally have a benign course, but are also subject to serious complications. This issue provides a current review of evidence-based management of the most common acute complications of sickle cell disease seen in pediatric patients in the emergency department.

  12. Umbilical cord blood transplantation in hematologic diseases in patients over 15 years old: long-term experience at the Pontificia Universidad Católica de Chile.

    Science.gov (United States)

    Ramirez, P; Nervi, B; Bertin, P; Poggi, H; Lagos, M; Selman, C; Pizarro, I; Jara, V; Wiestruck, A; Barriga, F

    2013-01-01

    Most patients who require a sibling stem cell transplantation do not have a matched donor. In our experience, only 1/3 patients have a matched unrelated donor (MUD); therefore, the majority of the patients will require umbilical cord blood (UCB). Patients treated for hematologic diseases with UCB transplants were included. UCB selection and conditioning regimens were performed according to the Minnesota group. Graft-versus-host disease (GVHD) prophylaxis, infection prevention, and patient care were performed according to institutional guidelines. We analyzed patients and graft demography, neutrophil and platelet recovery, chimerism kinetics, GVHD incidence, overall (OS), progression-free survival (PFS) and transplant-related mortality (TRM). We included 29 patients with a median age of 34.8 years (range 15-55). Eighteen were male and the median weight was 72.6 kg (range 54-100). Nineteen patients had acute leukemia. Myeloablative (MA) conditioning was used in 27 patients. Seventeen received double UCB (DUCB) grafts. Median total nucleated cell (10(7)/kg) was 4.2 (range 3.9-4.9) and 4.4 (range 2.8-6.3) for single UCB (SUCB) and DUCB transplants, respectively. Median time for neutrophil engraftment was 24.7 (range 14-43) and 25.8 days (range 14-52) after SUCB and DUCB transplants, respectively. Median time for platelet engraftment was 147 (range 30-516) and 81 days (range 37-200) after SUCB and DUCB transplants, respectively. All the patients receiving MA conditioning had >95% chimerism shortly after transplant. Cumulative incidence of grades II-IV and III-IV acute GVHD was 41% and 20%, respectively. Localized chronic GVHD was seen in 14% of the patients. Median follow-up was 16.7 months (range 1-63). Five-year OS and PFS were 38% and 39%, respectively. One-year TRM was 42%. UCB transplantation is associated with potential cure of hematologic malignancies and our results are similar to other series. Studies are needed to decrease mortality and improve immune

  13. Radiolabeled anti-CD45 antibody with reduced-intensity conditioning and allogeneic transplantation for younger patients with advanced acute myeloid leukemia or myelodysplastic syndrome.

    Science.gov (United States)

    Mawad, Raya; Gooley, Ted A; Rajendran, Joseph G; Fisher, Darrell R; Gopal, Ajay K; Shields, Andrew T; Sandmaier, Brenda M; Sorror, Mohamed L; Deeg, Hans Joachim; Storb, Rainer; Green, Damian J; Maloney, David G; Appelbaum, Frederick R; Press, Oliver W; Pagel, John M

    2014-09-01

    We treated patients under age 50 years with iodine-131 ((131)I)-anti-CD45 antibody combined with fludarabine and 2 Gy total body irradiation to create an improved hematopoietic cell transplantation (HCT) strategy for advanced acute myeloid leukemia or high-risk myelodysplastic syndrome patients. Fifteen patients received 332 to 1561 mCi of (131)I, delivering an average of 27 Gy to bone marrow, 84 Gy to spleen, and 21 Gy to liver. Although a maximum dose of 28 Gy was delivered to the liver, no dose-limiting toxicity was observed. Marrow doses were arbitrarily capped at 43 Gy to avoid radiation-induced stromal damage; however, no graft failure or evidence of stromal damage was observed. Twelve patients (80%) developed grade II graft-versus-host disease (GVHD), 1 patient developed grade III GVHD, and no patients developed grade IV GVHD during the first 100 days after HCT. Of the 12 patients with chronic GVHD data, 10 developed chronic GVHD, generally involving the skin and mouth. Six patients (40%) are surviving after a median of 5.0 years (range, 4.2 to 8.3 years). The estimated survival at 1 year was 73% among the 15 treated patients. Eight patients relapsed, 7 of whom subsequently died. The median time to relapse among these 8 patients was 54 days (range, 26 to 1364 days). No cases of nonrelapse mortality were observed in the first year after transplantation. However, 2 patients died in remission from complications of chronic GVHD and cardiomyopathy, at 18 months and 14 months after transplantation, respectively. This study suggests that patients may tolerate myeloablative doses >28 Gy delivered to the liver using (131)I-anti-CD45 antibody in addition to standard reduced-intensity conditioning. Moreover, the arbitrary limit of 43 Gy to the marrow may be unnecessarily conservative, and continued escalation of targeted radioimmunotherapy doses may be feasible to further reduce relapse.

  14. MRI in acute neuropathic Gaucher's disease

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Y.C. [Department of Paediatrics, Chang Gung Memorial Children' s Hospital in Kaohsiung, Taiwan (Taiwan); Huang, C.C. [National Cheng Kung University Hospital, Taiwan (Taiwan); Chen, C.Y. [Department of Diagnostic Radiology, Tri-Service General Hospital and National Defence Medical Centre, Taipei (Taiwan); Zimmerman, R.A. [Department of Radiology, Children' s Hospital of Philadelphia (United States)

    2000-01-01

    We present the cranial MRI findings in a 6-month-old girl with biopsy-proven acute neuropathic Gaucher's disease, which include unilateral cerebral atrophy and dural thickening with contrast enhancement. (orig.)

  15. ACUTE RESPIRATORY DISEASE AS THE DEBUT OF SYSTEMIC LUPUS ERYTHEMATOSUS

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    A. Yu. Ischenko

    2015-01-01

    Full Text Available Systemic lupus erythematosus — a chronic autoimmune disease that is often associated with infectious processes. The paper presents two clinical cases of systemic lupus erythematosus , debuted with acute respiratory infection.

  16. 单倍型相合骨髓移植治疗伴髓外侵犯的难治复发变异型急性早幼粒细胞白血病获长期生存1例并文献复习%Haploidentical bone marraw transplantation for acute promyelocytic leukemia patients with extra-myeloid invasion:one case report

    Institute of Scientific and Technical Information of China (English)

    朱玲; 薛梅; 闫洪敏; 段连宁; 刘静; 丁丽; 王恒湘

    2011-01-01

    Objective:To study the effect of Haploidentical bone marraw transplantation on an acute promyelocytic leukemia patient with extra-myeloid invasion. Method:A case of acute promyelocytic leukemia with extra-myeloid invasion who accepted Haploidentical bone marraw transplantation was reported and related literatures were reviewed. The conditioning regimen consisted of high dose cytosine (Ara-C), cyclophosphamide (CTX) and total body irradiation (TBI) . The graft versus host disease(GVHD) prophylaxis included the administration of a combination of immunosuppressive drugs including CsA, short-course MTX, MMF, anti-CD25 monoclonal antibody and ATG. The donors were given G-CSF for continuous five days prior to bone marrow harvest . Result:The patient showed hematopoietic reconstitution + 1 month after BMT. Immune function was established gradually. The patient was followed up regularly, PML/RARα fusion gene was continuous negative. The patient has survived successfully for 76 months. Conclusion:The haploidentical bone marraw transplantation is an effective regiment for treating acute promyelocytic leukemia with extra-myeloid invasion.%目的:探讨单倍型相合骨髓移植治疗伴有髓外侵犯的难治性变异型急性早幼粒细胞白血病的疗效.方法:采用母亲供髓的单倍型相合移植治疗1例伴髓外侵犯的难治复发变异型急性早幼粒细胞白血病,预处理方案为CyTBI加Ara-c,GVHD预防采用联合免疫抑制剂和供者应用G-CSF的方法,联合免疫抑制剂包括环胞素A、短程氨甲碟呤、霉酚酸酯、CD25 单抗和抗胸腺细胞球蛋白的应用.结果:移植后+1个月造血重建,植入成功,免疫功能逐渐恢复,定期随访,PML/RARα融合基因持续(-),现已无病生存76个月.结论:单倍型相合骨髓是治愈高危难治复发急性早幼粒白血病的有效措施,为患者提供了长期生存的机会.

  17. Acute myeloid leukaemia as a cause of acute ischaemic heart disease

    NARCIS (Netherlands)

    van Haelst, P.L.; Schot, Bart; Hoendermis, E.S.; van den Berg, M.P.

    2006-01-01

    Ischaemic heart disease is almost invariably the result of atherosclerotic degeneration of the coronary arteries. However, other causes of ischaemic heart disease should always be considered. Here we describe two patients with a classic presentation of ischaemic heart disease resulting from acute le

  18. Atmospheric pressure does not influence acute diverticular disease

    OpenAIRE

    Velayos, Benito; Pons-Renedo, Fernando; Feranández-Salazar, Luis; Muñoz, María Fe; Olmo, Lourdes del; Almaraz Gómez, Ana; Beltrán de Heredia, Juan; Hernández-González, José Manuel

    2013-01-01

    Producción Científica The article offers information on a study which examines the influence of atmospheric pressure on the development of acute diverticular disease. The value of atmospheric pressure and its daily trends in 2012 was collected to prove whether atmospheric pressure influence this disease by raising intra-diverticular pressure in days with higher atmospheric pressure. The study involved patients with acute diverticulitis who underwent computed tomography.

  19. Acute Demyelinating Disease after Oral Therapy with Herbal Extracts

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    Alex Kostianovsky

    2011-06-01

    Full Text Available Central nervous system demyelinating processes such as multiple sclerosis and acute disseminated encephalomyelitis constitute a group of diseases not completely understood in their physiopathology. Environmental and toxic insults are thought to play a role in priming autoimmunity. The aim of the present report is to describe a case of acute demyelinating disease with fatal outcome occurring 15 days after oral exposure to herbal extracts.

  20. Busulfan plus fludarabine as a myeloablative conditioning regimen compared with busulfan plus cyclophosphamide for acute myeloid leukemia in first complete remission undergoing allogeneic hematopoietic stem cell transplantation: a prospective and multicenter study

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    Liu Hui

    2013-02-01

    Full Text Available Abstract Objective We conducted a prospective, randomized, open-label, multicenter study to compare busulfan plus fludarabine (BuFlu with busulfan plus cyclophosphamide (BuCy as the conditioning regimen in allogeneic hematopoietic stem cell transplantation (allo-HSCT for acute myeloid leukemia (AML in first complete remission (CR1. Methods Totally 108 AML-CR1 patients undergoing allo-HSCT were randomized into BuCy (busulfan 1.6 mg/kg, q12 hours, -7 ~ -4d; cyclophosphamide 60 mg/kg.d, -3 ~ -2d or BuFlu (busulfan 1.6 mg/kg, q12 hours, -5 ~ -2d; fludarabine 30 mg/m2.d, -6 ~ -2d group. Hematopoietic engraftment, regimen-related toxicity (RRT, graft-versus-host disease (GVHD, transplant related mortality (TRM, and overall survival were compared between the two groups. Results All patients achieved hematopoietic reconstitution except for two patients who died of RRT during conditioning. All patients obtained complete donor chimerism by day +30 post-transplantation. The incidence of total and III-IV RRT were 94.4% and 81.5% (P = 0.038, and 16.7% and 0.0% (P = 0.002, respectively, in BuCy and BuFlu group. With a median follow up of 609 (range, 3–2130 days after transplantation, the 5-year cumulative incidence of TRM were 18.8 ± 6.9% and 9.9 ± 6.3% (P = 0.104; the 5-year cumulative incidence of leukemia relapse were 16.5 ± 5.8% and 16.2 ± 5.3% (P = 0.943; the 5-year disease-free survival and overall survival were 67.4 ± 7.6% and 75.3 ± 7.2% (P = 0.315, and 72.3 ± 7.5% and 81.9 ± 7.0% (P = 0.177, respectively in BuCy and BuFlu group. Conclusion Compared with BuCy, BuFlu as a myeloablative condition regimen was associated with lower toxicities and comparable anti-leukemic activity in AML-CR1 patients undergoing allo-HSCT.

  1. Upfront allogeneic blood stem cell transplantation for patients with high-risk myelodysplastic syndrome or secondary acute myeloid leukemia using a FLAMSA-based high-dose sequential conditioning regimen.

    Science.gov (United States)

    Saure, Christian; Schroeder, Thomas; Zohren, Fabian; Groten, Anke; Bruns, Ingmar; Czibere, Akos; Galonska, Lars; Kondakci, Mustafa; Weigelt, Christian; Fenk, Roland; Germing, Ulrich; Haas, Rainer; Kobbe, Guido

    2012-03-01

    Patients suffering from high-risk myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) secondary to MDS (sAML) are characterized by poor response to conventional cytotoxic chemotherapy. The purpose of our prospective single-center study was to examine the safety and efficacy of an allogeneic hematopoietic stem cell transplantation (HSCT) following a sequential conditioning regimen as first-line therapy for previously untreated patients with high-risk MDS or sAML. Between November 2003 and June 2010, 30 patients (20 high-risk MDS, 10 sAML) received fludarabine (4 × 30 mg/m(2)), amsacrine (4 × 100 mg/m(2)), and Ara-C (4 × 2 g/m(2), FLAMSA). After 2 to 3 days of rest, patients received high-dose melphalan alone (200 mg/m(2) for patients with an age 60 years; n = 24) or melphalan and thiotepa (10 mg/kg, Mel/Thio, n = 6). Following these high-dose conditioning regimens, a median number of 7.7 × 10(6) CD34(+) cells/kg body weight (range: 2.9 × 10(6)-17.2 × 10(6)) were transplanted from 13 related or 17 unrelated donors. Antithymocyte globulin (Fresenius 30-60 mg/kg) as well as tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis. All patients except 1 with primary graft failure achieved complete remission after HSCT. After a median follow-up time of 28 months (range: 7-81), 21 patients (70%) were alive and free of disease. Overall, 4 patients relapsed. At 2 years, overall survival, event-free survival, and treatment-related mortality were 70%, 63%, and 30%, respectively. Because of undue toxicity, thiotepa is no longer part of the conditioning regimen. Our results add to the body of evidence that a FLAMSA-based sequential conditioning therapy is effective for previously untreated patients with high-risk MDS or sAML.

  2. Long-term survival and late events after allogeneic stem cell transplantation from HLA-matched siblings for acute myeloid leukemia with myeloablative compared to reduced-intensity conditioning: a report on behalf of the acute leukemia working party of European group for blood and marrow transplantation

    Directory of Open Access Journals (Sweden)

    Avichai Shimoni

    2016-11-01

    Full Text Available Abstract Background Myeloablative (MAC and reduced-intensity conditioning (RIC are established approaches for allogeneic stem cell transplantation (SCT in acute myeloid leukemia (AML. Most deaths after MAC occur within the first 2 years after SCT, while patients surviving leukemia-free for 2 years can expect a favorable long-term outcome. However, there is paucity of data on the long-term outcome (beyond 10 years and the pattern of late events following RIC due to the relative recent introduction of this approach. Methods We analyzed long-term outcomes in a cohort of 1423 AML patients, age ≥50 years, after SCT from HLA-matched siblings, during the years 1997–2005, median follow-up 8.3 years (0.1–17. Results The 10-year leukemia-free survival (LFS was 31 % (95CI, 27–35 and 32 % (28–35 after MAC and RIC, respectively (P = 0.57. The 10-year GVHD/ relapse-free survival (GRFS, a surrogate for quality of life was 22 % (18–25 and 21 % (18–24, respectively (P = 0.79. The 10-year non-relapse mortality (NRM was higher and relapse rate was lower after MAC, throughout the early and late post-transplant course. The 10-year LFS among 584 patients surviving leukemia-free 2 years after SCT was 71 % (65–76 and 73 % (67–78 after MAC and RIC, respectively (P = 0.76. Advanced leukemia at SCT was the major predictor of LFS subsequent to the 2-year landmark. Relapse was the major cause of late death after both regimens; however, NRM and in particular chronic graft-versus-host disease and second cancers were more common causes of late death after MAC. Conclusions Long-term LFS and GRFS are similar after RIC and MAC. Most events after RIC or MAC occur within the first 2 years after SCT. Patients who are leukemia-free 2 years after SCT can expect similar good subsequent outcome after both approaches.

  3. Acute Exacerbation of Chronic Obstructive Pulmonary Disease: Cardiovascular Links

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    Cheryl R. Laratta

    2014-01-01

    Full Text Available Chronic obstructive pulmonary disease (COPD is a chronic, progressive lung disease resulting from exposure to cigarette smoke, noxious gases, particulate matter, and air pollutants. COPD is exacerbated by acute inflammatory insults such as lung infections (viral and bacterial and air pollutants which further accelerate the steady decline in lung function. The chronic inflammatory process in the lung contributes to the extrapulmonary manifestations of COPD which are predominantly cardiovascular in nature. Here we review the significant burden of cardiovascular disease in COPD and discuss the clinical and pathological links between acute exacerbations of COPD and cardiovascular disease.

  4. Targeting a single mismatched minor histocompatibility antigen with tumor-restricted expression eradicates human solid tumors

    NARCIS (Netherlands)

    L. Hambaeh (Lothar); M. Vermeij (Marcel); A. Buser (Andreas); Z. Aghai (Zohara); Th.H. van der Kwast (Theo); E. Goulmy (Els)

    2008-01-01

    textabstractRegressions of metastatic solid tumors after allogeneic human leukocyte antigen (HLA)-matched stem cell transplantation (SCT) are often associated with detrimental graft-versus-host disease (GVHD). The graft-versus-host reaction of the HLA-matched donor is directed mainly against the mul

  5. Acute Kidney Disease After Liver and Heart Transplantation.

    Science.gov (United States)

    Rossi, Ana P; Vella, John P

    2016-03-01

    After transplantation of nonrenal solid organs, an acute decline in kidney function develops in the majority of patients. In addition, a significant number of nonrenal solid organ transplant recipients develop chronic kidney disease, and some develop end-stage renal disease, requiring renal replacement therapy. The incidence varies depending on the transplanted organ. Acute kidney injury after nonrenal solid organ transplantation is associated with prolonged length of stay, cost, increased risk of death, de novo chronic kidney disease, and end-stage renal disease. This overview focuses on the risk factors for posttransplant acute kidney injury after liver and heart transplantation, integrating discussion of proteinuria and chronic kidney disease with emphasis on pathogenesis, histopathology, and management including the use of mechanistic target of rapamycin inhibition and costimulatory blockade.

  6. Outcomes of unrelated cord blood transplantation in patients with multiple myeloma: a survey on behalf of Eurocord, the Cord Blood Committee of Cellular Therapy and Immunobiology Working Party, and the Chronic Leukemia Working Party of the EBMT

    Science.gov (United States)

    Paviglianiti, Annalisa; Xavier, Erick; Ruggeri, Annalisa; Ceballos, Patrice; Deconinck, Eric; Cornelissen, Jan J.; Nguyen-Quoc, Stephanie; Maillard, Natacha; Sanz, Guillermo; Rohrlich, Pierre-Simon; Garderet, Laurent; Volt, Fernanda; Rocha, Vanderson; Kroeger, Nicolaus; Gluckman, Eliane; Fegueux, Nathalie; Mohty, Mohamad

    2016-01-01

    Although allogeneic stem cell transplantation is not a standard therapy for multiple myeloma, some patients can benefit from this intense therapy. There are few reports on outcomes after umbilical cord blood transplantation in multiple myeloma, and investigation of this procedure is warranted. We retrospectively analyzed 95 patients, 85 with multiple myeloma and 10 with plasma cell leukemia, receiving single or double umbilical cord blood transplantation from 2001 to 2013. Median follow up was 41 months. The majority of patients received a reduced intensity conditioning. The cumulative incidence of neutrophil engraftment was 97%±3% at 60 days, and that of 100-day acute graft-versus-host disease grade II-IV was 41%±5%. Chronic graft-versus-host disease at two years was 22%±4%. Relapse and non-relapse mortality was 47%±5% and 29%±5% at three years, respectively. Three-year progression-free survival and overall survival were 24%±5% and 40%±5%, respectively. Anti-thymocyte globulin was associated with decreased incidence of acute graft-versus-host disease, higher non-relapse mortality, decreased overall and progression-free survival. Patients with high cytogenetic risk had higher relapse, and worse overall and progression-free survival. In conclusion, umbilical cord blood transplantation is feasible for multiple myeloma patients. PMID:27229716

  7. Effect of antithymocyte globulin source on outcomes of bone marrow transplantation for severe aplastic anemia.

    Science.gov (United States)

    Kekre, Natasha; Zhang, Ying; Zhang, Mei-Jie; Carreras, Jeanette; Ahmed, Parvez; Anderlini, Paolo; Atta, Elias Hallack; Ayas, Mouhab; Boelens, Jaap Jan; Bonfim, Carmem; Deeg, H Joachim; Kapoor, Neena; Lee, Jong-Wook; Nakamura, Ryotaro; Pulsipher, Michael A; Eapen, Mary; Antin, Joseph H

    2017-03-24

    For treatment of severe aplastic anemia, immunosuppressive therapy with horse antithymocyte globulin results in superior response and survival compared with rabbit antithymocyte globulin. This relative benefit may be different in the setting of transplantation as rabbit antithymocyte globulin results in more profound immunosuppression. We analyzed 833 severe aplastic anemia transplants between 2008 and 2013 using HLA-matched siblings (n=546) or unrelated donors (n=287) who received antithymocyte globulin as part of their conditioning regimen and bone marrow graft. There were no differences in hematopoietic recovery by type of antithymocyte globulin. Among recipients of HLA-matched sibling transplants, day 100 incidence of acute (17% versus 6%, p<0.001) and chronic (20% versus 9%, p<0.001) graft-versus-host disease were higher with horse compared to rabbit antithymocyte globulin. There were no differences in 3 year overall survival, 87% and 92%, p=0.76. Among recipients of unrelated donor transplants acute graft-versus-host disease was also higher with horse compared to rabbit antithymocyte globulin (42% versus 23%, p<0.001) but not chronic graft-versus-host disease (38% versus 32%, p=0.35). Survival was lower with horse antithymocyte globulin after unrelated donor transplantation, 75% versus 83%, p=0.02. These data support the use of rabbit antithymocyte globulin for bone marrow transplant conditioning for severe aplastic anemia.

  8. Ultrasonographic Findings of Extratesticular Diseases Causing Acute Scrotal Disorders

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Jae Joon; Lee, Tack; Chang, So Yong; Kim, Myeong Jin; Yoo, Hyung Sik; Lee, Jong Tae [Yonsei University College of Medicine, Seoul (Korea, Republic of)

    1996-12-15

    To evaluate the kinds of extratesticular diseases causing acute scrotal disorders by emergent sonography of the scrotum. Scrotal sonography in sixty-five patients, with age ranging from 5months to 82 years (mean : 27.3 years), with acute scrotal pain and swelling, was prospectively carried out by either a 10 or 7.5 MHz transducer. We evaluated the size and echogenicity of the epididymis, the presence of extratesticular solid mass or cyst, testicular involvement by extratesticular diseases, calcification, hydrocele and scrotal wall thickening. The most common cause of acute scrotal disorders was acute epididymitis (n= 50), followed by acute epididymo-orchitis (n = 4), mumps epididymo-orchitis (n = 2), enlarged epididymis secondary to testicular torsion (n = 2), infected hydrocele (n = 2), epididymal cyst (n = 2), rupture of varicocele (n = 1), angioneurotic edema (n = 1), and sperm granuloma (n = 1). Hydrocele was seen in 20 cases, and epididymal calcification was noted in 6 cases. Emergent scrotal sonography was useful for correct diagnosis and proper treatment in patients with acute scrotal disorders, especially in the differentiation of the acute epididymitis from other intrascrotal diseases

  9. 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.

  10. Acute colonic disease: How to image in emergency

    Energy Technology Data Exchange (ETDEWEB)

    Romano, Stefania [Department of Diagnostic Imaging, A. Cardarelli Hospital, Viale Cardarelli 9, 80131 Naples (Italy)]. E-mail: stefromano@libero.it; Lombardo, Patrizia [Department of Diagnostic Imaging, A. Cardarelli Hospital, Viale Cardarelli 9, 80131 Naples (Italy); Cinque, Teresa [Department of Diagnostic Imaging, A. Cardarelli Hospital, Viale Cardarelli 9, 80131 Naples (Italy); Tortora, Giovanni [Department of Diagnostic Imaging, A. Cardarelli Hospital, Viale Cardarelli 9, 80131 Naples (Italy); Romano, Luigia [Department of Diagnostic Imaging, A. Cardarelli Hospital, Viale Cardarelli 9, 80131 Naples (Italy)

    2007-03-15

    The diseases affecting the large intestine represent a diagnostic problem in adult patients with acute abdomen, especially when clinical symptoms are not specific. The role of the diagnostic imaging is to help clinicians and surgeons in differential diagnosis for an efficient early and prompt therapy to perform. This review article summarizes the imaging spectrum of findings of colonic acute disease, from mechanical obstruction to inflammatory diseases and perforation, offering keys to problem solving in doubtful cases as well as discussing regarding the more indicated imaging method to use in emergency, particularly MDCT.

  11. 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.

  12. Graft-versus-lymphoma effect in a 64-year-old caucasian woman after allogeneic stem-cell transplantation: a case report

    Directory of Open Access Journals (Sweden)

    Behre Gerhard

    2009-01-01

    Full Text Available Abstract Introduction The existence of a graft-versus-lymphoma effect is well established. When lacking a firm diagnosis, however, the clinician is challenged to to weigh the potential benefits of the graft-versus-lymphoma effect against potential dangers of graft-versus-host disease as well as against generalized (viral infections. Case presentation We present evidence for a graft-versus-lymphoma effect in a 64-year-old caucasian woman with a transplanted peripheral blood-stem-cell graft from her Human Leukocyte Antigen-identical sister, and propose diagnostic measures to distinguish between graft-versus-host effect, and against viral disease or drug-induced reactions. Conclusion We were able to identify an allogeneic graft-reaction against progressive lymphoma alongside an erythema consistent with acute graft-versus-host disease of the skin. Establishing a firm diagnosis enabled us to decide against T-cell suppression (such as by using cyclosporine. Anti-lymphoma activity was favoured, by means of the allogeneic graft, local radiation and immunotherapy. This illustrates the importance of a sound differential diagnosis of erythema after allogeneic stem-cell transplantation, including assessment of viral disease of the affected tissue.

  13. Lithium-induced minimal change disease and acute kidney injury

    OpenAIRE

    Parul Tandon; Natalie Wong; Zaltzman, Jeffrey S.

    2015-01-01

    Context: Lithium carbonate is a psychiatric medication commonly used in the treatment of bipolar disorder. It has been implicated in inducing nephrogenic diabetes inspidus, chronic tubulointerstitial nephropathy, and acute tubular necrosis. We describe a case of lithium-induced minimal change disease (MCD) and acute kidney injury (AKI). Case Report: A 32-year-old female with a medical history of bipolar disorder treated with chronic lithium therapy presented with anasarca, fatigue, and tremor...

  14. Association between acute pancreatitis and peptic ulcer disease

    Institute of Scientific and Technical Information of China (English)

    Kang-Moon Lee; Chang-Nyol Paik; Woo Chul Chung; Jin Mo Yang

    2011-01-01

    AIM:To evaluate the relationship between peptic ulcer disease (PUD) and acute pancreatitis.METHODS:A cohort of 78 patients with acute pancreatitis were included in this study.The presence of PUD and the Helicobacter pylori (H.pylori ) status were assessed by an endoscopic method.The severity of acute pancreatitis was assessed using Ranson's score, the Acute Physiology and Chronic Health Evaluation (APACHE) Ⅱ score,computed tomography severity index and the clinical data during hospitalization,all of which were compared between the patients with and without PUD.The risk factors for PUD were also evaluated. RESULTS:Among 78 patients,41 patients (52.6%) with acute pancreatitis suffered from PUD,but only 13 (31.7%) patients with PUD were infected by H.pylori .On univariate analysis,male gender,an etiology of alcohol-induced pancreatitis,a history of smoking or alcohol consumption, elevated triglyceride and C-reactive protein levels, and high APACHE Ⅱ score were significantly associated with PUD.However,on multivariate logistic regression analysis,the APACHE Ⅱ score (odds ratio:7.69; 95% confidence interval:1.78-33.33; P < 0.01) was found to be the only independent risk factor for PUD.CONCLUSION:Patients with acute pancreatitis are liable to suffer from PUD.PUD is associated with severe acute pancreatitis according to the APACHE Ⅱ score, and treatment for PUD should be considered for patients with severe acute pancreatitis.

  15. Acute rheumatic fever and rheumatic heart disease in indigenous populations.

    Science.gov (United States)

    Steer, Andrew C; Carapetis, Jonathan R

    2009-12-01

    Acute rheumatic fever and rheumatic heart disease are diseases of socioeconomic disadvantage. These diseases are common in developing countries and in Indigenous populations in industrialized countries. Clinicians who work with Indigenous populations need to maintain a high index of suspicion for the potential diagnosis of acute rheumatic fever, particularly in patients presenting with joint pain. Inexpensive medicines, such as aspirin, are the mainstay of symptomatic treatment of rheumatic fever; however, antiinflammatory treatment has no effect on the long-term rate of progression or severity of chronic valvular disease. The current focus of global efforts at prevention of rheumatic heart disease is on secondary prevention (regular administration of penicillin to prevent recurrent rheumatic fever), although primary prevention (timely treatment of streptococcal pharyngitis to prevent rheumatic fever) is also important in populations in which it is feasible.

  16. Acute tubulointerstitial nephritis complicating Legionnaires' disease: a case report

    Directory of Open Access Journals (Sweden)

    Daumas Aurélie

    2012-04-01

    Full Text Available Abstract Introduction Legionnaires' disease is recognized as a multi-systemic illness. Afflicted patients may have pulmonary, renal, gastrointestinal tract and central nervous system complications. However, renal insufficiency is uncommon. The spectrum of renal involvement may range from a mild and transient elevation of serum creatinine levels to anuric renal failure requiring dialysis and may be linked to several causes. In our present case report, we would like to draw attention to the importance of the pathological documentation of acute renal failure by reporting a case of a patient with acute tubulointerstitial nephritis complicating Legionnaires' disease. Case presentation A 55-year-old Caucasian man was admitted to our hospital for community-acquired pneumonia complicated by acute renal failure. Legionella pneumophila serogroup type 1 was diagnosed. Although the patient's respiratory illness responded to intravenous erythromycin and ofloxacin therapy, his renal failure worsened, he became anuric, and hemodialysis was started. A renal biopsy was performed, which revealed severe tubulointerstitial nephritis. After initiation of steroid therapy, his renal function improved dramatically. Conclusions This case highlights the importance of kidney biopsies in cases where acute renal failure is a complicating factor in Legionnaires' disease. If the presence of acute tubulointerstitial nephritis can be confirmed, it will likely respond favorably to steroidal treatment and thus irreversible renal damage and chronic renal failure will be avoided.

  17. Acute Diarrhoeal Diseases Among Preschool Children in Western Maharashtra, India.

    Directory of Open Access Journals (Sweden)

    Mahesh B Tondare , Vaishali V Raje, Satish V Kakade , Madhavi V Rayate

    2014-01-01

    Full Text Available "Background: Malnutrition and infectious diseases both occur in the same unfortunate children and together they play a major role in causing the high morbidity and mortality in them. Out of all the childhood illnesses, acute respiratory tract infections, diarrhoeal diseases and malnutrition are the principle causes of illness and death in the developing countries. Acute Diarrhoeal diseases (ADD’s are reported to be the 2nd leading cause of child morbidity and mortality. Objectives: To study the attack rate of Acute Diarrhoeal Disease among pre-school children and to study the socio-demographic variables of pre-school children suffering from Acute Diarrhoeal Disease. Methods: A Longitudinal study was conducted among preschool children (3-5years who were selected from Private pre-primary school of urban area and followed for the period of one year. Mother/guardian/teacher was interviewed by using pre-tested proforma during this period. Results: About 56% of children found suffering from ADD with 0.6 episodes per children per year among private pre-primary school. Higher proportions of ADD affected children were residing in nuclear type of family, belonging to middle socio-economic class, mothers were literate & housewives, born with order >2 compared to non ADD affected children. Conclusion: Maximum number of children from private pre-primary schools suffered with nearly one attack of Acute Diarrhoeal Disease with maternal illiteracy and working mothers found favorable factors. Immunization coverage, EBF and proper weaning play a very important role in prevention of infections."

  18. Acute Rheumatic Fever: Global Persistence of a Preventable Disease.

    Science.gov (United States)

    Bono-Neri, Francine

    2016-10-21

    The persistence of acute rheumatic fever continues to be seen globally. Once thought to be eradicated in various parts of the world, the disease came back with a vengeance secondary to a lack of diligence on the part of providers. Today, the global burden of group A streptococcal infection, the culprit of the numerous sequelae manifested in acute rheumatic fever, is considerable. Although a completely preventable disease, rheumatic fever continues to exist. It is a devastating disease that involves long-term, multisystem treatment and monitoring for patients who were unsuccessful at eradicating the precipitating group A streptococcal infection. Prevention is the key to resolving the dilemma of the disease's global burden, yet the method to yield its prevention still remains unknown. Thus, meticulous attention to implementing proper treatment is the mainstay and remains a top priority.

  19. Postpartum Acute Pulmonary Oedema with Sub clinical Rheumatic Heart Disease

    OpenAIRE

    2015-01-01

    Acute dyspnea with pulmonary oedema in postpartum is uncommon but life-threatening event. Contributing factors for pulmonary oedema include, administration of tocolytics, underlying cardiac disease, iatrogenic fluid overload and preeclampsia acounting 0.08% of pregnancies. Pulmonary embolism, amniotic fluid embolism, pneumonia, aspiration and pulmonary oedema are some of the potentially devastating conditions that should be considered by the attending physician.

  20. Acute type II cryoglobulinaemic vasculitis mimicking atherosclerotic peripheral vascular disease.

    LENUS (Irish Health Repository)

    Saeed, A

    2012-01-31

    Atherosclerotic peripheral vascular disease is a common presenting cause for digital ischaemia in life long smokers. Acute severe Type II Cryoglobulinaemic vasculitis is a rare yet important cause, which may present with similar clinical features and which if undiagnosed may be rapidly fatal. Following the instigation of therapy with intravenous methylprednisolone and cyclophosphamide this patient made an excellent recovery.

  1. [Acute atrioventricular block in chronic Lyme disease].

    Science.gov (United States)

    Wagner, Vince; Zima, Endre; Gellér, László; Merkely, Béla

    2010-09-26

    The tick bite transmitted Lyme disease is one of the most common antropozoonosis, about 10 000 new infections are reported in Hungary each year. The progress and clinical presentation can vary, and carditis can occur in later stages. A serologically verified Lyme disease caused third degree atrioventricular block in young male presenting with presyncope. Based on the tick-bites mentioned a few weeks prior to hospital admission, Lyme carditis was considered with the administration of antibiotics and monitor observation. Typical skin lesions were not recognized and laboratory findings showed no pathology. An electrophysiological study recorded a predominant supra-His atrioventricular block. Total regression of conduction could be detected later and the serological tests established an underlying Lyme disease. Currently no definite treatment recommendation is available for the potentially reversible Lyme carditis. The tick bite seemed to be the key on our way to diagnosis; however, serological tests proved the disease to be older than one year. A detailed medical history and serological tests are essential in identifying the cause and pacemaker implantation can be avoided.

  2. Moyamoya disease in a child with previous acute necrotizing encephalopathy

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Taik-Kun; Cha, Sang Hoon; Chung, Kyoo Byung; Kim, Jung Hyuck; Kim, Baek Hyun; Chung, Hwan Hoon [Department of Diagnostic Radiology, Korea University College of Medicine, Ansan Hospital, 516 Kojan-Dong, Ansan City, Kyungki-Do 425-020 (Korea); Eun, Baik-Lin [Department of Pediatrics, Korea University College of Medicine, Seoul (Korea)

    2003-09-01

    A previously healthy 24-day-old boy presented with a 2-day history of fever and had a convulsion on the day of admission. MRI showed abnormal signal in the thalami, caudate nuclei and central white matter. Acute necrotising encephalopathy was diagnosed, other causes having been excluded after biochemical and haematological analysis of blood, urine and CSF. He recovered, but with spastic quadriparesis. At the age of 28 months, he suffered sudden deterioration of consciousness and motor weakness of his right limbs. MRI was consistent with an acute cerebrovascular accident. Angiography showed bilateral middle cerebral artery stenosis or frank occlusion with numerous lenticulostriate collateral vessels consistent with moyamoya disease. (orig.)

  3. Cerebrospinal fluid proteome of patients with acute Lyme disease.

    Science.gov (United States)

    Angel, Thomas E; Jacobs, Jon M; Smith, Robert P; Pasternack, Mark S; Elias, Susan; Gritsenko, Marina A; Shukla, Anil; Gilmore, Edward C; McCarthy, Carol; Camp, David G; Smith, Richard D; Warren, H Shaw

    2012-10-05

    During acute Lyme disease, bacteria can disseminate to the central nervous system (CNS), leading to the development of meningitis and other neurologic symptoms. Here we have analyzed pooled cerebrospinal fluid (CSF) allowing a deep view into the proteome for patients diagnosed with early disseminated Lyme disease and CSF inflammation. Additionally, we analyzed individual patient samples and quantified differences in protein abundance employing label-free quantitative mass spectrometry-based methods. We identified 108 proteins that differ significantly in abundance in patients with acute Lyme disease from controls. Comparison between infected patients and control subjects revealed differences in proteins in the CSF associated with cell death localized to brain synapses and others that likely originate from brain parenchyma.

  4. Recent developments in epigenetics of acute and chronic kidney diseases.

    Science.gov (United States)

    Reddy, Marpadga A; Natarajan, Rama

    2015-08-01

    The growing epidemic of obesity and diabetes, the aging population as well as prevalence of drug abuse has led to significant increases in the rates of the closely associated acute and chronic kidney diseases, including diabetic nephropathy. Furthermore, evidence shows that parental behavior and diet can affect the phenotype of subsequent generations via epigenetic transmission mechanisms. These data suggest a strong influence of the environment on disease susceptibility and that, apart from genetic susceptibility, epigenetic mechanisms need to be evaluated to gain critical new information about kidney diseases. Epigenetics is the study of processes that control gene expression and phenotype without alterations in the underlying DNA sequence. Epigenetic modifications, including cytosine DNA methylation and covalent post-translational modifications of histones in chromatin, are part of the epigenome, the interface between the stable genome and the variable environment. This dynamic epigenetic layer responds to external environmental cues to influence the expression of genes associated with disease states. The field of epigenetics has seen remarkable growth in the past few years with significant advances in basic biology, contributions to human disease, as well as epigenomics technologies. Further understanding of how the renal cell epigenome is altered by metabolic and other stimuli can yield novel new insights into the pathogenesis of kidney diseases. In this review, we have discussed the current knowledge on the role of epigenetic mechanisms (primarily DNAme and histone modifications) in acute and chronic kidney diseases, and their translational potential to identify much needed new therapies.

  5. Specific circulating immune complexes in acute chagas' disease

    Directory of Open Access Journals (Sweden)

    Ricardo Corral

    1987-02-01

    Full Text Available The presence of circulating immune complexes formed by IgM and IgG (CIC-IgM and CIC-IgG was investigated, using antigen-specific enzyme-immunoassays (ELISA, in 30 patients with acute Chagas' disease who showed parasitemia and inoculation chagoma. Control population consisted of patients with chronic T. cruzi infection (30, acute toxoplasmosis 10, leishmaniasis (8, rheumatoid arthritis (3 and healthy individuals with negative serology for Chagas* disease (30. Acute chagasic patients were 100% CIC-IgG and 96.66% CIC-IgM positive whereas immunofluorescence tests yielded 90% and 86.66% of positivity for specific IgG and IgM antibodies, respectively. Chronic patients were 68% CIC-IgG and 0% CIC-IgM positive. The 30 negative and the 21 cross-reaction controls proved negative for ELISA (CIC-IgM and CIC-IgG. The high sensitivity of ELISA assays would allow early immunologic diagnosis, as well as prompt treatment, of acute T. cruzi infection, thus eliminating the problem of the false-positive and false-negative results which affects traditional methods for detection of circulating antibodies.

  6. Hodgkin's disease and transplantation: a room with a (nontransplanter's) view.

    Science.gov (United States)

    Marshall, N A; DeVita, V T

    1999-02-01

    Hodgkin's disease is a malignancy curable by combination chemotherapy in newly diagnosed patients. Management of refractory disease or relapse has been unsatisfactory with salvage chemotherapy alone, although some patients with long initial remission can be cured with this approach. Because correlations between dose intensity and response to treatment in animal models and in clinical studies have been positive, high-dose chemotherapy (HDT) with bone marrow (BM) or peripheral blood stem-cell (PBSC) transplantation support has been used in an attempt to improve disease-free and overall survival in patients with refractory disease or relapse. Controversy exists over who and when to transplant. Results are difficult to interpret because of the heterogeneous nature of the patients under study and short follow-up times. In general, patient disease-free and overall survival appear to be improved with HDT and PBSC support when compared with historical controls. Allografting has also been tried in Hodgkin's disease as well, but is not recommended due to high associated mortality. Improvements in supportive care for transplantation in general, and antiviral and graft-versus-host disease prophylaxis in particular, have decreased early mortality associated with allografting in other malignancies, but not yet in Hodgkin's disease. The fact that allografted patients who survive the initial transplant procedure have an impressively lower relapse rate makes Hodgkin's disease patients potential candidates for future studies of allografting under more modern circumstances. Some suggestions are made about the introduction of new approaches to treatment.

  7. Type 2 Gaucher Disease (Acute Infantile Gaucher Disease or Neuropathic Type

    Directory of Open Access Journals (Sweden)

    Mohammad Mehdi TAGHDIRI

    2012-12-01

    Full Text Available How to Cite this Article: Taghdiri MM. Type 2 Gaucher Disease (Acute Infantile Gaucher Disease or Neuropathic Type. Iran J Child Neurol Autumn 2012; 6:4 (suppl. 1:12. Pls see PDF. 

  8. Role of anaerobes in acute pelvic inflammatory disease

    OpenAIRE

    2003-01-01

    Pouch of Douglas aspirates were collected from 50 women with history and examination suggestive of acute pelvic inflammatory disease (PID) and 20 healthy women admitted for tubal ligation served as control. A total of 57 microorganisms were isolated from 37 patients out of 50 in study group. Of 37 positive cultures 21(56.7%) were monomicrobial and 16(43.2%) were polymicrobial. Most common symptom in study group was lower abdominal pain (90%), vaginal discharge (70%...

  9. Muscle-specific kinase antibody associated myasthenia gravis after bone marrow transplantation.

    Science.gov (United States)

    Heidarzadeh, Zeinab; Mousavi, Seyyed-Asadollah; Ostovan, Vahid Reza; Nafissi, Shahriar

    2014-02-01

    Myasthenia gravis is a rare complication of bone marrow transplantation and graft versus host disease. We report a 30-year-old woman presented with oculobulbar and proximal limb weakness after allogeneic bone marrow transplantation for chronic myelogenous leukemia. Also, she developed graft versus host disease following bone marrow transplantation. Investigations led to the diagnosis of muscle specific kinase antibody related myasthenia gravis. There have been only two case reports of muscle specific kinase antibody positive myasthenia gravis after bone marrow transplantation in the literature, but none of the previously reported cases had graft versus host disease.

  10. Mesenchymal stem cells: potential in treatment of neurodegenerative diseases.

    Science.gov (United States)

    Tanna, Tanmay; Sachan, Vatsal

    2014-01-01

    Mesenchymal Stem Cells or Marrow Stromal Cells (MSCs) have long been viewed as a potent tool for regenerative cell therapy. MSCs are easily accessible from both healthy donor and patient tissue and expandable in vitro on a therapeutic scale without posing significant ethical or procedural problems. MSC based therapies have proven to be effective in preclinical studies for graft versus host disease, stroke, myocardial infarction, pulmonary fibrosis, autoimmune disorders and many other conditions and are currently undergoing clinical trials at a number of centers all over the world. MSCs are also being extensively researched as a therapeutic tool against neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD) and Multiple Sclerosis (MS). MSCs have been discussed with regard to two aspects in the context of neurodegenerative diseases: their ability to transdifferentiate into neural cells under specific conditions and their neuroprotective and immunomodulatory effects. When transplanted into the brain, MSCs produce neurotrophic and growth factors that protect and induce regeneration of damaged tissue. Additionally, MSCs have also been explored as gene delivery vehicles, for example being genetically engineered to over express glial-derived or brain-derived neurotrophic factor in the brain. Clinical trials involving MSCs are currently underway for MS, ALS, traumatic brain injuries, spinal cord injuries and stroke. In the present review, we explore the potential that MSCs hold with regard to the aforementioned neurodegenerative diseases and the current scenario with reference to the same.

  11. Postpartum Acute Pulmonary Oedema with Sub clinical Rheumatic Heart Disease.

    Science.gov (United States)

    R, Padmaja; Gande, Sri Krishna Padma Challa Rao

    2015-02-01

    Acute dyspnea with pulmonary oedema in postpartum is uncommon but life-threatening event. Contributing factors for pulmonary oedema include, administration of tocolytics, underlying cardiac disease, iatrogenic fluid overload and preeclampsia acounting 0.08% of pregnancies. Pulmonary embolism, amniotic fluid embolism, pneumonia, aspiration and pulmonary oedema are some of the potentially devastating conditions that should be considered by the attending physician. Here, we report a case of postpartum acute pulmonary oedema referred to causality after an emergency caesarean section in a private hospital. No matter what the underlying pathology, prompt administration and appropriate resuscitation is always the first priority. Only after the patient has been stabilized attention must be turned to diagnosis and specific treatment. A diagnosis of severe Mitral Stenosis, probably of rheumatic origin was made after stabilizing the patient.

  12. Acute Warfarin Toxicity as Initial Manifestation of Metastatic Liver Disease

    Directory of Open Access Journals (Sweden)

    Varalaxmi Bhavani Nannaka

    2016-01-01

    Full Text Available Near complete infiltration of the liver secondary to metastasis from the head and neck cancer is a rare occurrence. The prognosis of liver failure associated with malignant infiltration is extremely poor; the survival time of patients is extremely low. We present a case of acute warfarin toxicity as initial manifestation of metastatic liver disease. Our patient is a 64-year-old woman presenting with epigastric pain and discomfort, found to have unrecordable International Normalized Ratio. She rapidly deteriorated with acute respiratory failure requiring mechanical ventilation, profound shock requiring high dose vasopressor infusion, severe coagulopathy, worsening liver enzymes with worsening of lactic acidosis and severe metabolic abnormalities, and refractory to aggressive supportive care and died in less than 48 hours. Autopsy revealed that >90% of the liver was replaced by tumor masses.

  13. Cytomegalovirus Reactivation after Allogeneic Hematopoietic Stem Cell Transplantation is Associated with a Reduced Risk of Relapse in Patients with Acute Myeloid Leukemia Who Survived to Day 100 after Transplantation: The Japan Society for Hematopoietic Cell Transplantation Transplantation-related Complication Working Group.

    Science.gov (United States)

    Takenaka, Katsuto; Nishida, Tetsuya; Asano-Mori, Yuki; Oshima, Kumi; Ohashi, Kazuteru; Mori, Takehiko; Kanamori, Heiwa; Miyamura, Koichi; Kato, Chiaki; Kobayashi, Naoki; Uchida, Naoyuki; Nakamae, Hirohisa; Ichinohe, Tatsuo; Morishima, Yasuo; Suzuki, Ritsuro; Yamaguchi, Takuhiro; Fukuda, Takahiro

    2015-11-01

    Cytomegalovirus (CMV) infection is a major infectious complication after allogeneic hematopoietic cell transplantation (allo-HSCT). Recently, it was reported that CMV reactivation is associated with a decreased risk of relapse in patients with acute myeloid leukemia (AML). The aim of this study was to evaluate the impact of early CMV reactivation on the incidence of disease relapse after allo-HSCT in a large cohort of patients. The Japan Society for Hematopoietic Cell Transplantation's Transplantation-Related Complication Working Group retrospectively surveyed the database of the Transplant Registry Unified Management Program at the Japan Society for Hematopoietic Cell Transplantation. Patients with AML (n = 1836), acute lymphoblastic leukemia (ALL, n = 911), chronic myeloid leukemia (CML, n = 223), and myelodysplastic syndrome (MDS, n = 569) who underwent their first allo-HSCT from HLA-matched related or unrelated donors between 2000 and 2009 and who survived without disease relapse until day 100 after transplantation were analyzed. Patients who received umbilical cord blood transplantation were not included. Patients underwent surveillance by pp65 antigenemia from the time of engraftment, and the beginning of preemptive therapy was defined as CMV reactivation. Cox proportional hazards models were used to evaluate the risk factors of relapse, nonrelapse, and overall mortality. CMV reactivation and acute/chronic graft-versus-host disease (GVHD) were evaluated as time-dependent covariates. CMV reactivation was associated with a decreased incidence of relapse in patients with AML (20.3% versus 26.4%, P = .027), but not in patients with ALL, CML, or MDS. Among 1836 patients with AML, CMV reactivation occurred in 795 patients (43.3%) at a median of 42 days, and 436 patients (23.7%) relapsed at a median of 221 days after allo-HSCT. Acute GVHD grades II to IV developed in 630 patients (34.3%). By multivariate analysis considering competing risk factors, 3

  14. Color Doppler US in the acute scrotal disease

    Energy Technology Data Exchange (ETDEWEB)

    Cha, Yoo Mi; Yang, Dal Mo; Kang, Sook Wook; Kim, Hyung Sik; Lee, Young Seok; Kim, Hyeon Hoe [Chung Ang Gil Hospital, Incheon (Korea, Republic of)

    1993-12-15

    To evaluate the utility of Color doppler US in the patients with acute scrotal pain, we retrospectively analyzed 37 patients referred for Color Doppler US of the scrotum. The diagnosis was confirmed by means of appropriate response to antibiotic treatment (31 cases) or surgery (6 cases). Thirty one of 37 patients were diagnosed as inflammatory disease (24 cases of epididymitis, 7 cases of epididymo-orchitis). Twenty three of 24cases of epididymitis had increased epididymal flow, while 6 of 7 cases of epididymo-orchitis had increased epididymal and testicular flow. Five patients were confirmed as testicular torsion, and in all cases nointratesticular blood flow was identified on the symptomatic side. In one case of torsion of appendix testis, epididymis was enlarged and there were increased signals suggesting epididymitis on Color Doppler US, but was confirmed by surgery as torsion of appendix testis. Therefore, the differentiation between torsion and inflammatory disease was possible by using Color Doppler US of the scrotum in 34 of 37 cases in our study. On the basis of our results, we may conclude that Color Doppler US can simultaneously display blood flow and detailed anatomic images, and function as an effective means of evaluating patients with acute scrotal disease

  15. Lithium-induced minimal change disease and acute kidney injury

    Directory of Open Access Journals (Sweden)

    Parul Tandon

    2015-01-01

    Full Text Available Context: Lithium carbonate is a psychiatric medication commonly used in the treatment of bipolar disorder. It has been implicated in inducing nephrogenic diabetes inspidus, chronic tubulointerstitial nephropathy, and acute tubular necrosis. We describe a case of lithium-induced minimal change disease (MCD and acute kidney injury (AKI. Case Report: A 32-year-old female with a medical history of bipolar disorder treated with chronic lithium therapy presented with anasarca, fatigue, and tremors. Work-up revealed supra-therapeutic lithium levels, hypoalbuminemia, and significant proteinuria. The patient was treated conservatively with fluids and discontinuation of lithium therapy. Subsequently, she developed significant AKI and persistent proteinuria. She underwent a renal biopsy that demonstrated effacement of podocyte foot processes consistent with lithium-induced MCD. This was treated with corticosteroids, which decreased the proteinuria and resolved all the patient′s symptoms. Conclusion: Lithium-induced MCD is a rare disease that affects patients of all ages. It is often associated with therapeutic lithium and is typically resolved with discontinuation of lithium. In some cases, concurrent AKI may result due to vascular obstruction from hyperalbuminuria and associated renal interstitial edema. Corticosteroids may be needed to reduce the proteinuria and prevent progression to chronic kidney disease. As such, patients on lithium therapy may benefit from monitoring of glomerular function via urinalysis to prevent the onset of nephrotic syndrome.

  16. Acute Limb Ischemia and Coronary Artery Disease in a Case of Kimura’s Disease

    Science.gov (United States)

    Heo, Woon; Jun, Hee Jae; Kang, Do Kyun; Min, Ho-Ki; Hwang, Youn-Ho; Kim, Ji Yong; Nam, Kyung Han

    2017-01-01

    Kimura disease (KD) is an immune-mediated chronic inflammatory disease of unknown etiology. KD has many complications associated with hypereosinophilia, including various forms of allergic reactions and eosinophilic lung disease. Additionally, hypereosinophilia is associated with hypercoagulability, which may lead to thromboembolic events. A 36-year-old man with KD presented with acute limb ischemia and coronary artery occlusion. He underwent thrombectomy, partial endarterectomy of both popliteal arteries, and coronary artery stent insertion. KD is a systemic disease that affects many organs and presents with thromboembolism and vasculitis. In a patient with KD, physicians should evaluate the vascular system, including the coronary arteries. PMID:28382271

  17. Relationship Between Periodontal Disease and Acute Myocardial Infarction

    Directory of Open Access Journals (Sweden)

    M Zamirian

    2008-07-01

    Full Text Available Background: Conventional risk factors for coronary artery disease and myocardial infarction do not explain all of the clinical and epidemiological features of the disease. Periodontal disease is a common bacterial and destructive disorder of oral tissues. Many studies demonstrate close association between chronic periodontitis and development of generalized inflammation, vascular endothelial injury, and atherosclesis. Periodontal disease has been convincingly emerging as an important independent risk factor for ischemic heart disease. A case - control study was carried out to assess the prevalence of periodontitis in patients with Acute myocardial Infarction (AMI and evaluate the possible relationship between AMI and chronic periodontitis. Patients and Methods: A number of 160 patients, aged 35 to 70 years old, enrolled in the study. Eighty patients (43 men, 37 women were examined four days after hospitalization due to AMI. Control group consisted of 80 persons (38 men, 42 women with normal coronary angiography. The following periodontal parameters were examined: Plaque index (PI, gingiral index (GI, bleeding on probing (BOP, probing depth (PD, clinical attachment loss (CAL and number of sites with CAL.Results: The case, compared to control showed significantly worse results for some periodontal variables studied: The mean of PD and PD > 3 mm, CAL, and number of sites with CAL, had worse results compared to control despite similar oral hygiene and frequency of brushing. The confounding factors for the present study were found to be hypertension and diabetes. Conclusion: The association between periodontitis and acute myocardial infarction was significant after adjusting for conventional risk factors for AMI.

  18. Role of anaerobes in acute pelvic inflammatory disease

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    Saini S

    2003-01-01

    Full Text Available Pouch of Douglas aspirates were collected from 50 women with history and examination suggestive of acute pelvic inflammatory disease (PID and 20 healthy women admitted for tubal ligation served as control. A total of 57 microorganisms were isolated from 37 patients out of 50 in study group. Of 37 positive cultures 21(56.7% were monomicrobial and 16(43.2% were polymicrobial. Most common symptom in study group was lower abdominal pain (90%, vaginal discharge (70% and irregular bleeding (40% and 30% patients had history of intrauterine contraceptive device (IUCD implantation. The predominant aerobic isolates were Escherichia coli, Coagulase Negative Staphylococcus (CONS, Staphylococcus aureus, Klebsiella pneumoniae while common anaerobes were Bacteroides fragilis, Prevotella melaninogenica, Fusobacterium nucleatum and Peptostreptococcus spp. Our study shows that cefotaxime, cefuroxime and gentamicin may be used for gram negative aerobic bacilli; cloxacillin, cephaloridine and erythromycin for aerobic gram positive cocci and amikacin and ceftazidime for Pseudomonas aeruginosa. Thus for optimum therapy of acute PID it is beneficial to keep in mind major conceptual changes and therapeutic realities that have influenced current understanding of acute PID and have affected the choice of therapy.

  19. Role of anaerobes in acute pelvic inflammatory disease.

    Science.gov (United States)

    Saini, S; Gupta, N; Batra, G; Arora, D R

    2003-01-01

    Pouch of Douglas aspirates were collected from 50 women with history and examination suggestive of acute pelvic inflammatory disease (PID) and 20 healthy women admitted for tubal ligation served as control. A total of 57 microorganisms were isolated from 37 patients out of 50 in study group. Of 37 positive cultures 21(56.7%) were monomicrobial and 16(43.2%) were polymicrobial. Most common symptom in study group was lower abdominal pain (90%), vaginal discharge (70%) and irregular bleeding (40%) and 30% patients had history of intrauterine contraceptive device (IUCD) implantation. The predominant aerobic isolates were Escherichia coli, Coagulase Negative Staphylococcus (CONS), Staphylococcus aureus, Klebsiella pneumoniae while common anaerobes were Bacteroides fragilis, Prevotella melaninogenica, Fusobacterium nucleatum and Peptostreptococcus spp. Our study shows that cefotaxime, cefuroxime and gentamicin may be used for gram negative aerobic bacilli; cloxacillin, cephaloridine and erythromycin for aerobic gram positive cocci and amikacin and ceftazidime for Pseudomonas aeruginosa. Thus for optimum therapy of acute PID it is beneficial to keep in mind major conceptual changes and therapeutic realities that have influenced current understanding of acute PID and have affected the choice of therapy.

  20. Pulmonary Surfactants for Acute and Chronic Lung Diseases (Part II

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    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.

  1. Acute Chagas disease in El Salvador 2000-2012 - Need for surveillance and control

    OpenAIRE

    Emi Sasagawa; Ana Vilma Guevara de Aguilar; Marta Alicia Hernández de Ramírez; José Eduardo Romero Chévez; Jun Nakagawa; Rafael Antonio Cedillos; Kiyoshi Kita

    2014-01-01

    Several parasitological studies carried out in El Salvador between 2000-2012 showed a higher frequency of acute cases of Chagas disease than that in other Central American countries. There is an urgent need for improved Chagas disease surveillance and vector control programs in the provinces where acute Chagas disease occurs and throughout El Salvador as a whole.

  2. Mesenchymal stem cells for the treatment of neurodegenerative disease.

    Science.gov (United States)

    Joyce, Nanette; Annett, Geralyn; Wirthlin, Louisa; Olson, Scott; Bauer, Gerhard; Nolta, Jan A

    2010-11-01

    Mesenchymal stem cells/marrow stromal cells (MSCs) present a promising tool for cell therapy, and are currently being tested in US FDA-approved clinical trials for myocardial infarction, stroke, meniscus injury, limb ischemia, graft-versus-host disease and autoimmune disorders. They have been extensively tested and proven effective in preclinical studies for these and many other disorders. There is currently a great deal of interest in the use of MSCs to treat neurodegenerative diseases, in particular for those that are fatal and difficult to treat, such as Huntington's disease and amyotrophic lateral sclerosis. Proposed regenerative approaches to neurological diseases using MSCs include cell therapies in which cells are delivered via intracerebral or intrathecal injection. Upon transplantation into the brain, MSCs promote endogenous neuronal growth, decrease apoptosis, reduce levels of free radicals, encourage synaptic connection from damaged neurons and regulate inflammation, primarily through paracrine actions. MSCs transplanted into the brain have been demonstrated to promote functional recovery by producing trophic factors that induce survival and regeneration of host neurons. Therapies will capitalize on the innate trophic support from MSCs or on augmented growth factor support, such as delivering brain-derived neurotrophic factor or glial-derived neurotrophic factor into the brain to support injured neurons, using genetically engineered MSCs as the delivery vehicles. Clinical trials for MSC injection into the CNS to treat traumatic brain injury and stroke are currently ongoing. The current data in support of applying MSC-based cellular therapies to the treatment of neurodegenerative disorders are discussed.

  3. Acute erythroid leukemia: autopsy report of a rare disease

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    Cristiane Rúbia Ferreira

    2011-12-01

    Full Text Available Acute erythroid leukemia (AEL is a rare subtype of acute myeloid leukemia(AML, characterized by predominant erythroid proliferation. The 2008 WorldHealth Organization (WHO classification of AML defined two AEL subtypes:erythroleukaemia (EL, in which erythroid precursors account for 50% or moreof all nucleated bone marrow cells and myeloblasts account for 20% or more ofthe nonerythroid cell population; and pure erythroid leukemia (PEL, in whicherythroid precursors account for 80% or more of all nucleated bone marrowcells. We report the case of an elderly female patient with wasting syndromeand pancytopenia without evidence of blasts in peripheral blood. A diagnosisof PEL was established on the basis of bone marrow biopsy findings. Thepatient died on postadmission day 20, and an autopsy was performed. Wereclassified the disease as EL on the basis of the autopsy findings, whichincluded myeloblasts accounting for more than 20% of the nonerythroid cellsin the bone marrow, as well as leukemic infiltration and myeloid metaplasia insolid organs, such as the liver, spleen, kidneys, adrenal glands, and abdominallymph nodes. A rare disease, AEL accounts for less than 5% of all AMLs and ispractically a diagnosis of exclusion. Autopsy reports of AEL are extremely rarein the literature. We demonstrate that in the case reported here, leukemia cellstended to infiltrate solid organs with myeloid metaplasia. Our findings alsoshow that a larger neoplastic bone marrow sample is crucial to the correctdiagnosis of EL, which is based on morphological and quantitative criteria.

  4. Endothelial to Mesenchymal Transition (EndoMT in the Pathogenesis of Human Fibrotic Diseases

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    Sonsoles Piera-Velazquez

    2016-04-01

    Full Text Available Fibrotic diseases encompass a wide spectrum of clinical entities including systemic fibrotic diseases such as systemic sclerosis, sclerodermatous graft versus host disease, nephrogenic systemic fibrosis, and IgG4-associated sclerosing disease, as well as numerous organ-specific disorders including radiation-induced fibrosis, and cardiac, pulmonary, liver, and kidney fibrosis. Although their causative mechanisms are quite diverse, these diseases share the common feature of an uncontrolled and progressive accumulation of fibrous tissue macromolecules in affected organs leading to their dysfunction and ultimate failure. The pathogenesis of fibrotic diseases is complex and despite extensive investigation has remained elusive. Numerous studies have identified myofibroblasts as the cells responsible for the establishment and progression of the fibrotic process. Tissue myofibroblasts in fibrotic diseases originate from several sources including quiescent tissue fibroblasts, circulating CD34+ fibrocytes, and the phenotypic conversion of various cell types including epithelial and endothelial cells into activated myofibroblasts. However, the role of the phenotypic transition of endothelial cells into mesenchymal cells (Endothelial to Mesenchymal Transition or EndoMT in the pathogenesis of fibrotic disorders has not been fully elucidated. Here, we review the evidence supporting EndoMT’s contribution to human fibrotic disease pathogenesis.

  5. Endothelial to Mesenchymal Transition (EndoMT) in the Pathogenesis of Human Fibrotic Diseases

    Science.gov (United States)

    Piera-Velazquez, Sonsoles; Mendoza, Fabian A.; Jimenez, Sergio A.

    2016-01-01

    Fibrotic diseases encompass a wide spectrum of clinical entities including systemic fibrotic diseases such as systemic sclerosis, sclerodermatous graft versus host disease, nephrogenic systemic fibrosis, and IgG4-associated sclerosing disease, as well as numerous organ-specific disorders including radiation-induced fibrosis, and cardiac, pulmonary, liver, and kidney fibrosis. Although their causative mechanisms are quite diverse, these diseases share the common feature of an uncontrolled and progressive accumulation of fibrous tissue macromolecules in affected organs leading to their dysfunction and ultimate failure. The pathogenesis of fibrotic diseases is complex and despite extensive investigation has remained elusive. Numerous studies have identified myofibroblasts as the cells responsible for the establishment and progression of the fibrotic process. Tissue myofibroblasts in fibrotic diseases originate from several sources including quiescent tissue fibroblasts, circulating CD34+ fibrocytes, and the phenotypic conversion of various cell types including epithelial and endothelial cells into activated myofibroblasts. However, the role of the phenotypic transition of endothelial cells into mesenchymal cells (Endothelial to Mesenchymal Transition or EndoMT) in the pathogenesis of fibrotic disorders has not been fully elucidated. Here, we review the evidence supporting EndoMT’s contribution to human fibrotic disease pathogenesis. PMID:27077889

  6. Cognitive function in the acute course of allogeneic hematopoietic stem cell transplantation for hematological malignancies.

    Science.gov (United States)

    Schulz-Kindermann, F; Mehnert, A; Scherwath, A; Schirmer, L; Schleimer, B; Zander, A R; Koch, U

    2007-06-01

    The aim of the study was to assess cognitive performance in patients with hematological malignancies before, and 3 months after, allogeneic hematopoietic stem cell transplant (HSCT). A consecutive sample of 39 patients was assessed before admission with a comprehensive neuropsychological test battery and health-related quality-of-life (HRQoL) questionnaires; 19 of these patients were retested around 100 days post HSCT. Test results were compared with normative data and revealed minimal differences at both time points in the level of group-means. One parameter - simple reaction time - was significantly worse (prolonged) at second measurement after HSCT. According to the definition of an impairment score (more than three impaired functions), 26% of patients were classified as impaired before as well as after HSCT. Neuropsychological test results did not vary systematically according to medical variables such as extent of pretreatment, graft-versus-host-disease (GvHD) and kind of conditioning protocol. As a dimension of HRQoL, self-rated cognitive function was in the normal range before and after HSCT. Significant correlations between HRQoL and neuropsychological parameters were related to symptom scales. This study showed impairments of neuropsychological performance for a subgroup of patients before and after allogeneic HSCT. Systematic effects of conditioning, medical variables or self-rated HRQoL could not be observed.

  7. Detection of acute hepatopancreatic necrosis disease (AHPND) in Mexico.

    Science.gov (United States)

    Nunan, Linda; Lightner, Donald; Pantoja, Carlos; Gomez-Jimenez, Silvia

    2014-08-21

    Acute hepatopancreatic necrosis disease (AHPND), which has also been referred to as early mortality syndrome (EMS), initially emerged as a destructive disease of cultured shrimp species in Asia in 2009. The pathogen associated with the disease, Vibrio parahaemolyticus, subsequently spread to the Western Hemisphere and emerged in Mexico in early 2013. The spread to the Western Hemisphere is a major concern to shrimp producers in the region. To date, the only peer-reviewed published method for determining whether mortalities are due to AHPND is through histological examination. A novel PCR detection method was employed to assess samples from Mexico in order to confirm the presence of the pathogen in this country. This manuscript details the detection methods used to confirm the presence of AHPND in Mexico. Both immersion and per os challenge studies were used to expose the Penaeus vannamei to the bacteria in order to induce the disease. Histological analysis confirmed AHPND status following the challenge studies. Also provided are the details of the molecular test by PCR that was used for screening candidate V. parahaemolyticus isolates. A rapid PCR assay for detection of AHPND may help with early detection and help prevent the spread of AHPND to other countries.

  8. Langerhans cells and their role in oral mucosal diseases

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    Juhi Upadhyay

    2013-01-01

    Full Text Available Dendritic cells are arguably the most potent antigen-presenting cells and may be the only cells capable of initiating the adaptive immune response. The epithelial residents of dendritic cells are Langerhans cells, which serve as the "sentinels" of the mucosa, altering the immune system not only to pathogen entry but also of tolerance to self antigen and commensal microbes. Oral mucosal Langerhans cells are capable of engaging and internalizing a wide variety of pathogens and have been found responsive to nickel in patients with nickel allergies, oral Candida species, oral lichen planus, lichenoid drug eruptions, graft versus host diseases, periodontal diseases median rhomboid glossitis, human immunodeficiency virus infection, hairy leukoplakia of the tongue, and oral squamous cell carcinoma. Review focuses on the role of antigen-presenting cells in particular Langerhans cells to better understand the mechanisms underlying immune responses. In this review, comprehensive detail about mucosal diseases has been compiled using the PubMed database and through textbooks.

  9. Allogeneic hematopoietic stem cell transplantation for chronic myelomonocytic leukemia:a report of 12 patients

    Institute of Scientific and Technical Information of China (English)

    孙于谦

    2013-01-01

    Objective To retrospectively review the efficacy of allogeneic hematopoietic stem cell transplantation(allo-HSCT)for chronic myelomonocytic leukemia(CMML).Methods The engraftment,graft versus host disease(GVHD)

  10. Frequency analysis of TRBV subfamily sjTRECs to characterize T-cell reconstitution in acute leukemia patients after allogeneic hematopoietic stem cell transplantation

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    Yang Lijian

    2011-04-01

    Full Text Available Abstract Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT leads to a prolonged state of immunodeficiency and requires reconstitution of normal T-cell immunity. Signal joint T-cell receptor excision DNA circles (sjTRECs are markers of developmental proximity to the thymus that have been used to evaluate thymic function related to T-cell immune reconstitution after HSCT. To assess the proliferative history in different T-cell receptor beta variable region (TRBV subfamilies of T cells after HSCT, expansion of TRBV subfamily-naive T cells was determined by analysis of a series of TRBV-BD1 sjTRECs. Methods sjTRECs levels were detected by real-time quantitative polymerase chain reaction (PCR in peripheral blood mononuclear cells (PBMCs from 43 Chinese acute leukemia patients who underwent allo-HSCT. Twenty-three TRBV-BD1 sjTRECs were amplified by semi-nested PCR. Sixteen age-matched healthy volunteers served as normal controls. Results sjTRECs levels were low or undetectable in the first 6 weeks after allo-HSCT and increased after 8 weeks post HSCT; however, sjTRECs levels at week 20 post-HSCT were still less than normal controls. Frequencies of TRBV subfamily sjTRECs in PBMCs from recipients at week 8 post-HSCT (29.17 ± 20.97% or at week 16 post-HSCT (38.33 ± 9.03% were significantly lower than those in donors (47.92 ± 13.82% or recipients at pre-HSCT (45.83 ± 14.03%. However, frequencies of TRBV subfamily sjTRECs in recipients at week 30 post-HSCT (42.71 ± 21.62% were similar to those in donors and recipients at pre-HSCT. sjTRECs levels in donors had a positive linear correlation with sjTRECs levels in recipients within 8-12 weeks post-HSCT. Patients with acute graft-versus-host disease (GVHD or chronic GVHD had profoundly reduced TRECs levels during the first year post-HSCT. Frequencies of BV22-BD1 sjTRECs and BV23-BD1 sjTRECs in patients with GVHD were significantly lower than those in recipients at pre-HSCT, and the

  11. Recurrent myelitis after allogeneic stem cell transplantation. Report of two cases

    Directory of Open Access Journals (Sweden)

    Voß Martin

    2010-09-01

    Full Text Available Abstract Background Allogeneic and autologous haematopoietic stem cell transplantation are established treatment options for haematological malignancies and may possibly be employed to treat a range of genetic and autoimmune diseases. Case presentation We report two patients who developed an acute myelitis within their thoracic spinal cord after allogeneic stem cell transplantation. Myelitis in these patients was not related to graft versus host disease or immune reconstitution and was responsive to intravenous methylprednisolone and cyclophosphamide. Conclusions Myelitis is a possibly disabling consequence of haematopoietic stem cell transplantation.

  12. [Acute