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Sample records for acute graft-versus-host disease

  1. Intestinal acute graft versus host disease

    Rovani, C; Danse, E; Dragean, C

    2010-01-01

    Background: We present a case of a 23-year-old man having drug addiction. He is managed by the department of hematology for an idiopathic medullar aplasia. Two months before his admission, he was treated with bone marrow transplantation. During follow-up, we noted a nonspecific recent cutaneous lesion. He was admitted for acute digestive symptoms including anorexia, nausea, vomiting and abdominal pain.

  2. Pathogenic mechanisms of Acute Graft versus Host Disease

    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. Cyclosporine and methotrexate-related pharmacogenomic predictors of acute graft-versus-host disease.

    Laverdière, Isabelle; Guillemette, Chantal; Tamouza, Ryad; Loiseau, Pascale; Peffault de Latour, Regis; Robin, Marie; Couture, Félix; Filion, Alain; Lalancette, Marc; Tourancheau, Alan; Charron, Dominique; Socié, Gérard; Lévesque, Éric

    2015-02-01

    Effective immunosuppression is mandatory to prevent graft-versus-host disease and to achieve a successful clinical outcome of hematopoietic stem cell transplantation. Here we tested whether germline single nucleotide polymorphisms in 20 candidate genes related to methotrexate and cyclosporine metabolism and activity influence the incidence of graft-versus-host disease in patients who undergo stem cell transplantation for hematologic disorders. Recipient genetic status of the adenosine triphosphate-binding cassette sub-family C1 and adenosine triphosphate-binding cassette sub-family C2 transporters, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/ inosine monophosphate cyclohydrolase within the methotrexate pathway, and nuclear factor of activated T cells (cytoplasmic 1) loci exhibit a remarkable influence on severe acute graft-versus-host disease prevalence. Indeed, an increased risk of acute graft-versus-host disease was observed in association with single nucleotide polymorphisms located in 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (hazard ratio=3.04; P=0.002), nuclear factor of activated T cells (cytoplasmic 1) (hazard ratio=2.69; P=0.004), adenosine triphosphate-binding cassette sub-family C2 (hazard ratio=3.53; P=0.0018) and adenosine triphosphate-binding cassette sub-family C1 (hazard ratio=3.67; P=0.0005). While donor single nucleotide polymorphisms of dihydrofolate reductase and solute carrier family 19 (member 1) genes are associated with a reduced risk of acute graft-versus-host disease (hazard ratio=0.32-0.41; P=0.0009-0.008), those of nuclear factor of activated T cells (cytoplasmic 2) are found to increase such risk (hazard ratio=3.85; P=0.0004). None of the tested single nucleotide polymorphisms was associated with the occurrence of chronic graft-versus-host disease. In conclusion, by targeting drug-related biologically relevant genes, this work emphasizes the potential role of

  4. Etanercept for steroid-refractory acute graft versus host disease following allogeneic hematopoietic stem cell transplantation

    Park, Joo Han; Lee, Hyo Jung; Kim, Sei Rhan; Song, Ga Won; Lee, Seung Kyong; Park, Sun Young; Kim, Ki Chan; Hwang, Sun Hyuk; Park, Joon Seong

    2014-01-01

    Background/Aims The treatment for steroid-refractory acute graft versus host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT) needs to be standardized. We report our clinical experience with etanercept for steroid-refractory acute GVHD. Methods Eighteen patients who underwent allo-SCT and presented with steroid-refractory acute GVHD at Ajou University Hospital were studied retrospectively. They were given 25 mg of etanercept subcutaneously twice weekly for 4 weeks. The cli...

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

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

  6. Endothelial-cell injury in cutaneous acute graft-versus-host disease.

    Dumler, J S; Beschorner, W. E.; Farmer, E R; Di Gennaro, K. A.; Saral, R; Santos, G. W.

    1989-01-01

    The presence of an erythematous skin rash and hemorrhagic complications in acute graft-versus-host disease (GVHD) suggest that the vasculature may be involved in the immunopathologic process. We reviewed endothelial and vascular histopathologic changes on light microscopy and on immunoperoxidase stained sections of skin biopsies obtained from 41 HLA-identical allogeneic marrow transplant recipients with at least grade 2 GVHD. Biopsies taken from 14 allogeneic HLA-identical bone marrow transpl...

  7. Pathophysiology, prevention, and treatment of acute graft-versus-host disease

    Abhinav Deol; Voravit Ratanatharathorn; Uberti, Joseph P.

    2011-01-01

    Abhinav Deol, Voravit Ratanatharathorn, Joseph P UbertiDepartment of Oncology, Blood and Marrow Stem Cell Transplant Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USAAbstract: Acute graft-versus-host disease (aGVHD) is an immunologically mediated inflammatory reaction, which continues to be a major cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplant. Although the occurrence and severity...

  8. IMMUNOBIOLOGY OF ACUTE GRAFT-VERSUS-HOST DISEASE

    G. A. Efimov

    2016-01-01

    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.

  9. Immune Mechanisms of Mesenchymal Stem Cell Therapy for Acute Graft versus Host Disease

    Tobin, Laura M.

    2012-01-01

    The aim of this work was to investigate the role of Mesenchymal stem cells (MSC) in the modulation of immune responses, focusing on suppression and induction of immune tolerance. To date, MSC therapy has proved beneficial for the treatment of inflammatory and autoimmune diseases, such as acute Graft versus Host Disease (aGvHD) and Crohn’s disease. However, the exact mechanisms of therapeutic benefit remain unclear. The key goals of this study were to identify the role of MSC derived soluble a...

  10. Pathophysiology, prevention, and treatment of acute graft-versus-host disease

    Abhinav Deol

    2011-03-01

    Full Text Available Abhinav Deol, Voravit Ratanatharathorn, Joseph P UbertiDepartment of Oncology, Blood and Marrow Stem Cell Transplant Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USAAbstract: Acute graft-versus-host disease (aGVHD is an immunologically mediated inflammatory reaction, which continues to be a major cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplant. Although the occurrence and severity of this disease may be devastating, there is a proven immunologically mediated antitumor activity that accompanies the disease process, which has a beneficial effect on outcome. Animal models of graft-versus-host disease (GVHD have given us a conceptual model that has allowed a better understanding of the pathophysiology and offers a framework for understanding the complex interactions between antigen-presenting cells, donor T-cells, and cytokines in the development of aGVHD. It has also given us a model that allows testing of various strategies for prevention and treatment. New, innovative approaches for treatment and prevention of aGVHD including better donor selection with the use of sophisticated human leukocyte antigen typing, use of T-cell depletion, reduced-intensity transplant regimens, and improved pharmacologic immunosuppression have improved outcomes by decreasing the incidence and severity of aGVHD. However, the limitation of these strategies is that effective treatment and prevention of aGVHD is often accompanied by a concomitant rise in relapses, graft failure and infections, and ultimately no improvement in overall survival. Investigators are working on understanding the difference between GVHD and graft versus tumor effect, as this would be the key in improving outcomes for our patients. In this review, we will discuss the pathophysiology of aGVHD along with the preventative and treatment strategies.Keywords: acute GVHD, GVHD, acute graft-versus-host

  11. Pharmacologic prophylaxis regimens for acute graft-versus-host disease: past, present and future.

    Ram, Ron; Storb, Rainer

    2013-08-01

    Abstract Acute graft-versus-host disease (GVHD) has compromised and continues to compromise the benefits associated with allogeneic hematopoietic cell transplant to cure malignant and non-malignant diseases. Pharmacologic interventions to prevent GVHD have emerged as a major objective of research in the immunology and transplant fields. A better understanding of the pathobiology behind the GVHD process has led the way to novel approaches and medications. Here we review the present arsenal of medications used to prevent GVHD, focusing on past experience and the current evidence, and discuss future potential targets. PMID:23278640

  12. Cyclosporine and methotrexate-related pharmacogenomic predictors of acute graft-versus-host disease

    Laverdière, Isabelle; Guillemette, Chantal; Tamouza, Ryad; Loiseau, Pascale; de Latour, Regis Peffault; Robin, Marie; Couture, Félix; Filion, Alain; Lalancette, Marc; Tourancheau, Alan; Charron, Dominique; Socié, Gérard; Lévesque, Éric

    2015-01-01

    Effective immunosuppression is mandatory to prevent graft-versus-host disease and to achieve a successful clinical outcome of hematopoietic stem cell transplantation. Here we tested whether germline single nucleotide polymorphisms in 20 candidate genes related to methotrexate and cyclosporine metabolism and activity influence the incidence of graft-versus-host disease in patients who undergo stem cell transplantation for hematologic disorders. Recipient genetic status of the adenosine triphos...

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

    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.

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

    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...

  15. The Role of Intestinal Microbiota in Acute Graft-versus-Host Disease

    Yuanyuan Chen

    2015-01-01

    Full Text Available The mammalian intestinal microbiota is a complex ecosystem that plays an important role in host immune responses. Recent studies have demonstrated that alterations in intestinal microbiota composition are linked to multiple inflammatory diseases in humans, including acute graft-versus-host disease (aGVHD. aGVHD is one of the major obstacles in allogeneic hematopoietic stem cell transplantation (allo-HSCT, characterized by tissue damage in the gastrointestinal (GI tract, liver, lung, and skin. Here, we review the current understanding of the role of intestinal microbiota in the control of immune responses during aGVHD. Additionally, the possibility of using probiotic strains for potential treatment or prevention of aGVHD will be discussed.

  16. Endothelial-cell injury in cutaneous acute graft-versus-host disease.

    Dumler, J. S.; Beschorner, W. E.; Farmer, E. R.; Di Gennaro, K. A.; Saral, R.; Santos, G. W.

    1989-01-01

    The presence of an erythematous skin rash and hemorrhagic complications in acute graft-versus-host disease (GVHD) suggest that the vasculature may be involved in the immunopathologic process. We reviewed endothelial and vascular histopathologic changes on light microscopy and on immunoperoxidase stained sections of skin biopsies obtained from 41 HLA-identical allogeneic marrow transplant recipients with at least grade 2 GVHD. Biopsies taken from 14 allogeneic HLA-identical bone marrow transplant recipients who never developed GVHD were used as controls. Sections were evaluated for evidence of immunologic vascular injury using the rank file analysis of histologic features, expression of HLA-DR antigen, and the distribution of fibrin and factor VIII-related antigen (F VIII RAg). Patients with acute GVHD had significantly greater intimal lymphocytic infiltrates, perivascular nuclear dust deposition, perivascular F VIII Rag extravasation and deposition and vascular proliferation than controls. We find significantly greater endothelial injury in GVHD patients, which may represent primary immunologic injury to the vasculature. The clinical findings in acute GVHD probably result from cumulative endothelial as well as epithelial injury. Images Figure 1 Figure 2 Figure 3 PMID:2596572

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

    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. PMID:25455279

  18. An acute graft-versus-host disease activity index to predict survival after hematopoietic cell transplantation with myeloablative conditioning regimens

    Leisenring, Wendy M.; Martin, Paul J.; Petersdorf, Effie W.; Regan, Anne E.; Aboulhosn, Nada; Stern, Jean M.; Aker, Saundra N.; Salazar, Raymond C.; McDonald, George B.

    2006-01-01

    Algorithms for grading acute graft-versus-host disease (GVHD) are inaccurate in assessing mortality risk. We developed a method to predict mortality by using data from 386 patients with acute GVHD. From the onset of GVHD to day 100, GVHD manifestations were scored for the skin, liver, and upper and lower gastrointestinal tract, and data were recorded for immunosuppressive treatment, performance, and fever. Logistic regression models predicting nonrelapse mortality (NRM) at day 200 were develo...

  19. Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect

    Reddy, Pavan; Maeda,Yoshinobu; Hotary, Kevin; Liu, Chen; Reznikov, Leonid L.; Dinarello, Charles A.; Ferrara, James L.M.

    2004-01-01

    Acute graft-versus-host disease (GVHD) and leukemic relapse are the two major obstacles to successful outcomes after allogeneic bone marrow transplantation (BMT), an effective therapy for hematological malignancies. Several studies have demonstrated that the dysregulation of proinflammatory cytokines and the loss of gastrointestinal tract integrity contribute to GVHD, whereas the donor cytotoxic responses are critical for graft-versus-leukemia (GVL) preservation. Suberoylanilide hydroxamic ac...

  20. MR findings of acute graft-versus-host disease involving gastrointestinal tracts

    To evaluate the MR findings of gastrointestinal graft-versus-host disease (GVHD) after allogenic bone marrow transplantation. Five patients (M:F=3:2, age range: 9-58 years) with suspected gastrointestinal GVHD underwent abdominal MRI, and the findings were evaluated. Because of acute myelocytic leukemia (n=4) or non-Hodgkin's lymphoma (n=1), all had undergone allogenic bone marrow transplantation 2-6 (mean, 3.5) weeks earlier. T2-weighted half-fourier acquisition snapshot turbo spin-echo, T1-weighted spoiled gradient-echo (SGE), and postcontrast T1-weighted SGE MR imaging, with and without fat-suppression, was performed. All five patients showed bowel wall thickening and marked contrast enhancement in the jejunum (n=5), ileum (n=4), duodenum (n=3), sigmoid colon (n=3), gastric antrum (n=2), and rectum (n=2). Bowel wall thickening showed a target appearance in the jejunum (n=2, 40.4%), lieum (n=1, 25.0%), sigmoid colon (n=1, 33.3%), and rectum (n=1, 50.0%), while the remaining cases showed diffuse wall thickening without layering. Small amount of ascites was noted in four patients (80%), and multiple small conglomerated retroperitoneal lymph nodes in three (60%). In all patients, a signal intensity of slightly enlarged liver due to iron overload secondary to multiple blood transfusions, gave rise to decreased signal intensity at both T1- and T2-weighted MR imaging. In patients with GVHD, the commonly noted MR findings were bowel was thickening with contrast enhancement, ascites and retroperitoneal lymphadenopathy

  1. Follicular Mucinosis in a Male Adolescent with a History of Acute Myelogenous Leukemia and Graft-versus-Host Disease.

    Jefferson, Julie; Taube, Janis; Grossberg, Anna

    2016-01-01

    Although many cases of follicular mucinosis are idiopathic, numerous others are associated with mycosis fungoides or, rarely, other neoplastic or inflammatory disorders. There are only three reported cases, all in adults, of follicular mucinosis arising in association with acute myelogenous leukemia, two of which involved mycosis fungoides-associated follicular mucinosis, including one case in which the patient had a preceding bone marrow transplant. We present the first reported case of follicular mucinosis arising in an adolescent with acute myelogenous leukemia and acute graft-versus-host disease after an allogeneic bone marrow transplantation. PMID:26645410

  2. Doença enxerto versus hospedeiro aguda A- GVHD Acute graft-versus-host disease

    Wellington Azevedo

    2010-05-01

    Full Text Available A doença enxerto contra hospedeiro aguda (A-GVHD é síndrome sistêmica que acomete pacientes transplantados de medula óssea que recebem linfócitos imuno-competentes. A fisiopatologia do fenômeno é complexa e envolve uma série de respostas de diversos efetores imunológicos a estímulos antigênicos naturais ou que são expressos devido ao dano tecidual provocado pela doença ou pelo condicionamento. A ocorrência desta complicação é frequente em transplantes de medula óssea e determina, em grande parte, a evolução clínica do paciente. Neste capítulo são discutidos aspectos da biologia da doença do enxerto versus hospedeiro aguda, da sua evolução clínica e do manejo profilático e terapêutico deste problema, que pode ser devastador para pacientes submetidos a transplantes alogênicos de medula óssea.Graft versus host disease (A-GVHD is a systemic disease that affects bone marrow transplant patients receiving immunocompetent lymphocytes. The pathophysiology of this phenomenon is complex and involves a number of different effector immune responses to antigenic stimuli that are expressed due to tissue damage caused by disease or conditioning. This complication is frequent in bone marrow transplants and often determines the clinical outcome. In this chapter we discuss aspects of the biology of chronic graft versus host disease, its clinical evolution and the prophylactic and therapeutic management of this problem which can be devastating for patients undergoing allogeneic bone marrow transplantation.

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

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

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

    SimonRobinson

    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.

  5. The Role of Biomarkers in the Diagnosis and Risk Stratification of Acute Graft-versus-Host Disease: A Systematic Review.

    Ali, Alaa M; DiPersio, John F; Schroeder, Mark A

    2016-09-01

    Allogeneic hematopoietic cell transplantation (HCT) is an increasingly used curative modality for hematologic malignancies and other benign conditions. Attempts to reduce morbidity and mortality and improve survival in patients undergoing HCT are crucial. The ability to diagnose acute graft-versus-host disease (aGVHD) in a timely manner, or to even predict aGVHD before clinical manifestations, along with the accurate stratification of these patients, are critical steps to improve the treatment and outcomes of these patients. Many novel biomarkers that may help achieve these goals have been studied recently. This overview is intended to assist clinicians and investigators by providing a comprehensive review and analytical interpretation of the current knowledge concerning aGVHD and biomarkers likely to prove useful in diagnosis and risk stratification of this condition, along with the difficulties that hamper this approach. PMID:27158050

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

    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...

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

    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.

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

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

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

    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.

  10. Pretransplant helper T-lymphocyte determination in bone marrow donors: acute graft-versus-host disease prediction and relation with long-term survival

    Winandy, Marie; Lewalle, Philippe; Deneys, Véronique; Ferrant, Augustin; Bruyère, Marc

    1999-01-01

    Helper T-lymphocyte precursor (HTLp) frequency from 19 allogeneic bone marrow donors was tested to detect weak antigenic differences with the recipient, and then compared to the outcome. HTLp frequency was estimated in limiting dilution cultures, and HLA-DR and CD 80 expression by stimulating cells was measured by flow cytometry. 12/19 patients experienced acute graft-versus-host disease (aGVHD) grade II–IV. A good correlation was found between high pretransplant HTLp ...

  11. Graft-versus-host disease: unexpected presentation with simultaneous hepatitis and pancreatitis.

    Fernandes, Samuel Raimundo; Alves, Antonio T; Cortes, Margarida Barreto; Cortez-Pinto, Helena

    2016-01-01

    We report the case of a 37-year-old man with a previous bone marrow transplantation presenting with abdominal pain, diarrhoea and jaundice. Laboratory evaluation showed marked elevated liver enzymes, amylase and lipase with ultrasonographic evidence of acute alithiasic pancreatitis. Liver biopsy was compatible with graft-versus-host disease and toxic hepatitis. The patient rapidly improved after increasing immunosuppression. Although gastrointestinal manifestations are common in graft-versus-host disease, clinical acute pancreatitis is rarely seen. Patients with graft versus host are seldom managed by gastroenterologists and hepatologists. An awareness of this condition is essential for the experienced clinician. PMID:27485875

  12. Peritransplant Serum Albumin Decline Predicts Subsequent Severe Acute Graft-versus-Host Disease after Mucotoxic Myeloablative Conditioning.

    Rashidi, Armin; DiPersio, John F; Westervelt, Peter; Abboud, Camille N; Schroeder, Mark A; Cashen, Amanda F; Pusic, Iskra; Romee, Rizwan

    2016-06-01

    Conditioning-related gut toxicity can result in a protein-losing enteropathy manifesting as a decline in serum albumin in the peritransplant period. Inspired by the pathogenesis of acute graft-versus-host disease (aGVHD), we hypothesized that the magnitude of decline in serum albumin from the day of conditioning initiation until its nadir in the first 2 weeks after hematopoietic cell transplantation HCT (DeltaAlb) predicts the risk for subsequent severe aGVHD. We reviewed the medical records of all 88 patients with acute myeloid leukemia or myelodysplastic syndrome who underwent highly mucotoxic myeloablative (busulfan/cyclophosphamide or cyclophosphamide/total body irradiation) allogeneic HCT from a matched related donor (MRD) or matched unrelated donor (MUD) at our institution between January 1, 2012 and January 1, 2015. Severe aGVHD was associated with MUD (47% versus 14% with MRD; P = .001) and DeltaAlb, which was significantly greater among patients who developed versus did not develop severe aGVHD (1.2 ± .5 versus .8 ± .4 g/dL, respectively; P HCT, each .1-g/dL increase in DeltaAlb was associated with an approximately 23% increase in the odds of developing severe aGVHD. As an early biomarker of gut damage, DeltaAlb can be incorporated in composite risk models for aGVHD prediction, with hopes for ultimately allowing for individualized GVHD prophylaxis and potential intervention according to the predicted risk. PMID:26988741

  13. History of graft-versus-host disease.

    Vriesendorp, Huib M; Heidt, Peter J

    2016-08-01

    Nuclear warfare at the end of World War II inspired Dick W. van Bekkum to study total-body irradiation (TBI) in animal models. After high-dose TBI, mice died from "primary disease" or bone marrow (BM) aplasia. Intravenous administration of allogeneic BM cells delayed mortality but did not prevent it. Initially the delayed deaths were said to be caused by "secondary disease," which was later renamed graft-versus-host disease (GvHD). GvHD is caused by donor T lymphocytes that destroy recipient cells in skin, intestinal mucosa, bile ducts, and lymph nodes. GvHD is opposed by host-versus-graft disease (HvGD), in which host T lymphocytes destroy the administered allogeneic BM cells, including the administered T lymphocytes of the BM donor. In 1960, van Bekkum became the director of the Radiobiological Institute of the Dutch Organization for Applied Scientific Research TNO, Rijswijk, The Netherlands, where he built a multidisciplinary team that defined the variables controlling the outcome of a BM transplant. The team published their early results in the Journal of Experimental Hematology [1981;9:904-916 and 1956;4:482-488]. Later, protocols were established for BM transplantation (BMT) in patients with severe combined immunodeficiency disease, leukemia, lymphoma, and other diseases of the hematopoietic system. This review honors the scientific contributions made by Dick van Bekkum and his team in defining the four dominant variables for improving the therapeutic ratio of allogeneic BMT and in fostering the international collaboration necessary to translate this knowledge into current clinical practice. PMID:27235758

  14. The Role Of Interleukin - 18 And Interleukin – 2 Receptors In Acute Graft-Versus-Host Disease After Bone Marrow Transplantation

    Iravani M

    2004-08-01

    Full Text Available Background: Graft-versus-host disease is one of the major complications after allogenic bone marrow transplantation, but it is not easy to anticipate the onset. Cytokines released by type 1 T-helper cells are thought to play a pivotal role in acute graft-versus-host disease (aGVHD. The ability to predict the likely occurrence of graft-versus-host-disease (GVHD after BMT would be extremely valuable. By serially measuring serum levels of soluble IL-2 receptor (sIL-2R, IL-18 and following allogeneic bone marrow transplantation (BMT, we tried to define their relationship to aGVHD as complication of the transplantation and determine useful markers for aGVHD predictors. Materials and Methods: Serum sIL-2R, IL-18, and levels were measured by sandwich ELISA in 219 sera samples from 39 patients (with hematological disorders before and after allogeneic BMT and 28 controls. All patients received BMT from HLA-identical siblings. Results: 25 patients developed aGVHD and serum levels of sIL-2 R and IL-18 , in sera drawn before transplantation , in patients with acute graft-versus-host disease (aGVHD + , were increased in comparison of patients without acute graft-versus-host disease (aGVHD ¯ and control group and there wasn’t any significant differences in serum levels of sIL-2 R and IL-18 in aGVHD ¯ patients and controls. Serum level of IL-18, in aGVHD+ patients, was increased during day 3 - 24 after BMT, and there was a significant difference in patients with GVHD 0 – GVHD III. In majority of patients with acute GVHD (60 % , the peak levels of IL-18 and IL-2R was achieved on day 10 after BMT and the rise in sIL-2R and IL-18 preceded of clinical signs of GVHD (mean day 15 after BMT. Level of IL-18 in patients with aGVHD had strongly correlated with the severity of aGVHD on Day 10 after BMT. IL-18 level mean (before BMT, in patients who received Busulfan and Fludarabin to treat aGVHD, was lower than in patients who received Busulfan - Endoxan, or

  15. Bone marrow transplantation in the rat. III. Structure of the liver inflammatory lesion in acute graft-versus-host disease

    The liver is a major parenchymal target organ of acute graft-versus-host disease (aGVHD) after bone marrow transplantation in the rat. The authors have analyzed the nature of cellular infiltrates in the liver using monoclonal antibodies against white cell subsets and investigated the anatomic distribution of the inflammatory cell subsets inside the liver parenchyma. Several types of white cells are present in a normal control liver: In the portal area the T-helper (Th) cells predominate, (surface) immunoglobulin-expressing B cells are present in ample numbers, and most of the phagocytes are Ia-positive. In the central vein area the T-suppressor/killer cells (Tsk) dominate, no B cells are present, and most of the phagocytes are Ia-negative. During aGVHD the number of T cells increases rapidly in the portal area; and after an initial strong increase, the Th/Tsk ratio decreases but remains still above 1. In the central vein area there is also an increase in the number of T cells, compared with that in the syngeneic recipient, but the Th/Tsk ratio rapidly decreases and remains uniformly below 1. During aGVHD the B cells entirely disappear from the portal area, whereas a small but distinct number of mature plasma cells with intracellular immunoglobulin appear in the central vein area. Following irradiation the Ia-positive phagocytic cells entirely disappear from the portal area and decrease distinctly in number in the central vein area. During aGVHD the number of Ia-positive phagocytes increases again in both locations. In the central vein area the positive phagocytes are seen over the background level, and, concomitantly, the Ia-negative phagocytes disappear

  16. Preventing Graft-versus-Host Disease during Hemato

    Researchers are investigating whether an immunosuppressive drug, sirolimus, can work with cyclosporine to prevent graft-versus-host disease (GVHD) more effectively than cyclosporine alone following allogeneic hematopoietic stem cell transplantation.

  17. Increased serum IgE concentrations during infection and graft versus host disease after bone marrow transplantation.

    Walker, S. A.; Rogers, T. R.; Perry, D; Hobbs, J R; Riches, P G

    1984-01-01

    Serum IgE concentrations estimated in 25 bone marrow transplant recipients during episodes of infection or graft versus host disease, or both, were raised not only in some patients with acute graft versus host disease but also in many patients with infection. Raised values were not seen in chronic graft versus host disease. The routine estimation of serum IgE in bone marrow transplant recipients had minimal value because of the lack of specificity of the IgE response.

  18. Rituximab in Preventing Acute Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant for Hematologic Cancer

    2014-05-28

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Blastic 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; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Graft Versus Host Disease; 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; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III

  19. Graft versus host disease following liver transplantation: A case report

    Zhang, Changsong; YANG, GUANGSHUN; LING, YANG; Chen, Guihua; Zhou, Tianbao

    2014-01-01

    Graft versus host disease (GVHD) is an uncommon complication following liver transplantation. In the present case report, a 53-year-old male hepatitis B virus carrier was diagnosed with primary liver cancer with post-hepatitis cirrhosis. Preoperative cytomegalovirus (CMV), Epstein-Barr virus, coxsackievirus, herpes simplex virus and autoimmune antibody series were negative. Preoperative human leukocyte antigen type was also negative. Following classic orthotropic liver transplantation, postop...

  20. Azacytidine mitigates experimental sclerodermic chronic graft-versus-host disease

    Fransolet, Gilles; Ehx, Grégory; Somja, Joan; Delens, Loïc; Hannon, Muriel; Muller, Joséphine; Dubois, Sophie; Drion, Pierre; Caers, Jo; Humblet-Baron, Stéphanie; Delvenne, Philippe; Beguin, Yves; Conteduca, Giuseppina; Baron, Frédéric

    2016-01-01

    Background Previous studies have demonstrated that regulatory T cells (Tregs) play a protective role in the pathogenesis of chronic graft-versus-host disease (cGVHD). Tregs constitutively express the gene of the transcription factor Foxp3 whose CNS2 region is heavily methylated in conventional CD4+ T cells (CD4+Tconvs) but demethylated in Tregs. Methods Here, we assessed the impact of azacytidine (AZA) on cGVHD in a well-established murine model of sclerodermic cGVHD (B10.D2 (H-2d) → BALB/cJ ...

  1. Ibrutinib treatment ameliorates murine chronic graft-versus-host disease

    Dubovsky, Jason A.; Flynn, Ryan; Du, Jing; Harrington, Bonnie K.; Zhong, Yiming; Kaffenberger, Benjamin; Yang, Carrie; Towns, William H; Lehman, Amy; Johnson, Amy J.; Muthusamy, Natarajan; Devine, Steven M.; Jaglowski, Samantha; Serody, Jonathan S.; Murphy, William J.

    2014-01-01

    Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD4+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton’s tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells and produces durable remissi...

  2. Chronic graft versus host disease and nephrotic syndrome

    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.

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

    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

    2014-10-01

    The use of TGF-β-induced CD4(+)Foxp3(+) T cells (induced regulatory T cells [iTregs]) is an important prevention and treatment strategy in autoimmune diseases and other disorders. However, the potential use of iTregs as a treatment modality for acute graft-versus-host disease (aGVHD) has not been realized because they may be unstable and less suppressive in this disease. We restudied the ability of iTregs to prevent and treat aGVHD in two mouse models. Our results showed that, as long as an appropriate iTreg-generation protocol is used, these iTregs consistently displayed a potent ability to control aGVHD development and reduce mortality in the aGVHD animal models. iTreg infusion markedly suppressed the engraftment of donor CD8(+) cells and CD4(+) cells, the expression of granzyme A and B, the cytotoxic effect of donor CD8(+) cells, and the production of T cell cytokines in aGVHD. Therefore, we conclude that as long as the correct methods for generating iTregs are used, they can prevent and even treat aGVHD. PMID:25156367

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

    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. PMID:25617807

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

    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. PMID:27031239

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

    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. PMID:27044906

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

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

  8. Bilateral Sequential Dacryocystitis in a Patient With Graft-Versus-Host Disease.

    Campbell, Ashley A; Jakobiec, Frederick A; Rashid, Alia; Dana, Reza; Yoon, Michael K

    2016-01-01

    A 29-year-old woman with a history of 2 bone marrow transplants for acute myelogenous leukemia developed bilateral sequential dacryocystitis in the context of known ocular graft-versus-host disease. With each infection, the patient underwent uneventful dacryocystorhinostomy. Postoperatively, she developed severe dry eye disease requiring replacement of punctal plugs and use of a prosthetic replacement of the ocular surface ecosystem lens. Histopathologic and immunohistochemical examination of the lacrimal sac showed a dense diffuse nonfollicular lymphocytic subepithelial infiltrate in the lacrimal sac that contained moderately more T-cells than B-cells. This is the first report of acute dacryocystitis associated with graft-versus-host disease. The authors caution that similar patients may develop worsening of ocular surface dryness due to restoration of normal lacrimal outflow. PMID:25192327

  9. FDG PET/CT in Acute Tumefactive Multiple Sclerosis Occurring in a Case of Chronic Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation.

    Dong, Aisheng; Gao, Mingjun; Wang, Yang; Gao, Lei; Zuo, Changjing

    2016-09-01

    Tumefactive multiple sclerosis refers to the presentation of large demyelinating lesions (≥2 cm in diameter) mimicking brain tumors clinically and radiologically. We present the MRI and FDG PET/CT findings in a case with tumefactive multiple sclerosis, who had chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Head MRI showed 7 cerebral lesions with incomplete ring enhancement. All but one lesion had size more than 2 cm. All these demyelinating lesions showed increased uptake at the rims of the lesions with central hypometabolism. Stereotactic brain biopsy of the right frontal lesion revealed extensive macrophage and lymphocyte infiltration. PMID:26909714

  10. CIDP-like neuropathies in graft versus host disease.

    Cocito, Dario; Romagnolo, Alberto; Rosso, Michela; Peci, Erdita; Lopiano, Leonardo; Merola, Aristide

    2015-03-01

    Cases of chronic inflammatory demyelinating poliradiculoneuropathy (CIDP) have been reported in hematopoietic stem cells transplantation complicated by graft versus host disease (GVHD). A systematic review of the CIDP-like neuropathies associated with GVHD was conducted until January 2015, analyzing the clinical presentation and the response to different therapeutic regimens. Nineteen patients have been reported in literature including the present one. Fourteen subjects fulfilled the criteria for CIDP, whereas two cases presented with an asymmetric motor onset and one showed motor involvement only associated with anti-ganglioside antibodies. In addition, two subjects already affected by CIDP developed a significant relapse after GVHD. This study reviews the literature data and reports one additional case of CIDP and GVHD, suggesting that the two clinical entities might share a similar immunological background. PMID:25864585

  11. Endothelial microparticles carrying hedgehog-interacting protein induce continuous endothelial damage in the pathogenesis of acute graft-versus-host disease.

    Nie, Di-Min; Wu, Qiu-Ling; Zheng, Peng; Chen, Ping; Zhang, Ran; Li, Bei-Bei; Fang, Jun; Xia, Ling-Hui; Hong, Mei

    2016-05-15

    Accumulating evidence suggests that endothelial microparticles (EMPs), a marker of endothelial damage, are elevated in acute graft-versus-host disease (aGVHD), and that endothelial damage is implicated in the pathogenesis of aGVHD, but the mechanisms remain elusive. In this study, we detected the plasma EMP levels and endothelial damage in patients and mice with aGVHD in vivo and then examined the effects of EMPs derived from injured endothelial cells (ECs) on endothelial damage and the role of hedgehog-interacting protein (HHIP) carried by EMPs in these effects in vitro. Our results showed that EMPs were persistently increased in the early posttransplantation phase in patients and mice with aGVHD. Meanwhile, endothelial damage was continuous in aGVHD mice, but was temporary in non-aGVHD mice after transplantation. In vitro, EMPs induced endothelial damage, including increased EC apoptosis, enhanced reactive oxygen species, decreased nitric oxide production and impaired angiogenic activity. Enhanced expression of HHIP, an antagonist for the Sonic hedgehog (SHH) signaling pathway, was observed in patients and mice with aGVHD and EMPs from injured ECs. The endothelial damage induced by EMPs was reversed when the HHIP incorporated into EMPs was silenced with an HHIP small interfering RNA or inhibited with the SHH pathway agonist, Smoothened agonist. This work supports a feasible vicious cycle in which EMPs generated during endothelial injury, in turn, aggravate endothelial damage by carrying HHIP into target ECs, contributing to the continuously deteriorating endothelial damage in the development of aGVHD. EMPs harboring HHIP would represent a potential therapeutic target for aGVHD. PMID:27009877

  12. Steroids Versus Steroids Plus Additional Agent in Frontline Treatment of Acute Graft-versus-Host Disease: A Systematic Review and Meta-Analysis of Randomized Trials.

    Rashidi, Armin; DiPersio, John F; Sandmaier, Brenda M; Colditz, Graham A; Weisdorf, Daniel J

    2016-06-01

    Despite extensive research in the last few decades, progress in treatment of acute graft-versus-host disease (aGVHD), a common complication of allogeneic hematopoietic cell transplantation (HCT), has been limited and steroids continue to be the standard frontline treatment. Randomized clinical trials (RCTs) have failed to find a beneficial effect of escalating immunosuppression using additional agents. Considering the small number of RCTs, limited sample sizes, and frequent early termination because of anticipated futility, we conducted a systematic review and an aggregate data meta-analysis to explore whether a true efficacy signal has been missed because of the limitations of individual RCTs. Seven reports met our inclusion criteria. The control arm in all studies was 2 mg/kg/day prednisone (or equivalent). The additional agent(s) used in the experimental arm(s) were higher-dose steroids, antithymocyte globulin, infliximab, anti-interleukin-2 receptor antibody (daclizumab and BT563), CD5-specific immunotoxin, and mycophenolate mofetil. Random effects meta-analysis revealed no efficacy signal in pooled response rates at various times points. Overall survival at 100 days was significantly worse in the experimental arm (relative risk [RR], .83; 95% confidence interval [CI], .74 to .94; P = .004, data from 3 studies) and showed a similar trend (albeit not statistically significantly) at 1 year as well (RR, .86; 95% CI, .68 to 1.09; P = .21, data from 5 studies). In conclusion, these results argue against the value of augmented generic immunosuppression beyond steroids for frontline treatment of aGVHD and emphasize the importance of developing alternative strategies. Novel forms of immunomodulation and targeted therapies against non-immune-related pathways may enhance the efficacy of steroids in this setting, and early predictive and prognostic biomarkers can help identify the subgroup of patients who would likely need treatments other than (or in addition to

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

    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...... incompatible BM, but in none of five recipients of DP-compatible BM. This difference was highly significant (p less than 0.001, Fisher's exact test). Moreover, severe acute GVHD was significantly increased in recipients of haploidentical, DR compatible, but DP incompatible BM as compared to severe acute GVHD...... in 88 recipients of HLA-identical BM (p less than 0.0001). In contrast, there was no difference in acute GVHD between recipients of haploidentical, DR and DP compatible BM and recipients of HLA-identical BM. The data presented here provide strong evidence for the first time that HLA-DP antigens play...

  14. Lithium Carbonate in Treating Patients With Acute Intestinal Graft-Versus-Host-Disease After Donor Stem Cell Transplant

    2011-01-04

    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, 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; Recurrent Adult Acute Myeloid Leukemia; Recurrent

  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.

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

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

  17. 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

    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

  18. Cyclosporine Plus Methotrexate or Cyclosporine Plus Mycophenolate Mofetil as Graft Versus Host Disease Prophylaxis in Acute Leukemia Transplant: Comparison of Toxicity, Engraftment Kinetics and Transplant Outcome.

    Gupta, Alok; Punatar, Sachin; Mathew, Libin; Kannan, Sadhana; Khattry, Navin

    2016-09-01

    We sought to compare two graft-versus-host disease (GVHD) prophylaxis regimen, cyclosporine and methotrexate (CsA+MTX) with CsA+mycophenolate mofetil (MMF) in 77 acute leukemia patients who underwent hematopoietic stem cell transplant (HSCT) between January 2008 and March 2013. Fifty-three patients received CsA+MTX while 24 received CsA+MMF. The incidence of grade 3-4 mucositis and grade 3-4 diarrhea was 74 and 6 % with CsA+MTX compared to 33 % and 21 % with CsA+MMF (P = 0.001 and 0.09 respectively). Forty-two (79 %) patients in CsA+MTX group required total parenteral nutrition compared to 14 (58 %) in CsA+MMF group (P = 0.09). The incidence of engraftment fever was 17 % with CsA+MTX and 41 % with CsA+MMF (P = 0.02). The median time to neutrophil and platelet engraftment was 14 days and 13 days with CsA+MTX compared to 12 days and 10 days with CsA+MMF (P = 0.003 and 0.08 respectively). The incidence of any grade and grade II-IV acute GVHD was 45 and 13 % with CsA+MTX compared to 42 and 29 % with CsA+MMF (P = NS). Incidence of overall and extensive chronic GVHD was 57 and 38 % with CsA+MTX compared to 42 and 17 % with CsA+MMF (P = NS). Incidence of relapse was 38 % with CsA+MTX compared to 33 % with CsA+MMF (P = NS). TRM was 6 % with CsA+MTX and 21 % with CsA+MMF (P = NS). At 2 years, overall survival (OS) was 64 % in CsA+MTX group compared to 46 % in CsA+MMF group (P = NS). We conclude that CsA+MMF is associated with lesser toxicity, faster myeloid engraftment and similar rates of acute and chronic GVHD, TRM, relapse and OS compared to CsA+MTX in acute leukemia transplant. PMID:27429515

  19. Total body irradiation correlates with chronic graft versus host disease and affects prognosis of patients with acute lymphoblastic leukemia receiving an HLA identical allogeneic bone marrow transplant

    Purpose: To investigate whether different procedure variables involved in the delivery of fractionated total body irradiation (TBI) impact on prognosis of patients affected by acute lymphoblastic leukemia (ALL) receiving allogeneic bone marrow transplant (BMT). Methods and Materials: Ninety-three consecutive patients with ALL receiving a human leukocyte antigen (HLA) identical allogeneic BMT between 1 August 1983 and 30 September 1995 were conditioned with the same protocol consisting of cyclophosphamide and fractionated TBI. The planned total dose of TBI was 12 Gy (2 Gy, twice a day for 3 days). Along the 12-year period, variations in delivering TBI schedule occurred with regard to used radiation source, instantaneous dose rate, technical setting, and actual total dose received by the patient. We tested these different TBI variables as well as factors related to patient, state of disease, and transplant-induced disease to investigate their influence on transplant-related mortality, leukemia relapse, and survival. Results: At median follow-up of 7 years (range 3-15 years) the probabilities of leukemia-free survival (LFS) and overall survival (OS) for the 93 patients were 60% and 41%, respectively. At univariate analysis, chronic graft versus host disease (cGvHd) (p = 0.0005), age (p = 0.01), and state of disease (p 0.03) were factors affecting LFS whereas chronic GvHd (p = 0.0005), acute GvHd (p = 0.03), age (p = 0.0001), and GvHd prophylaxis (p = 0.01) were factors affecting overall survival. The occurrence of chronic GvHd was correlated with actually delivered TBI dose (p = 0.04). Combined stratification of prognostic factors showed that patients who received the planned total dose of TBI (12 Gy) and were affected by chronic GvHd had higher probabilities of LFS (p = 0.01) and OS (p = n.s.) than patients receiving less than 12 Gy and/or without occurrence of chronic GvHd. Moreover, TBI dose had a significant impact on LFS in patients transplanted in first

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

    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

  1. Graft-versus-host disease versus graft-versus-leukemia.

    Negrin, Robert S

    2015-01-01

    Graft-versus-host disease (GVHD) is a significant clinical problem after allogenic hematopoietic cell transplantation (HCT) associated with substantial morbidity and mortality that limits the potential utility of transplantation. Associated with GVHD is the well-recognized phenomenon of the graft-versus-leukemia (GVL) effect that results in reduced risk of disease relapse. GVL effects have been observed after treatment for a broad range of hematological malignancies. Both GVHD and GVL are the results of T cell-effector functions that frames a major question in the field of how linked are these two phenomena. A major goal of basic science and translational research has been to develop strategies to reduce the risk of GVHD while maintaining or enhancing GVL. In this review, a number of different strategies developed from preclinical animal models will be explored with a focus on those approaches that have been extended to the clinic in an attempt to achieve this goal. Needless to say, there is no proven strategy; however, with the use of modern technology and clinical translation, there has been substantial progress toward this goal of reducing the risks of GVHD while promoting and enhancing GVL responses. PMID:26637726

  2. Oral disease profiles in chronic graft versus host disease.

    Bassim, C W; Fassil, H; Mays, J W; Edwards, D; Baird, K; Steinberg, S M; Cowen, E W; Naik, H; Datiles, M; Stratton, P; Gress, R E; Pavletic, S Z

    2015-04-01

    At least half of patients with chronic graft-versus-host-disease (cGVHD), the leading cause of morbidity and non-relapse mortality after allogeneic stem cell transplantation, have oral manifestations: mucosal lesions, salivary dysfunction, and limited mouth-opening. cGVHD may manifest in a single organ or affect multiple organ systems, including the mouth, eyes, and the skin. The interrelationship of the 3 oral manifestations of cGVHD with each other and with the specific manifestations of extraoral cGVHD has not been studied. In this analysis, we explored, in a large group of patients with cGVHD, the potential associations between: (1) oral mucosal disease and erythematous skin disease, (2) salivary gland dysfunction and lacrimal gland dysfunction, and (3) limited mouth-opening and sclerotic skin cGVHD. Study participants, enrolled in a cGVHD Natural History Protocol (NCT00331968, n = 212), underwent an oral examination evaluating: (1) mucosal cGVHD [NIH Oral Mucosal Score (OMS)], (2) salivary dysfunction (saliva flow and xerostomia), and (3) maximum mouth-opening measurement. Parameters for dysfunction (OMS > 2, saliva flow ≤ 1 mL/5 min, mouth-opening ≤ 35 mm) were analyzed for association with skin cGVHD involvement (erythema and sclerosis, skin symptoms), lacrimal dysfunction (Schirmer's tear test, xerophthalmia), Lee cGVHD Symptom Scores, and NIH organ scores. Oral mucosal disease (31% prevalence) was associated with skin erythema (P prevalence) was associated with lacrimal dysfunction (P = 0.010) and xerostomia with xerophthalmia (r = 0.32, P = 0.001); and limited mouth-opening (17% prevalence) was associated with skin sclerosis (P = 0.008) and skin symptoms (P = 0.001). There was no association found among these 3 oral cGVHD manifestations. This analysis supports the understanding of oral cGVHD as 3 distinct diseases: mucosal lesions, salivary gland dysfunction, and mouth sclerosis. Clear classification of oral cGVHD as 3 separate manifestations will

  3. Effects of bone marrow mesenchymal stem cells on hematopoietic recovery and acute graft-versus-host disease in murine allogeneic umbilical cord blood transplantation model.

    Li, Zhen Yu; Wang, Chun Qing; Lu, Guang; Pan, Xiu Ying; Xu, Kai Lin

    2014-09-01

    To investigate the effect of bone marrow mesenchymal stem cells (MSC) on hematopoietic recovery and acute graft-versus-host disease (GVHD) in a murine allogeneic umbilical cord blood transplantation (allo-UCBT) model. MSCs were obtained from C57/BL mouse bone marrow. The MSC phenotypes were identified by flow cytometry (FCM), and their ability to differentiate into osteoblasts and adipocytes was tested. Once murine allo-UCBT and aGVHD models were established, mice were divided into five groups: (1) total body irradiation (TBI) group, each mouse receiving 0.3 ml sterile saline infusion after TBI and used as control; (2) UCB group, receiving 2 × 10(6) umbilical cord blood mononuclear cells (UCB-MNC) after TBI; (3) UCB+MSC group, receiving 2 × 10(6) UCB-MNC and 2 × 10(7) MSC after TBI; (4) UCB+SC group, receiving 2 × 10(6) UCB-MNC and 2 × 10(6) spleen cells after TBI; and (5) UCB+SC+MSC group, receiving 2 × 10(6) UCB-MNC, 2 × 10(7) MSC and 2 × 10(6) spleen cells after TBI. To evaluate the engraftment of HSC, the white blood cells, red blood cells, and platelets counts were tested at different time points after transplantation, and the ratio of chimerism was identified by FCM. The acute GVHD clinical scores, recipient mice survival, and the histopathological analyses were used to evaluate the effect of MSC on acute GVHD. MSCs were successfully obtained in vitro and FCM analysis showed that these cells are highly positive for CD90.2, CD44, and negative for CD34, CD45, and they are capable to differentiate into osteoblasts and adipocytes after being induced. Compared to UCB group, the UCB+MSC mice had shorter duration of myelosuppression and higher percentage of donor-derived cells which was up to 22.87 ± 4.3 % and the white blood cell (WBC), red blood cell (RBC), and platelet counts started to increase by day 6 after transplantation. Moreover, the average survival time for UCB+MSC mice was 25.0 ± 10.55 days, while for the UCB group it was 15.5 ± 12.50 days

  4. The Gut Microbiota and Immune System Relationship in Human Graft-versus-Host Disease

    Laterza, Lucrezia; Rizzatti, Gianenrico; Gaetani, Eleonora; Chiusolo, Patrizia; Gasbarrini, Antonio

    2016-01-01

    Gut microbiota has gained increasing interest in the pathogenesis of immune-related diseases. In this context, graft-versus-host disease is a condition characterized by an immune response which frequently complicates and limits the outcomes of hematopoietic stem cell transplantations. Past studies, carried mostly in animals, already supported a relationship between gut microbiota and graft-versus-host disease. However, the possible mechanisms underlying this connection remain elusory. Moreove...

  5. Predictive models for ocular chronic graft-versus-host disease diagnosis and disease activity in transplant clinical practice

    Curtis, Lauren M.; Datiles, Manuel B.; Steinberg, Seth M.; Mitchell, Sandra A.; Bishop, Rachel J.; Cowen, Edward W.; Mays, Jacqueline; McCarty, John M.; Kuzmina, Zoya; Pirsl, Filip; Fowler, Daniel H; Gress, Ronald E.; Pavletic, Steven Z.

    2015-01-01

    Ocular chronic graft-versus-host disease is one of the most bothersome common complications following allogeneic hematopoietic stem cell transplantation. The National Institutes of Health Chronic Graft-versus-Host Disease Consensus Project provided expert recommendations for diagnosis and organ severity scoring. However, ocular chronic graft-versus-host disease can be diagnosed only after examination by an ophthalmologist. There are no currently accepted definitions of ocular chronic graft-ve...

  6. Beclomethasone Dipropionate in Preventing Acute Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant for Hematologic Cancer

    2015-03-05

    Hematopoietic/Lymphoid Cancer; 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; 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; 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; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Graft Versus Host Disease; Isolated Plasmacytoma of Bone; Juvenile Myelomonocytic Leukemia; Meningeal Chronic Myelogenous Leukemia; Myelodysplastic/Myeloproliferative Disease, 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 Small

  7. B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality.

    Veenstra, Rachelle G; Flynn, Ryan; Kreymborg, Katharina; McDonald-Hyman, Cameron; Saha, Asim; Taylor, Patricia A; Osborn, Mark J; Panoskaltsis-Mortari, Angela; Schmitt-Graeff, Annette; Lieberknect, Elisabeth; Murphy, William J; Serody, Jonathan S; Munn, David H; Freeman, Gordon J; Allison, James P; Mak, Tak W; van den Brink, Marcel; Zeiser, Robert; Blazar, Bruce R

    2015-05-21

    Members of the B7 family have been shown to be important for regulating immune responses by providing either positive or negative costimulatory signals. The function of B7-H3 has been controversial. We show that B7-H3 is upregulated in graft-versus-host disease (GVHD) target organs, including the colon, liver, and lung. Infusion of allogeneic donor T cells into B7-H3(-/-) vs wild-type (WT) recipients resulted in increased GVHD lethality associated with increased T-cell proliferation, colonic inflammatory cytokines, and destruction of epithelial barriers. Allogeneic B7-H3(-/-) vs WT donor T cells also had increased T-cell proliferation and GVHD lethality associated with increased proliferation and cytokine secretion in the spleen, intraepithelial lymphocyte inflammatory cytokines, and intestinal permeability. Both resting and activated regulatory T cells (Tregs) lack B7-H3 messenger RNA. Consistent with these data, GVHD was augmented in recipients of B7-H3(-/-) Treg-depleted grafts. In two delayed lymphocyte infusion (DLI) models, T cells lacking B7-H3 are capable of providing graft-versus-leukemia (GVL) effects. We conclude that B7-H3 is responsible for providing a negative costimulatory signal. Our studies provide support for developing and testing new therapies directed toward the B7-H3 pathway, including approaches to augment host B7-H3 early after bone marrow transplantation to prevent GVHD and to develop potent antagonistic antibodies later after transplant to facilitate DLI-mediated GVL without GVHD complications. PMID:25814530

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

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

    2015-07-15

    Naturally derived regulatory T cells (Tregs) may prevent graft-versus-host disease (GVHD) while preserving graft-versus-leukemia (GVL) activity. However, clinical application of naturally derived regulatory T cells has been severely hampered by their scarce availability and nonselectivity. To overcome these limitations, we took alternative approaches to generate Ag-specific induced Tregs (iTregs) and tested their efficacy and selectivity in the prevention of GVHD in preclinical models of bone marrow transplantation. We selected HY as a target Ag because it is a naturally processed, ubiquitously expressed minor histocompatibility Ag (miHAg) with a proven role in GVHD and GVL effect. We generated HY-specific iTregs (HY-iTregs) from resting CD4 T cells derived from TCR transgenic mice, in which CD4 cells specifically recognize HY peptide. We found that HY-iTregs were highly effective in preventing GVHD in male (HY(+)) but not female (HY(-)) recipients using MHC II-mismatched, parent→F1, and miHAg-mismatched murine bone marrow transplantation models. Interestingly, the expression of target Ag (HY) on the hematopoietic or nonhematopoietic compartment alone was sufficient for iTregs to prevent GVHD. Furthermore, treatment with HY-iTregs still preserved the GVL effect even against pre-established leukemia. We found that HY-iTregs were more stable in male than in female recipients. Furthermore, HY-iTregs expanded extensively in male but not female recipients, which in turn significantly reduced donor effector T cell expansion, activation, and migration into GVHD target organs, resulting in effective prevention of GVHD. This study demonstrates that iTregs specific for HY miHAgs are highly effective in controlling GVHD in an Ag-dependent manner while sparing the GVL effect. PMID:26048147

  9. Dynamic regulation of effector IFN-γ-producing and IL-17-producing T cell subsets in the development of acute graft-versus-host disease.

    Zhao, Kai; Ruan, Suhong; Yin, Lingling; Zhao, Dongmei; Chen, Chong; Pan, Bin; Zeng, Lingyu; Li, Zhenyu; Xu, Kailin

    2016-02-01

    Graft-versus-host disease (GVHD) as the predominant complication of allogeneic hematopoietic stem cell transplantation remains to be fully understood. It is known that the cytokines produced by allogeneic reactive effector CD4+ and CD8+ T cells are involved in GVHD. However, the regulation and coordination of IFN-γ-producing and IL-17-producing effector T cells remain unclear. The present study aimed to investigate the dynamic changes of alloantigen-specific effector CD4+ T and CD8+ T cell subsets by flow cytometry, which produce inflammatory cytokines involved in the multistep GVHD pathogenesis progress. The results demonstrated that IL-17-producing CD8+ T (Tc17) cells and IFN-γ+CD8+ T (Tc1) cells were detected in the early stage of GVHD. The differentiation of CD4+ T cells into Th1 cell (IFN-γ+CD4+ T) and Th17 (IL-17+CD4+ T) cells was later than that of the Tc1 and Tc17 cells. The effector CD4+ T and CD8+ T cell subsets either became exhausted or became memory cells, exhibiting a CD62L-CD44+ phenotype following marked expansion during GVHD. Furthermore, T cell-associated type I (IL-2 and IFN-γ) and type II (IL-4 and IL-10) classical cytokines exhibited coordinated dynamic regulation. It was concluded that the differentiation of cytokine-producing Tc1 and Tc17 cells may be the key step in the initiation of GVHD, whereas CD4+ effector Th1 and Th17 cells are considered to be pathophysiological factors leading to the continuous aggravation of GVHD. PMID:26647759

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

    A Tendas

    2011-01-01

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

  11. Heparanase promotes engraftment and prevents graft versus host disease in stem cell transplantation.

    Menachem Bitan

    Full Text Available BACKGROUND: Heparanase, endoglycosidase that cleaves heparan sulfate side chains of heparan sulfate proteoglycans, plays important roles in cancer metastasis, angiogenesis and inflammation. DESIGN AND METHODS: Applying a mouse model of bone marrow transplantation and transgenic mice over-expressing heparanase, we evaluated the effect of heparanase on the engraftment process and the development of graft-versus-host disease. RESULTS: Analysis of F1 mice undergoing allogeneic bone marrow transplantation from C57BL/6 mice demonstrated a better and faster engraftment in mice receiving cells from donors that were pretreated with heparanase. Moreover, heparanase treated recipient F1 mice showed only a mild appearance of graft-versus-host disease and died 27 days post transplantation while control mice rapidly developed signs of graft-versus-host disease (i.e., weight loss, hair loss, diarrhea and died after 12 days, indicating a protective effect of heparanase against graft-versus-host disease. Similarly, we applied transgenic mice over-expressing heparanase in most tissues as the recipients of BMT from C57BL/6 mice. Monitoring clinical parameters of graft-versus-host disease, the transgenic mice showed 100% survival on day 40 post transplantation, compared to only 50% survival on day 14, in the control group. In vitro and in vivo studies revealed that heparanase inhibited T cell function and activation through modulation of their cytokine repertoire, indicated by a marked increase in the levels of Interleukin-4, Interleukin-6 and Interleukin-10, and a parallel decrease in Interleukin-12, tumor necrosis factor-alfa and interferon-gamma. Using point mutated inactive enzyme, we found that the shift in cytokine profile was independent of heparanase enzymatic activity. CONCLUSIONS: Our results indicate a significant role of heparanase in bone marrow transplantation biology, facilitating engraftment and suppressing graft-versus-host disease, apparently

  12. Predictive models for ocular chronic graft-versus-host disease diagnosis and disease activity in transplant clinical practice.

    Curtis, Lauren M; Datiles, Manuel B; Steinberg, Seth M; Mitchell, Sandra A; Bishop, Rachel J; Cowen, Edward W; Mays, Jacqueline; McCarty, John M; Kuzmina, Zoya; Pirsl, Filip; Fowler, Daniel H; Gress, Ronald E; Pavletic, Steven Z

    2015-09-01

    Ocular chronic graft-versus-host disease is one of the most bothersome common complications following allogeneic hematopoietic stem cell transplantation. The National Institutes of Health Chronic Graft-versus-Host Disease Consensus Project provided expert recommendations for diagnosis and organ severity scoring. However, ocular chronic graft-versus-host disease can be diagnosed only after examination by an ophthalmologist. There are no currently accepted definitions of ocular chronic graft-versus-host disease activity. The goal of this study was to identify predictive models of diagnosis and activity for use in clinical transplant practice. A total of 210 patients with moderate or severe chronic graft-versus-host disease were enrolled in a prospective, cross-sectional, observational study (clinicaltrials.gov identifier: 00092235). Experienced ophthalmologists determined presence of ocular chronic graft-versus-host disease, diagnosis and activity. Measures gathered by the transplant clinician included Schirmer's tear test and National Institutes of Health 0-3 Eye Score. Patient-reported outcome measures were the ocular subscale of the Lee Chronic Graft-versus-Host Disease Symptom Scale and Chief Eye Symptom Intensity Score. Altogether, 157 (75%) patients were diagnosed with ocular chronic graft-versus-host disease; 133 of 157 patients (85%) had active disease. In a multivariable model, the National Institutes of Health Eye Score (Pscore (P=0.027). These results support the use of selected transplant clinician- and patient-reported outcome measures for ocular chronic graft-versus-host disease screening when providing care to allogeneic hematopoietic stem cell transplantation survivors with moderate to severe chronic graft-versus-host disease. Prospective studies are needed to determine if the Lee ocular subscale demonstrates adequate responsiveness as a disease activity outcome measure. PMID:26088932

  13. Impact of graft versus host disease on outcome of allogeneic peripherial blood stem cell transplantation for leukemia

    黎美章

    2014-01-01

    Objective To analyze the impact of the occurrence and severity of acute and chronic graft versus host disease(GVHD)on the long-term outcome of allogeneic peripheral blood stem cell transplantation(allo-PBSCT)for leukemia.Methods A total of 231 patients with leukemia,who underwent allo-HSCT in Changhai Hospital from Jan1st,2001 to Dec 31th,2011,were retrospectively analyzed.The overall survival(OS),disease-free survival

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

    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

  15. LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation

    Cooke, Kenneth R.; Gerbitz, Armin; Crawford, James M.; Teshima, Takanori; Hill, Geoffrey R.; Tesolin, Amy; Rossignol, Daniel P.; Ferrara, James L.M.

    2001-01-01

    Acute graft-versus-host disease (GVHD) and leukemic relapse remain the two major obstacles to successful outcomes after allogeneic bone marrow transplantation (BMT). Recent studies have demonstrated that the loss of gastrointestinal tract integrity, and specifically the translocation of LPS into the systemic circulation, is critical to the induction of cytokine dysregulation that contributes to GVHD. Using a mouse BMT model, we studied the effects of direct LPS antagonism on GVHD severity and...

  16. Functional asplenia in patients with chronic graft-versus-host disease: concise communication

    Liver/spleen images were performed with technetium-99m sulfur colloid in 53 patients who had undergone bone-marrow transplantation. The spleen was not seen in the images in five out of the ten patients with chronic graft-versus-host disease (GVHD). None of the five had a history of splenectomy, In two of these patients, anatomical presence of the spleen had been documented earlier by scintigram. The spleen was visible in all seven patients with acute and in all 36 patients without GVHD. Neither the differences in methods of treating the patients before bone-marrow transplantation nor the time lapse between transplantation and the liver/spleen image correlated with the observed effect among these three groups of transplant patients. The authors conclude that there is a high association between chronic GVHD and functional asplenia

  17. Brazilian actual conditions of the blood irradiation practice in graft-versus-host disease prevention

    Transfusion of blood and cellular components containing viable lymphocytes can result in Graft-Versus Host Disease (GVHD) in immuno compromised patients. It can be prevented by irradiation, prior to transfusion, of blood components. This work presents an overview of the Brazilian reality and suggests policies to optimise GVHD prevention. (author). 4 refs

  18. Donor-recipient mismatch for common gene deletion polymorphisms in graft-versus-host disease

    McCarroll, Steven A.; Bradner, James E.; Turpeinen, Hannu; Volin, Liisa; Martin, Paul J.; Chilewski, Shannon D.; Antin, Joseph H.; Lee, Stephanie J.; Ruutu, Tapani; Storer, Barry; Warren, Edus H.; ZHANG, BO; Zhao, Lue Ping; Ginsburg, David; Soiffer, Robert J.

    2009-01-01

    Transplantation and pregnancy, in which two diploid genomes reside in one body, can each lead to diseases in which immune cells from one individual target antigens encoded in the other’s genome. One such disease, graft-versus-host disease (GVHD) after hematopoetic stem cell transplantation (HSCT, or bone marrow transplant), is common even after transplants between HLA-identical siblings, indicating that cryptic histocompatibility loci exist outside the HLA locus. The immune system of an indiv...

  19. Association between a High BK Virus Load in Urine Samples of Patients with Graft-Versus-Host Disease and Development of Hemorrhagic Cystitis after Hematopoietic Stem Cell Transplantation

    Bogdanovic, G; Priftakis, P.; Giraud, G.; Kuzniar, M.; Ferraldeschi, R; Kokhaei, P.; Mellstedt, H.; Remberger, M; Ljungman, P.; Winiarski, J.; Dalianis, T

    2004-01-01

    BK virus (BKV) load in urine alone or in combination with acute graft-versus-host disease (GVHD) was correlated to development of hemorrhagic cystitis (HC). BKV load in combination with acute GVHD discriminated the best, while BKV and viral load alone, but not GVHD, still showed predictive ability for HC.

  20. MicroRNAs: The Missing Link in the Biology of Graft-Versus-Host Disease?

    Atarod, Sadaf; Dickinson, Anne Mary

    2013-01-01

    Graft-versus-host disease (GVHD) is still the major complication of allogeneic hematopoietic stem cell transplantation. Despite extensive studies in understanding the pathophysiology of GVHD, its pathogenesis remains unclear. Recently, important functions of microRNAs have been demonstrated in various autoimmune diseases and cancers such as psoriasis and lymphoma. This review highlights the need to investigate the role of microRNAs in GVHD and hypothesizes that microRNAs may be one of the mis...

  1. Serious graft-versus-host disease after hematopoietic cell transplantation following nonmyeloablative conditioning.

    Flowers, M E D; Traina, F; Storer, B; Maris, M; Bethge, W A; Carpenter, P; Appelbaum, F; Storb, R; Sandmaier, B M; Martin, P J

    2005-02-01

    The efficacy of allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning depends on the balance between the desirable antineoplastic effects of donor cells weighed against the undesirable morbidity of graft-versus-host disease (GVHD). Development of serious acute or chronic GVHD was analyzed retrospectively in 171 consecutive patients, who had related or unrelated nonmyeloablative HCT for hematologic malignancies. GVHD was defined as serious when it resulted in (1) death, (2) disability, (3) three or more major infections in 1 year, (4) prolonged hospitalization or (5) suicide or hospitalization for suicidal ideation. According to this definition, 43 of 171 (25%) patients developed serious GVHD with a median follow-up of 30 (range, 12-65) months. The incidence of serious GVHD was similar after related and unrelated HCT. Among the 43 patients with serious GVHD, 20 had grade III-IV acute GVHD, and 30 had extensive chronic GVHD. Among the 171 patients, seven had grade III acute GVHD and 84 had extensive chronic GVHD that did not meet criteria for serious GVHD. Assessment of serious GVHD provides additional useful information to acute GVHD grades and classification of limited and extensive chronic GVHD in describing the overall risk and impact complications caused by donor cells. PMID:15558037

  2. MicroRNAs as biomarkers for graft-versus-host disease following allogeneic stem cell transplantation.

    Tomuleasa, Ciprian; Fuji, Shigeo; Cucuianu, Andrei; Kapp, Markus; Pileczki, Valentina; Petrushev, Bobe; Selicean, Sonia; Tanase, Alina; Dima, Delia; Berindan-Neagoe, Ioana; Irimie, Alexandru; Einsele, Hermann

    2015-07-01

    Allogeneic hematopoietic stem cell transplantation (HCT) is a well-established treatment for many malignant and non-malignant hematological disorders. As frequent complication in up to 50 % of all patients, graft-versus-host disease (GVHD) is still the main cause for morbidity and non-relapse mortality. Diagnosis of GVHD is usually done clinically, even though confirmation by pathology is often used to support the clinical findings. Effective treatment requires intensified immunosuppression as early as possible. Although several promising biomarkers have been proposed for an early diagnosis, no internationally recognized consensus has yet been established. Here, microRNAs (miRs) represent an interesting tool since miRs have been recently reported to be an important regulator of various cells, including immune cells such as T cells. Therefore, we could assume that miRs play a key role in the pathogenesis of acute GVHD, and their detection might be an interesting possibility in the early diagnosis and monitoring of acute GVHD. Recent studies additionally demonstrated the implication of miRs in the pathogenesis of acute GVHD. In this review, we aim to summarize the previous reports of miRs, focusing on the pathogenesis of acute GVHD and possible implications in diagnostic approaches. PMID:25900787

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

    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.

  4. 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.

    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. PMID:20601038

  5. β2 integrins separate graft-versus-host disease and graft-versus-leukemia effects

    Liang, Yaming; Liu, Chen; Djeu, Julie Y.; Zhong, Bin; Peters, Thorsten; Scharffetter-Kochanek, Karin; Anasetti, Claudio; Yu, Xue-Zhong

    2008-01-01

    Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation. Migration of donor-derived T cells into GVHD target organs plays an essential role in the development of GVHD. β2 integrins are critically important for leukocyte extravasation through vascular endothelia and for T-cell activation. We asked whether CD18-deficient T cells would induce less GVHD while sparing the graft-versus-leukemia (GVL) effect. In murine a...

  6. Innate memory CD4+ T cells suppress autoimmune graft-versus-host disease

    Weishan Huang; Jianfang Hu; Laufer, Terri M.

    2013-01-01

    Chronic graft-versus-host disease (cGVHD) is the major complication post hematopoietic cell transplantation. Major histocompatibility complex class II (MHCII) mediated CD4+ T cell differentiation and function plays a critical role in cGVHD, and the lack of hematopoietic MHCII (H-MHCII) causes cGVHD in syngeneic irradiated murine recipients. We have studied this process using murine bone marrow transplant of MHCII deficient or sufficient donors. We find that irradiated WT recipients that recei...

  7. Heparanase Promotes Engraftment and Prevents Graft versus Host Disease in Stem Cell Transplantation

    Menachem Bitan; Lola Weiss; Michael Zeira; Eyal Zcharia; Shimon Slavin; Arnon Nagler; Israel Vlodavsky

    2010-01-01

    BACKGROUND: Heparanase, endoglycosidase that cleaves heparan sulfate side chains of heparan sulfate proteoglycans, plays important roles in cancer metastasis, angiogenesis and inflammation. DESIGN AND METHODS: Applying a mouse model of bone marrow transplantation and transgenic mice over-expressing heparanase, we evaluated the effect of heparanase on the engraftment process and the development of graft-versus-host disease. RESULTS: Analysis of F1 mice undergoing allogeneic bone marrow transpl...

  8. Extracorporeal photopheresis for chronic graft-versus-host disease: a systematic review and meta-analysis

    Malik, Mohsin Ilyas; Litzow, Mark; Hogan, William; Patnaik, Mrinal; Murad, Mohammad Hassan; Prokop, Larry J.; Winters, Jeffrey L.; Hashmi, Shahrukh

    2014-01-01

    Background The safety of extracorporeal photopheresis (ECP) in steroid-refractory chronic graft-versus-host disease (SR-cGVHD) has been explored in multiple studies but reported response rates (RR) vary significantly across studies. Methods We conducted a meta-analysis to assess the efficacy of ECP for SR-cGVHD. A search of electronic databases for studies published between 1984 and 2012 was conducted. End points included RR: complete response (CR), overall response rates (ORR), and organ-spe...

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

    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 differentia...

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

    Yuan, Lijuan; Shen, Jianliang

    2016-01-01

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

  11. Mouse models of graft-versus-host disease: advances and limitations

    Mark A. Schroeder

    2011-05-01

    Full Text Available The limiting factor for successful hematopoietic stem cell transplantation (HSCT is graft-versus-host disease (GvHD, a post-transplant disorder that results from immune-mediated attack of recipient tissue by donor T cells contained in the transplant. Mouse models of GvHD have provided important insights into the pathophysiology of this disease, which have helped to improve the success rate of HSCT in humans. The kinetics with which GvHD develops distinguishes acute from chronic GvHD, and it is clear from studies of mouse models of GvHD (and studies of human HSCT that the pathophysiology of these two forms is also distinct. Mouse models also further the basic understanding of the immunological responses involved in GvHD pathology, such as antigen recognition and presentation, the involvement of the thymus and immune reconstitution after transplantation. In this Perspective, we provide an overview of currently available mouse models of acute and chronic GvHD, highlighting their benefits and limitations, and discuss research and clinical opportunities for the future.

  12. Interleukin-10 spot-forming cells as a novel biomarker of chronic graft-versus-host disease

    Hirayama, Masahiro; Azuma, Eiichi; Nakagawa-Nakazawa, Atsuko; Kumamoto, Tadashi; Iwamoto, Shotaro; Amano, Keishiro; Tamaki, Shigehisa; Usui, Eiji; Komada, Yoshihiro

    2013-01-01

    Although there are National Institutes of Health consensus criteria for the global assessment of chronic graft-versus-host disease, no validated biomarkers have been established for this disease. Furthermore, whereas the role of T cells, B cells, and dendritic cells in chronic graft-versus-host disease has been established, the contribution of monocytes has not been clearly addressed. Using an enzyme-linked immunospot assay, we measured the spot-forming cells for interferon-γ, interleukin-4, ...

  13. Valproic Acid Ameliorates Graft-versus-Host Disease by Downregulating Th1 and Th17 Cells.

    Long, Jun; Chang, Li; Shen, Yan; Gao, Wen-Hui; Wu, Yue-Nv; Dou, Han-Bo; Huang, Meng-Meng; Wang, Ying; Fang, Wei-Yue; Shan, Jie-Hui; Wang, Yue-Ying; Zhu, Jiang; Chen, Zhu; Hu, Jiong

    2015-08-15

    Graft-versus-host disease (GVHD) is the major complication after allogeneic bone marrow transplantation. Valproic acid (VPA) was described as a histone deacetylase inhibitor that had anti-inflammatory effects and reduced the production of proinflammatory cytokines in experimental autoimmune disease models. Using well-characterized mouse models of MHC-mismatched transplantation, we studied the effects of VPA on GVHD severity and graft-versus-leukemia (GVL) activity. Administration of VPA significantly attenuated the clinical severity of GVHD, the histopathology of GVHD-involved organs, and the overall mortality from GVHD. VPA downregulated Th1 and Th17 cell responses and cytokine production in vitro and in vivo, whereas its effect on GVHD was regulatory T cell independent. The effect of VPA was related to its ability to directly reduce the activity of Akt, an important regulator of T cell immune responses. Importantly, when mice received lethal doses of host-type acute leukemia cells, administration of VPA did not impair GVL activity and resulted in significantly improved leukemia-free survival. These findings reveal a unique role for VPA as a histone deacetylase inhibitor in reducing the donor CD4(+) T cells that contribute to GVHD, which may provide a strategy to reduce GVHD while preserving the GVL effect. PMID:26179902

  14. A case of graft-versus-host disease following irradiated fresh blood transfusion

    We reported a case of a fatal graft-versus-host disease (GVHD) which developed in a 65-year-old, male patient which was considered to have been induced by irradiated fresh blood donated by his son after a coronary bypass surgery. Fresh blood was obtained from his relatives, and a 15 Gy irradiation was performed before transfusion. The diagnosis of acute GVHD was made by clinical symptoms and histological examinations of the skin and the bone marrow. He died of sepsis on the 19th post-operative day. The HLA typing of the lymphocytes, revealed that the patient had A 2, A 24, Bw 52, Bw 62, Cw 4, DR 2, and his son had A 24, Bw 52, DR 2. A 24 and Bw 52 were homogeneous making his son histocompatible with one of the patient's haplotype. This might well be attributable to the occurrence of GVHD in this case, meaning that 15 Gy irradiation was not sufficient for the prevention of this disease. (author)

  15. Separating graft-versus-leukemia from graft-versus-host disease in allogeneic hematopoietic stem cell transplantation

    Li, Jian-Ming; Giver, Cynthia R.; Lu, Ying; Hossain, Mohammad S.; Akhtari, Mojtaba; Waller, Edmund K.

    2009-01-01

    Routine methods to maximize the graft-versus-leukemia (GvL) activity of allogeneic hematopoietic stem cell transplantation (HSCT) without the detrimental effects of graft-versus-host disease (GvHD) are lacking. Depletion or inhibition of alloreactive T cells is partially effective in preventing GvHD, but usually leads to decreased GvL activity. The current model for the pathophysiology of acute GvHD describes a series of immune pathways that lead to activation of donor T cells and inflammator...

  16. Innate protection from graft-versus-host disease

    T. Cupedo (Tom)

    2014-01-01

    textabstractIn this issue of Blood, Hazenberg and Spits provide a detailed overview of human innate lymphoid cell (ILC) subsets and their development and distribution throughout the human body, discussing these cells in the context of human disease. In the same issue, Munneke et al for the first tim

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

    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.

  18. The role of programmed cell death ligand-1 (PD-L1/CD274 in the development of graft versus host disease.

    Heevy Al-Chaqmaqchi

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

  19. The Impact of HLA-E Polymorphisms in Graft-versus-Host Disease following HLA-E Matched Allogeneic Hematopoietic Stem Cell Transplantation

    Ehteramolsadat Hosseini

    2012-03-01

    Full Text Available The  non-classical MHC  class-I mainly involves in the  regulation of  innate  immune responses where HLA-E  plays a significant role in the cell identification by natural killer cells. HLA-E is a main regulatory ligand for natural killer cells and given the importance of these effector cells in hematopoietic stem cell transplantation, we investigated the effect of HLA-E polymorphisms on post-hematopoietic stem cell transplantation outcomes.The study group included 56 donor-patient pairs with underlying malignant hematological disorders undergoing HLA-E  matched allogeneic hematopoietic stem cell transplantation. They were genotyped for HLA-E locus using a sequence specific primer-polymerase chain reaction. The  median follow-up was 20.6 months  (range 0.2-114.8 and  the  parameters assessed were acute and chronic graft-versus-host disease and overall survival.We showed a lower frequency of acute graft-versus-host disease (grade II or more; p=0.02and chronic graft-versus-host disease (extensive; p=0.04 in the patients with HLA- E*0103/0103 genotype compared to other genotypes of HLA-E. There was also an association between HLA-E*0103/0103 and improved overall survival (p=0.001.Conclusively, our  results  suggest a  protective  role  for  HLA-E*0103/0103  genotypeagainst acute graft-versus-host disease (grade II or more and chronic graft-versus-host disease (extensive as well as an association between this genotype and a better overall survival after HLA-E matched allogeneic hematopoietic stem cell transplantation.

  20. Treatment of Graft-versus-Host Disease with Naturally Occurring T Regulatory Cells

    Trzonkowski, Piotr; Dukat-Mazurek, Anna; Bieniaszewska, Maria; Marek-Trzonkowska, Natalia; Dobyszuk, Anita; Juścińska, Jolanta; Dutka, Magdalena; Myśliwska, Jolanta; Hellmann, Andrzej

    2013-01-01

    A significant body of evidence suggests that treatment with naturally occurring CD4+CD25+ T regulatory cells (Tregs) is an appropriate therapy for graft-versus-host disease (GvHD). GvHD is a major complication of bone marrow transplantation in which the transplanted immune system recognizes recipient tissues as a non-self and destroys them. In many cases, this condition significantly deteriorates the quality of life of the affected patients. It is also one of the most important causes of deat...

  1. Rapamycin Prevents Experimental Sclerodermatous Chronic Graft-versus-Host Disease in mice

    Belle, Ludovic; Binsfeld, Marilène; Dubois, Sophie; Hannon, Muriel; Caers, Jo; Briquet, Alexandra; MENTEN, Catherine; Beguin, Yves; Humblet-Baron, S; Baron, Frédéric

    2012-01-01

    Background: The most widely used mice model of chronic graft-versus-host disease (cGvHD) is an MHC-matched bone marrow transplantation model of sclerodermatous cGvHD. A limitation of that model is that mortality is relatively low, making difficult to study the impact of potentially therapeutic compounds. Aims: To develop a more severe model of cGVHD and to assess the impact of Rapamycin administration in that model. Results: Lethally irradiated Balb/C mice were injected with 10x106 bon...

  2. Donor Requirements for Regulatory T Cell Suppression of Murine Graft Versus Host Disease

    Pierini, Antonio; Colonna, Lucrezia; Alvarez, Maite; Schneidawind, Dominik; Nishikii, Hidekazu; Baker, Jeanette; Pan, Yuqiong; Florek, Mareike; Kim, Byung-Su; Negrin, Robert S.

    2015-01-01

    Adoptive transfer of freshly isolated natural occurring CD4+CD25+FoxP3+ regulatory T cells (Treg) prevents graft versus host disease (GvHD) in several animal models and following hematopoietic cell transplantation (HCT) in clinical trials. Donor derived Treg have been mainly used as they share the same MHC with conventional CD4+ and CD8+ T cells (Tcon) that are primarily responsible for GvHD. Third-party derived Treg are a promising alternative for cellular therapy as they can be prepared in ...

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

    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.

  4. Tacrolimus and Mycophenolate Mofetil With or Without Sirolimus in Preventing Acute Graft-Versus-Host Disease in Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer

    2015-10-14

    Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndrome; Refractory Chronic Lymphocytic Leukemia; Refractory Plasma Cell Myeloma; Waldenstrom Macroglobulinemia; Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Lymphoma; Childhood Myelodysplastic Syndrome; Stage II Contiguous Adult Burkitt Lymphoma; Stage II Contiguous Adult Diffuse Large Cell Lymphoma; Stage II Contiguous Adult Diffuse Mixed Cell Lymphoma; Stage II Contiguous Adult Diffuse Small Cleaved Cell Lymphoma; Stage II Adult Contiguous Immunoblastic Lymphoma; Stage II Contiguous Adult Lymphoblastic Lymphoma; Stage II Grade 1 Contiguous Follicular Lymphoma; Stage II Grade 2 Contiguous Follicular Lymphoma; Stage II Grade 3 Contiguous Follicular Lymphoma; Stage II Contiguous Mantle Cell Lymphoma; Stage II Non-Contiguous Adult Burkitt Lymphoma; Stage II Non-Contiguous Adult Diffuse Large Cell Lymphoma; Stage II Non-Contiguous Adult Diffuse Mixed Cell Lymphoma; Stage II Non-Contiguous Adult Diffuse Small Cleaved Cell Lymphoma; Stage II Adult Non-Contiguous Immunoblastic Lymphoma; Stage II Non-Contiguous Adult Lymphoblastic Lymphoma; Stage II Grade 1 Non-Contiguous Follicular Lymphoma; Stage II Grade 2 Non-Contiguous Follicular Lymphoma; Stage

  5. Chronic Graft-versus-Host Disease: Disease Biology and Novel Therapeutic Strategies

    Nishimori,Hisakazu

    2013-02-01

    Full Text Available Graft-versus-host disease (GVHD is a major complication after allogeneic hematopoietic stem cell transplantation. Chronic GVHD often presents with clinical manifestations that resemble those observed in autoimmune diseases. Standard treatment is 1-2mg/kg/day of prednisone or an equivalent dose of methylprednisolone, with continued administration of a calcineurin inhibitor for steroid sparing. However, the prognosis of steroid-refractory chronic GVHD remains poor. Classically, chronic GVHD was said to involve predominantly Th2 responses. We are now faced with a more complex picture, involving possible roles for thymic dysfunction, transforming growth factor-β (TGF-β and platelet-derived growth factor (PDGF, B cells and autoantibodies, and Th1/Th2/Th17 cytokines, as well as regulatory T cells (Tregs, in chronic GVHD. More detailed research on the pathophysiology of chronic GVHD may facilitate the establishment of novel strategies for its prevention and treatment.

  6. Bilateral herpes simplex keratitis in a patient with chronic graft-versus-host disease

    Takahiko Hayashi

    2008-06-01

    Full Text Available Takahiko Hayashi1, Misaki Ishioka2, Norihiko Ito1, Yoko Kato1, Hisashi Nakagawa3, Hiroshi Hatano4, Nobuhisa Mizuki11Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan; 2Ryogoku Eye Clinic, Tokyo, Japan; 3Tokushima Eye Clinic, Higashimurayama-shi, Tokyo, Japan; 4Lumine Hatano Eye Clinic, Fujisawa, Fujisawa-shi, Kanagawa, JapanPurpose: To describe a case of bilateral herpes simplex keratitis accompanying chronic graft-versus-host disease (GVHD.Design: Observational case report.Case report: An 11-year-old boy with myelocytic leukemia underwent allogeneic bone marrow transplantation. He developed symptoms of the skin, eyes, and mouth, and lip biopsy indicated chronic GVHD. Persistent keratitis with corneal filaments and neovascularization was noted in both eyes. Sodium hyaluronate, autoserum, and 0.1% fluorometholone eyedrops were instilled for approximately 2 years to treat this keratitis, and there were no other ocular changes. Bilateral herpes simplex keratitis developed with geographic ulcers after topical betamethasone therapy, but responded to acyclovir ointment.Conclusions: Herpes keratitis should be considered in the differential diagnosis of bilateral keratitis in patients with reduced immunocompetence. During the course of chronic GVHD, corneal herpes may occur, so ocular treatment with topical corticosteroids should be managed by an ophthalmologist to monitor sight-threatening conditions such as corneal herpes.Keywords: chronic graft-versus-host disease, bone marrow transplant, corneal herpes, bilateral herpes simplex keratitis, dry eyes

  7. Impact of Ocular Chronic Graft-versus-Host Disease on Quality of Life.

    Sun, Yi-Chen; Chai, Xiaoyu; Inamoto, Yoshihiro; Pidala, Joseph; Martin, Paul J; Flowers, Mary E D; Shen, Tueng T; Lee, Stephanie J; Jagasia, Madan

    2015-09-01

    Ocular involvement can be quite symptomatic in patients with chronic graft-versus-host disease (GVHD). The prevalence of and risk factors for ocular GVHD and its impact on quality of life (QOL) in patients with chronic GVHD were studied in a prospective, multicenter, longitudinal, observational study. This study enrolled 342 patients with 1483 follow-up visits after allogeneic hematopoietic cell transplantation. All patients in this analysis were diagnosed with chronic GVHD requiring systemic treatment and enrolled within 3 months of chronic GVHD diagnosis. The symptom burden of ocular GVHD was based on the degree of dry eye symptoms, frequency of artificial tear usage, and impact on activities of daily living. Patients' QOL was measured by self-administered questionnaires. Variables associated with ocular GVHD at enrollment and subsequent new-onset ocular GVHD and the associations with QOL were studied. Of the 284 chronic GVHD patients, 116 (41%) had ocular GVHD within 3 months of chronic GVHD diagnosis ("early ocular GVHD"). Late ocular GVHD (new onset > 3 months after chronic GVHD diagnosis) occurred in 64 patients. Overall cumulative incidence at 2 years was 57%. Female gender (P = .005), higher acute GVHD grade (P = .04), and higher prednisone dose at study entry (P = .04) were associated with early ocular GVHD. For patients who did not have ocular GVHD within 3 months of chronic GVHD diagnosis, presence of prior grades I to IV acute GVHD (HR 1.78, P = .04) was associated with shorter time to late ocular GVHD, whereas female donor-male recipient (HR .53, P = .05) was associated with longer time to late ocular GVHD onset. Using all visit data, patients with ocular GVHD had worse QOL, as measured by Functional Assessment of Cancer Therapy Bone Marrow Transplantation (P = .002), and greater chronic GVHD symptom burden, as measured by the Lee symptom overall score excluding the eye component (P history of acute GVHD were at higher risk for ocular GVHD. Strong

  8. The Role of Pattern-Recognition Receptors in Graft-Versus-Host Disease and Graft-Versus-Leukemia after Allogeneic Stem Cell Transplantation

    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 inv...

  9. Experimental study of ANNAO tablets on preventing acute graft-versus-host disease in bone marrow transplanted mice%安脑片干预异体移植小鼠aGVHD效应的实验研究

    吴顺杰; 罗藤; 黄海定

    2012-01-01

    In order to observe the effect of ANNAO tablets on acute graft versus host disease, we set up an acute graft-versus-host disease mouse model. Hematopoietic stem cells of male Balb/c mice were transplanted to female C57BL/6 mice, which was irradiated by 60Co X rays with dose 9.0 Gy before transplantation. Then recipient mice were randomly divided into two groups (ANNAO group and blank group), and respectively administrated with ANNAO soup and 0.9% sodium chloride intragastrically. We observed and recorded clinical symptom, survival time and body weight of mice everyday during observation time. At day 15 posttransplantation, three mice died and seven mice survived in ANNAO group, and their mean survival time was 27.3 days, which was much longer than blank group (their mean survival time was 11.9 days). The majority of ANNAO group demonstrated good mental state, good appetite, no weigh loss, normal stool, and burnish hairs after day 12. Their clinical scores of skin, weight, diarrhea, posture and activity were respectively 0.10 ± 032, 020 ± 0.42, 0.12 ± 0.00, and 0.10 ± 0.10, with the whole score of ANNAO group being 0.31 ± 0.14, which was distinctly different as compared with that of blank group (P = 0.000). 30 days later, survived mice were sacrificed and the samples of liver, intestine and skin were taken to observe histological features. We found there some improvements in liver, skin, and intestine tissue of ANNAO group as compared with blank control group. In conclusion, ANNAO tablets can relieve symptoms of acute GVHD mice effectively and prolong their survival time, and improve histopathological manifestations.%目的 观察中药安脑片对异体移植小鼠aGVHD的干预作用.方法 SPF级Balb/c雄性小鼠作为供鼠.以SPF级C57BL/6雌性小鼠为受鼠,建立aGVHD模型,分为安脑片组和空白组,每组10只.观察期间记录小鼠的一般状况及称质量、存活时间,给予临床aGVHD评价,移植后第30天杀鼠取材,制备肝脏、

  10. Prevention of graft-versus-host disease by a novel immunosuppressant LLT, through expansion of regulatory T cells

    WeiTANG; RuZHOU; Pei-lanHE; Xiao-yuLI; Yi-fuYANG; Jian-pingZUO

    2005-01-01

    AIM To evaluate the validity of LLT in prevention and therapy of acute graft versus host disease and to clarify the underlying mechanisms. LLT is a new compound derived from triptolide, which is the major immunosuppressive fraction of Tripterygium wilfordii Hook. F (TWHF). Studies in vitro and in vivo demonstrated that LLT had potent immunosuppressive activities. Here we tested the immunosuppressive effects of LLT in murine allogeneic bone marrow transplantation (BMT) and investigated the mechanisms underlying its suppressive effects. METHODS LLT was administered to recipients in BALB/cA→C57BL/6 murine BMT model, in which donor and recipient differ at major and minor histocompatibility antigens.Survival and weight change were recorded in recipients after alloBMT. Spleen size, chimerism and splenic T cell subpopulation were analysed by using flow cytometry.

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

  12. Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease.

    Flynn, Ryan; Allen, Jessica L; Luznik, Leo; MacDonald, Kelli P; Paz, Katelyn; Alexander, Kylie A; Vulic, Ante; Du, Jing; Panoskaltsis-Mortari, Angela; Taylor, Patricia A; Poe, Jonathan C; Serody, Jonathan S; Murphy, William J; Hill, Geoffrey R; Maillard, Ivan; Koreth, John; Cutler, Corey S; Soiffer, Robert J; Antin, Joseph H; Ritz, Jerome; Chao, Nelson J; Clynes, Raphael A; Sarantopoulos, Stefanie; Blazar, Bruce R

    2015-06-25

    Novel therapies for chronic graft-versus-host disease (cGVHD) are needed. Aberrant B-cell activation has been demonstrated in mice and humans with cGVHD. Having previously found that human cGVHD B cells are activated and primed for survival, we sought to further evaluate the role of the spleen tyrosine kinase (Syk) in cGVHD in multiple murine models and human peripheral blood cells. In a murine model of multiorgan system, nonsclerodermatous disease with bronchiolitis obliterans where cGVHD is dependent on antibody and germinal center (GC) B cells, we found that activation of Syk was necessary in donor B cells, but not T cells, for disease progression. Bone marrow-specific Syk deletion in vivo was effective in treating established cGVHD, as was a small-molecule inhibitor of Syk, fostamatinib, which normalized GC formation and decreased activated CD80/86(+) dendritic cells. In multiple distinct models of sclerodermatous cGVHD, clinical and pathological disease manifestations were not eliminated when mice were therapeutically treated with fostamatinib, though both clinical and immunologic effects could be observed in one of these scleroderma models. We further demonstrated that Syk inhibition was effective at inducing apoptosis of human cGVHD B cells. Together, these data demonstrate a therapeutic potential of targeting B-cell Syk signaling in cGVHD. PMID:25852057

  13. Graft versus host disease: New insights into A2A receptor agonist therapy

    Karlie R. Jones

    2015-01-01

    Full Text Available Allogeneic transplantation can cure many disorders, including sickle cell disease, chronic granulomatous disease (CGD, severe combined immunodeficiency (SCID and many types of cancers. However, there are several associated risks that can result in severe immunological reactions and, in some cases, death. Much of this morbidity is related to graft versus host disease (GVHD [1]. GVHD is an immune mediated reaction in which donor T cells recognize the host as antigenically foreign, causing donor T cells to expand and attack host tissues. The current method of treating recent transplant patients with immunosuppressants to prevent this reaction has met with only partial success, emphasizing a need for new methods of GVHD treatment and prevention. Recently, a novel strategy has emerged targeting adenosine A2A receptors (A2AR through the use of adenosine agonists. These agonists have been shown in vitro to increase the TGFβ-induced generation of FoxP3+ regulatory T cells (Tregs and in vivo to improve weight gain and mortality as well as inhibit the release of pro-inflammatory cytokines in GVHD murine models [2,3]. Positive results involving A2AR agonists in vitro and in vivo are promising, suggesting that A2AR agonists should be a part of the management of clinical GvHD.

  14. Graft-versus-host disease after liver transplantation: A comprehensive literature review

    Sami Akbulut; Mehmet Yilmaz; Sezai Yilmaz

    2012-01-01

    AIM:To determine the factors affecting mortality in patients who developed graft-versus-host disease (GvHD) after liver transplantation (LT).METHODS:We performed a review of studies of GvHD following LT published in the English literature and accessed the PubMed,Medline,EBSCO,EMBASE,and Google Scholar databases.Using relevant search phrases,88 articles were identified.Of these,61 articles containing most of the study parameters were considered eligible for the study.Risk factors were first examined using a univariate Kaplan-Meier model,and variables with a significant association (P < 0.05) were then subjected to multivariate analyses using a Cox proportional-hazards model.RESULTS:The 61 articles reported 87 patients,58 male and 29 female,mean age,40.4 ± 15.5 years (range:8 mo to 74 years),who met the inclusion criteria for the present study.Deaths occurred in 59 (67.8%) patients,whereas 28 (32.2%) survived after a mean follow-up period of 280.8 ± 316.2 d (range:27-2285 d).Among the most frequent symptoms were rash (94.2%),fever (66.6%),diarrhea (54%),and pancytopenia (54%).The average time period between LT and first symptom onset was 60.6 ± 190.1 d (range:2-1865 d).The Kaplan-Meier analysis revealed that pancytopenia (42.8% vs 59.3%,P =0.03),diarrhea (39.2% vs 61.0%,P =0.04),age difference between the recipient and the donor (14.6 ± 3.1 years vs 22.6 ± 2.7 years,P < 0.0001),and time from first symptom occurrence to diagnosis or treatment (13.3 ± 2.6 mo vs 15.0 ± 2.3 mo,P < 0.0001) were significant factors affecting mortality,whereas age,sex,presence of rash and fever,use of immunosuppressive agents,acute rejection before GvHD,etiological causes,time of onset,and donor type were not associated with mortality risk.The Cox proportional-hazards model,determined that an age difference between the recipient and donor was an independent risk factor (P =0.03;hazard ratio,7.395,95% confidence interval,1.2-46.7).CONCLUSION:This study

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

    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.

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

    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

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

    Long Wang

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

  18. Miniature Swine as a Clinically Relevant Model of Graft-Versus-Host Disease

    Duran-Struuck, Raimon; Huang, Christene A; Orf, Katherine; Bronson, Roderick T; Sachs, David H; Spitzer, Thomas R

    2015-01-01

    Miniature swine provide a preclinical model of hematopoietic cell transplantation (HCT) for studies of graft-versus-host disease. HCT between MHC-matched or ‑mismatched pigs can be performed to mimic clinical scenarios with outcomes that closely resemble those observed in human HCT recipients. With myeloablative conditioning, HCT across MHC barriers is typically fatal, with pigs developing severe (grade III or IV) GVHD involving the gastrointestinal tract, liver, and skin. Unlike rodent models, miniature swine provide an opportunity to perform extended longitudinal studies on individual animals, because multiple tissue biopsies can be harvested without the need for euthanasia. In addition, we have developed a swine GVHD scoring system that parallels that used in the human clinical setting. Given the similarities of GVHD in pigs and humans, we hope that the use of this scoring system facilitates clinical and scientific discourse between the laboratory and the clinic. We anticipate that results of swine studies will support the development of new strategies to improve the identification and treatment of GVHD in clinical HCT scenarios. PMID:26473348

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

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

  20. Treatment of graft-versus-host disease with naturally occurring T regulatory cells.

    Trzonkowski, Piotr; Dukat-Mazurek, Anna; Bieniaszewska, Maria; Marek-Trzonkowska, Natalia; Dobyszuk, Anita; Juścińska, Jolanta; Dutka, Magdalena; Myśliwska, Jolanta; Hellmann, Andrzej

    2013-12-01

    A significant body of evidence suggests that treatment with naturally occurring CD4(+)CD25(+) T regulatory cells (Tregs) is an appropriate therapy for graft-versus-host disease (GvHD). GvHD is a major complication of bone marrow transplantation in which the transplanted immune system recognizes recipient tissues as a non-self and destroys them. In many cases, this condition significantly deteriorates the quality of life of the affected patients. It is also one of the most important causes of death after bone marrow transplantation. Tregs constitute a population responsible for dominant tolerance to self-tissues in the immune system. These cells prevent autoimmune and allergic reactions and decrease the risk of rejection of allotransplants. For these reasons, Tregs are considered as a cellular drug in GvHD. The results of the first clinical trials with these cells are already available. In this review we present important experimental facts which led to the clinical use of Tregs. We then critically evaluate specific requirements for Treg therapy in GvHD and therapies with Tregs currently under clinical investigation, including our experience and future perspectives on this kind of cellular treatment. PMID:23813436

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

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

    2008-10-15

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

  2. Risk factors for syngeneic graft-versus-host disease after adult hematopoietic cell transplantation.

    Adams, Kristina M; Holmberg, Leona A; Leisenring, Wendy; Fefer, Alexander; Guthrie, Katherine A; Tylee, Tracy S; McDonald, George B; Bensinger, William I; Nelson, J Lee

    2004-09-15

    Syngeneic graft-versus-host disease (sGVHD) has been described after hematopoietic cell transplantation (HCT) but remains poorly defined. We retrospectively reviewed adult syngeneic HCTs at our center (1980-2002) for sGVHD to investigate incidence, morbidity, and risk factors with a primary focus on parity. Among 119 transplantations, there were 21 cases of biopsy-proven sGVHD. The cumulative incidence was 18%, with multiorgan involvement in 6 cases and 1 death. sGVHD was more frequent when the donor was parous (32%) than nulliparous (9%) or male (13%; P =.03) and when the recipient was parous (31%) than nulliparous (7%) or male (13%; P =.02). Other univariable risk factors included older age (P <.01), busulfan/melphalan/thiotepa conditioning (P <.01), interleukin-2 (P =.02), HLA-A26 (P =.03), and more recent transplantation year (P <.01). Overall, risk factors were similar to those described in GVHD. Although an independent effect of parity could not be completely separated from other factors, donor and recipient pregnancy history merits further investigation. PMID:15117763

  3. Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease

    Li, Wei; Liu, Liangyi; Gomez, Aurelie; Zhang, Jilu; Ramadan, Abdulraouf; Zhang, Qing; Choi, Sung W.; Zhang, Peng; Greenson, Joel K.; Liu, Chen; Jiang, Di; Virts, Elizabeth; Kelich, Stephanie L.; Chu, Hong Wei; Flynn, Ryan; Blazar, Bruce R.; Hanenberg, Helmut; Hanash, Samir; Paczesny, Sophie

    2016-01-01

    Gastrointestinal graft-versus-host-disease (GI-GVHD) is a life-threatening complication occurring after allogeneic hematopoietic cell transplantation (HCT), and a blood biomarker that permits stratification of HCT patients according to their risk of developing GI-GVHD would greatly aid treatment planning. Through in-depth, large-scale proteomic profiling of presymptomatic samples, we identified a T cell population expressing both CD146, a cell adhesion molecule, and CCR5, a chemokine receptor that is upregulated as early as 14 days after transplantation in patients who develop GI-GVHD. The CD4+CD146+CCR5+ T cell population is Th17 prone and increased by ICOS stimulation. shRNA knockdown of CD146 in T cells reduced their transmigration through endothelial cells, and maraviroc, a CCR5 inhibitor, reduced chemotaxis of the CD4+CD146+CCR5+ T cell population toward CCL14. Mice that received CD146 shRNA–transduced human T cells did not lose weight, showed better survival, and had fewer CD4+CD146+CCR5+ T cells and less pathogenic Th17 infiltration in the intestine, even compared with mice receiving maraviroc with control shRNA– transduced human T cells. Furthermore, the frequency of CD4+CD146+CCR5+ Tregs was increased in GI-GVHD patients, and these cells showed increased plasticity toward Th17 upon ICOS stimulation. Our findings can be applied to early risk stratification, as well as specific preventative therapeutic strategies following HCT. PMID:27195312

  4. Ocular Graft Versus Host Disease Following Allogeneic Stem Cell Transplantation: A Review of Current Knowledge and Recommendations

    Nariman Nassiri; Medi Eslani; Nekoo Panahi; Shiva Mehravaran; Alireza Ziaei; Djalilian, Ali R.

    2013-01-01

    Graft versus host disease (GVHD) is a common complication of allogeneic stem cell transplantation (allo-SCT). Ocular GVHD develops in approximately 40-60% of patients following allo-SCT and its most common clinical manifestations include keratoconjunctivitis sicca and cicatricial conjunctivitis. Ocular GVHD may lead to severe ocular surface disease, which can significantly diminish quality of life and restrict daily activities. It is thus important to monitor the condition closely since with ...

  5. Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease

    ZHENG, HONG; Matte-Martone, Catherine; Li, Hongmei; Anderson, Britt E.; Venketesan, Srividhya; Sheng Tan, Hung; Jain, Dhanpat; McNiff, Jennifer; Shlomchik, Warren D.

    2008-01-01

    Much of the efficacy of allogeneic hematopoietic stem cell transplantation (alloSCT) in curing hematologic malignancies is due to a graft-versus-leukemia (GVL) effect mediated by donor T cells that recognize recipient alloantigens on leukemic cells. Donor T cells are also important for reconstituting immunity in the recipient. Unfortunately, donor T cells can attack nonmalignant host tissues and cause graft-versus-host disease (GVHD). We previously reported that donor CD4+ effector memory T c...

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

    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)

  7. Emerging new clinical applications for palifermin: beyond its use in oral mucositis and graft versus host disease

    Kapoor S

    2012-06-01

    Full Text Available Shailendra KapoorRichmond, VA, USATo the editorI read with great interest the recent article by Barasch et al in a recent issue of your journal. The article is highly thought-provoking. Interestingly, the past few years have seen the emergence of a number of novel clinical applications of palifermin, in addition to its use in oral mucositis and graft versus host disease.  

  8. Emerging new clinical applications for palifermin: beyond its use in oral mucositis and graft versus host disease

    Kapoor S

    2012-01-01

    Shailendra KapoorRichmond, VA, USATo the editorI read with great interest the recent article by Barasch et al in a recent issue of your journal. The article is highly thought-provoking. Interestingly, the past few years have seen the emergence of a number of novel clinical applications of palifermin, in addition to its use in oral mucositis and graft versus host disease.  

  9. Fecal calprotectin as a biomarker of intestinal graft versus host disease after allogeneic hematopoietic stem cell transplantation

    Lorenz, Fryderyk; Marklund, Stefan; Werner, Mårten; Palmqvist, Richard; Wahlin, Bjorn Engelbrekt; Wahlin, Anders

    2015-01-01

    The diagnosis of gastrointestinal graft versus host disease (GI-GVHD) is based on clinical symptoms and histological findings. In clinical practice, it is often difficult to decide whether abdominal symptoms in an allogeneic transplant recipient are caused by GVHD or other disorders. Endoscopic biopsies are helpful in establishing the diagnosis, but endoscopy is not always possible to perform due to poor general condition of the patients. No biomarkers are routinely used to predict GVHD. The ...

  10. Anaplerotic Metabolism of Alloreactive T Cells Provides a Metabolic Approach To Treat Graft-Versus-Host Disease

    Glick, Gary D.; Rossignol, Rodrigue; Lyssiotis, Costas A.; Wahl, Daniel; Lesch, Charles; Sanchez, Brian; Liu, Xikui; Hao, Ling-Yang; Taylor, Clarke; Hurd, Alexander; Ferrara, James L. M.; Tkachev, Victor; Byersdorfer, Craig A.; Boros, Laszlo; Opipari, Anthony W.

    2014-01-01

    T-cell activation requires increased ATP and biosynthesis to support proliferation and effector function. Most models of T-cell activation are based on in vitro culture systems and posit that aerobic glycolysis is employed to meet increased energetic and biosynthetic demands. By contrast, T cells activated in vivo by alloantigens in graft-versus-host disease (GVHD) increase mitochondrial oxygen consumption, fatty acid uptake, and oxidation, with small increases of glucose uptake and aerobic g...

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

    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. Comments on Brazilian workshop model for training investigators in chronic graft-versus-host disease according to the 2005-2006 National Institutes of Health recommendations

    Rita de Cássia Barbosa da Silva Tavares; Márcia de Matos Silva; Luis Fernando da Silva Bouzas; Maria Cláudia Rodrigues; Afonso Celso Vigorito; Vaneusa Funke; Marcos Mauad; Maria Elvira Pizzigatti Correa; Clarissa Vasconcellos de Souza; Elenaide Nunes; Alessandra Ferrari; Ariana Paixão; Talita Martins; Érika Pallottino; Mary Evelyn Dantas Flowers

    2011-01-01

    BACKGROUND: The lack of standardization of clinical diagnostic criteria, classification and severity scores of chronic graft-versus-host disease led the National Institutes of Health to propose consensus criteria for the purpose of clinical trials. METHODS: Here we describe a one-day workshop model conducted by the Chronic Graft-versus-Host Disease Brazil-Seattle Consortium Study Group to train investigators interested in participating in multicenter clinical trials in Brazil. Workshop partic...

  13. Targeting the IL17 pathway for the prevention of graft-versus-host disease.

    van der Waart, Anniek B; van der Velden, Walter J F M; Blijlevens, Nicole M; Dolstra, Harry

    2014-06-01

    Graft-versus-host disease (GVHD) is still a major complication of allogeneic stem cell transplantation (allo-SCT). The pathophysiology of GVHD is a multistep process initiated by tissue damage and proinflammatory cytokine cascades induced by the pretransplantation conditioning therapy. This eventually results in Th1-driven tissue damage. However, increasing evidence indicates the involvement of IL17-producing T cells in GVHD pathogenesis. Both CD4(+) and CD8(+) IL17-producing T cells are suspected of initiating the Th1 response and aggravating tissue inflammation, resulting in full-blown GVHD. In this review, we discuss the involvement of IL17-producing T cells in GVHD and the factors involved in their expansion, differentiation, and activation. Different dendritic cell (DC) subsets, such as plasmacytoid DCs and DC NK lectin group receptor 1(+) myeloid DCs have the capability to stimulate Th/Tc17 responses through the release of cytokines. Pivotal cytokines include IL1β, IL6, IL23, and TGFβ, which are known to drive differentiation and expansion of IL17-producing T cells, and these cytokines are highly elevated in patients after allo-SCT. Potent activators of these DC subsets are motifs that are released upon tissue damage and microbial exposure during allo-SCT. These motifs aggravate the Th/Tc17 response via the activation of various pathogen recognition receptors, thereby initiating and perpetuating GVHD. A more comprehensive understanding of the factors and DC subsets driving the IL17 pathway will result in developing and testing novel therapeutic approaches for the prevention of GVHD. PMID:24565991

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

    Mauro M. Teixeira

    2013-07-01

    Full Text Available 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.

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

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

  16. CCR1/CCL5 (RANTES) receptor-ligand interactions modulate allogeneic T-cell responses and graft-versus-host disease following stem-cell transplantation

    Choi, Sung W.; Hildebrandt, Gerhard C.; Olkiewicz, Krystyna M.; Hanauer, David A.; Chaudhary, Meghana N.; Silva, Ines A.; Rogers, Clare E.; Deurloo, Daphne T.; Fisher, Jacki M.; Liu, Chen; Adams, David; Chensue, Stephen W.; Cooke, Kenneth R.

    2007-01-01

    Acute graft-versus-host disease (GVHD) and leukemic relapse are serious complications of allogeneic stem-cell transplantation (SCT). Recruitment of activated T cells to host target tissues or sites of leukemic infiltration (graft-versus-leukemia [GVL]) is likely mediated by chemokine receptor–ligand interactions. We examined the contribution of donor cell CCR1 expression to the development of GVHD and GVL using a well-established murine SCT model (B6 → B6D2F1) and CCR1-deficient mice (CCR1−/−...

  17. TGF-β Codon 25 Polymorphism and the Risk of Graft-Versus-Host Disease after Allogenic Hematopoietic Stem Cell Transplantation

    Ali Rashidi–Nezhad

    2010-03-01

    Full Text Available Some of the genotypes of cytokines are associated with acute graft versus host disease after bone marrow transplantation. The purpose of the present investigation was to find out the possible association between transforming growth factor beta-1 (TGF-β1 codon 25 polymorphism (rs:1800471 and acute graft versus host disease (aGVHD after bone marrow transplantation from the sibling with the similar HLA among the Iranian population. In this retrospective case-control investigation, 172 subjects including 86 Iranian patients and their siblings with the similar HLA as donor/recipient pairs were recruited. All of the patients were diagnosed with one group of blood disorder consisting of Acute Myeloid Leukemia (AML=40, Acute Lymphoblastic Leukemia (ALL=25 and Chronic Myeloid Leukemia (CML=21. PCR-SSP method was carried out to ascertain TGF- β1 codon 25 G/C polymorphism genotypes. The frequency of TGF- β1 codon 25 GG, GC and CC genotypes among all cases were 77.3%, 21.5% and 1.2%, respectively. Recipients with the GG genotype developed severe aGVHD significantly more than those with CC or GC genotypes (Odds Ratio =12.133, P=0.015. Genetic background of TGF-β1 may be involved in aGVHD development and/or severity in the patients who received Bone Marrow Transplantation (BMT from their siblings with the similar HLA among the Iranian population.

  18. Mesenchymal stromal cells from pooled mononuclear cells of multiple bone marrow donors as rescue therapy in pediatric severe steroid-refractory graft-versus-host disease: a multicenter survey.

    Kuçi, Zyrafete; Bönig, Halvard; Kreyenberg, Hermann; Bunos, Milica; Jauch, Anna; Janssen, Johannes W G; Škifić, Marijana; Michel, Kristina; Eising, Ben; Lucchini, Giovanna; Bakhtiar, Shahrzad; Greil, Johann; Lang, Peter; Basu, Oliver; von Luettichau, Irene; Schulz, Ansgar; Sykora, Karl-Walter; Jarisch, Andrea; Soerensen, Jan; Salzmann-Manrique, Emilia; Seifried, Erhard; Klingebiel, Thomas; Bader, Peter; Kuçi, Selim

    2016-08-01

    To circumvent donor-to-donor heterogeneity which may lead to inconsistent results after treatment of acute graft-versus-host disease with mesenchymal stromal cells generated from single donors we developed a novel approach by generating these cells from pooled bone marrow mononuclear cells of 8 healthy "3(rd)-party" donors. Generated cells were frozen in 209 vials and designated as mesenchymal stromal cell bank. These vials served as a source for generation of clinical grade mesenchymal stromal cell end-products, which exhibited typical mesenchymal stromal cell phenotype, trilineage differentiation potential and at later passages expressed replicative senescence-related markers (p21 and p16). Genetic analysis demonstrated their genomic stability (normal karyotype and a diploid pattern). Importantly, clinical end-products exerted a significantly higher allosuppressive potential than the mean allosuppressive potential of mesenchymal stromal cells generated from the same donors individually. Administration of 81 mesenchymal stromal cell end-products to 26 patients with severe steroid-resistant acute graft-versus-host disease in 7 stem cell transplant centers who were refractory to many lines of treatment, induced a 77% overall response at the primary end point (day 28). Remarkably, although the cohort of patients was highly challenging (96% grade III/IV and only 4% grade II graft-versus-host disease), after treatment with mesenchymal stromal cell end-products the overall survival rate at two years follow up was 71±11% for the entire patient cohort, compared to 51.4±9.0% in graft-versus-host disease clinical studies, in which mesenchymal stromal cells were derived from single donors. Mesenchymal stromal cell end-products may, therefore, provide a novel therapeutic tool for the effective treatment of severe acute graft-versus-host disease. PMID:27175026

  19. Mesenchymal stromal cells from pooled mononuclear cells of multiple bone marrow donors as rescue therapy in pediatric severe steroid-refractory graft-versus-host disease: a multicenter survey

    Kuçi, Zyrafete; Bönig, Halvard; Kreyenberg, Hermann; Bunos, Milica; Jauch, Anna; Janssen, Johannes W.G.; Škifić, Marijana; Michel, Kristina; Eising, Ben; Lucchini, Giovanna; Bakhtiar, Shahrzad; Greil, Johann; Lang, Peter; Basu, Oliver; von Luettichau, Irene; Schulz, Ansgar; Sykora, Karl-Walter; Jarisch, Andrea; Soerensen, Jan; Salzmann-Manrique, Emilia; Seifried, Erhard; Klingebiel, Thomas; Bader, Peter; Kuçi, Selim

    2016-01-01

    To circumvent donor-to-donor heterogeneity which may lead to inconsistent results after treatment of acute graft-versus-host disease with mesenchymal stromal cells generated from single donors we developed a novel approach by generating these cells from pooled bone marrow mononuclear cells of 8 healthy “3rd-party” donors. Generated cells were frozen in 209 vials and designated as mesenchymal stromal cell bank. These vials served as a source for generation of clinical grade mesenchymal stromal cell end-products, which exhibited typical mesenchymal stromal cell phenotype, trilineage differentiation potential and at later passages expressed replicative senescence-related markers (p21 and p16). Genetic analysis demonstrated their genomic stability (normal karyotype and a diploid pattern). Importantly, clinical end-products exerted a significantly higher allosuppressive potential than the mean allosuppressive potential of mesenchymal stromal cells generated from the same donors individually. Administration of 81 mesenchymal stromal cell end-products to 26 patients with severe steroid-resistant acute graft-versus-host disease in 7 stem cell transplant centers who were refractory to many lines of treatment, induced a 77% overall response at the primary end point (day 28). Remarkably, although the cohort of patients was highly challenging (96% grade III/IV and only 4% grade II graft-versus-host disease), after treatment with mesenchymal stromal cell end-products the overall survival rate at two years follow up was 71±11% for the entire patient cohort, compared to 51.4±9.0% in graft-versus-host disease clinical studies, in which mesenchymal stromal cells were derived from single donors. Mesenchymal stromal cell end-products may, therefore, provide a novel therapeutic tool for the effective treatment of severe acute graft-versus-host disease. PMID:27175026

  20. IL-11 separates graft-versus-leukemia effects from graft-versus-host disease after bone marrow transplantation

    Teshima, Takanori; Hill, Geoffrey R.; Pan, Luying; Brinson, Yani S.; van den Brink, Marcel R. M.; Cooke, Kenneth R.; Ferrara, James L.M.

    1999-01-01

    We recently showed that IL-11 prevents lethal graft-versus-host disease (GVHD) in a murine bone marrow transplantation (BMT) model of GVHD directed against MHC and minor antigens. In this study, we have investigated whether IL-11 can maintain a graft-versus-leukemia (GVL) effect. Lethally irradiated B6D2F1 mice were transplanted with either T cell–depleted (TCD) bone marrow (BM) alone or with BM and splenic T cells from allogeneic B6 donors. Animals also received host-type P815 mastocytoma ce...

  1. Mechanisms of Cyclic Nucleotide Phosphodiesterases in Modulating T Cell Responses in Murine Graft-versus-Host Disease

    Weber, Michael; Lupp, Corinna; Stein, Pamela; Kreft, Andreas; Bopp, Tobias; WEHLER, THOMAS C.; Schmitt, Edgar; Schild, Hansjörg; Radsak, Markus P.

    2013-01-01

    Graft-versus-host disease (GvHD) is a key contributor to the morbidity and mortality after allogeneic hematopoetic stem cell transplantation (HSCT). Regulatory Foxp3+ CD4+ T cells (Treg) suppress conventional T cell activation and can control GvHD. In our previous work, we demonstrate that a basic mechanism of Treg mediated suppression occurs by the transfer of cyclic adenosine monophosphate (cAMP) to responder cells. Whether this mechanism is relevant for Treg mediated suppression of GvHD is...

  2. Induction of Graft-versus-host Disease and In Vivo T Cell Monitoring Using an MHC-matched Murine Model

    Anthony, Bryan A.; Hadley, Gregg A.

    2012-01-01

    Graft-versus-host disease (GVHD) is the limiting barrier to the broad use of bone marrow transplant as a curative therapy for a variety of hematological deficiencies. GVHD is caused by mature alloreactive T cells present in the bone marrow graft that are infused into the recipient and cause damage to host organs. However, in mice, T cells must be added to the bone marrow inoculum to cause GVHD. Although extensive work has been done to characterize T cell responses post transplant, bioluminesc...

  3. Essential Role of Interleukin-12/23p40 in the Development of Graft-versus-Host Disease in Mice.

    Wu, Yongxia; Bastian, David; Schutt, Steven; Nguyen, Hung; Fu, Jianing; Heinrichs, Jessica; Xia, Changqing; Yu, Xue-Zhong

    2015-07-01

    Graft-versus-host disease (GVHD), in both its acute (aGVHD) and chronic (cGVHD) forms, remains a major obstacle impeding successful allogeneic hematopoietic stem cell transplantation (allo-HSCT). T cells, in particular pathogenic T helper (Th) 1 and Th17 subsets, are a driving force for the induction of GVHD. IL-12 and IL-23 cytokines share a common p40 subunit and play a critical role in driving Th1 differentiation and in stabilizing the Th17 phenotype, respectively. In our current study, we hypothesized that p40 is an essential cytokine in the development of GVHD. By using p40-deficient mice, we found that both donor- and host-derived p40 contribute to the development of aGVHD. Neutralization of p40 with an anti-p40 mAb inhibited Th1- and Th17-polarization in vitro. Furthermore, anti-p40 treatment reduced aGVHD severity while preserving the graft-versus-leukemia (GVL) activity. Alleviation of aGVHD was associated with an increase of Th2 differentiation and a decrease of Th1 and Th17 effector T cells in the GVHD target organs. In addition, anti-p40 treatment attenuated the severity of sclerodermatous cGVHD. These results provide a strong rationale that blockade of p40 may represent a promising therapeutic strategy in preventing and treating aGVHD and cGVHD while sparing the GVL effect after allo-HSCT. PMID:25846718

  4. Immunobiology of the graft-versus-host reaction. I. Symptons of graft-versus-host disease in mice are preceded by delayed-type hypersensitivity to host histocompatibility antigens

    During initiation of an acute graft-versus-host reaction by injection of C57BL/Rij spleen cells into lethally irradiated (C57BL/Rij x CBA/Rij)F1 hybrid mice, a state of delayed-type hypersensitivity (DTH) against host histocompatibility (H) antigens occurs. This was demonstrated by means of transfer of host spleen and lymph node cells into C57BL/Rij recipients, which received a challenge with CBA/Rij spleen cells. Initiation and transfer of the graft-versus-host-related DTH reactivity was highly dependent on Thy-1.2+ cells. The development of DTH reactivity started between 8 and 24 hr after semiallogeneic spleen cell transplantation and increased during the days thereafter. In the spleen maximum DTH reactivity was found on day 4, whereas in the lymph nodes maximal reactivity occurred on day 5 after irradiation and reconstitution. Thereafter, the reactivity decreased until there was no further DTH reactivity--demonstrable on day 13. The specificity of the DTH reactivity for host H antigens was proved by no reactivity to a challenge of DBA/2 and Swiss spleen cells, which are H-2-incompatible with CBA cells

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

    Rehan Khan

    2015-01-01

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

  6. Bortezomib for the prevention and treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

    Al-Homsi, Ahmad Samer; Feng, Yuxin; Duffner, Ulrich; Al Malki, Monzr M; Goodyke, Austin; Cole, Kelli; Muilenburg, Marlee; Abdel-Mageed, Aly

    2016-09-01

    Allogeneic hematopoietic stem cell transplantation is the standard treatment for a variety of benign and malignant conditions. However, graft-versus-host disease (GvHD) continues to present a major barrier to the success and wide applicability of this procedure. Although current GvHD prevention and treatment regimens exclusively target T cells, bortezomib, a reversible proteasome inhibitor, possesses unique immune regulatory activities that span a wide variety of cellular processes of T and dendritic cells essential for the development of GvHD. Herein, we review the current understanding of the effects of bortezomib in vitro and in animal models and summarize the clinical data relevant to its use in the prevention and treatment of GvHD. We conclude with an outline of the remaining challenges and opportunities to optimize bortezomib's potential role in this setting. PMID:27224851

  7. The oral manifestations of chronic graft-versus-host disease (cGVHD) in paediatric allogeneic bone marrow transplant recipients.

    Nicolatou-Galitis, O; Kitra, V; Van Vliet-Constantinidou, C; Peristeri, J; Goussetis, E; Petropoulos, D; Grafakos, S

    2001-03-01

    The oral manifestations of chronic graft-versus-host disease (cGVHD) in eight allogeneic bone marrow transplant (BMT) paediatric recipients were studied clinically, and lip biopsies were performed in seven of them. A prominent lichenoid reaction was observed in four patients, two with accompanying ulceration. Superficial mucoceles were present in three children. Clinically obvious xerostomia was seen in seven patients. Lip biopsies were positive and correlated with the clinical manifestations. Both clinical and histological findings confirmed the diagnosis of cGVHD. In three additional children, with systemic manifestations indicating cGVHD, the oral mucosa was clinically and histologically normal, and the systemic manifestations were, thus, attributed to drug reactions. The above findings indicate the high value of oral examination in diagnosing or confirming paediatric cGVHD. Superficial mucoceles, reported for the first time in paediatric recipients, seem to be important in the early diagnosis of cGVHD. PMID:11271629

  8. Liver transplantation for chronic graft-versus-host disease: case report with 10-year follow-up.

    Orlando, Giuseppe; Ferrant, Augustin; Schots, Rik; Goffette, Pierre; Mathijs, Jules; Lemaire, Julien; Danse, Etienne; Talpe, Stéphanie; Latinne, Dominique; Lerut, Jan

    2005-01-01

    Graft-versus-host disease (GVHD) is a frequent complication of bone marrow transplantation (BMT). Chronic GVHD (cGVHD) may lead to irreversible liver failure. We report a case of successful liver transplantation (LT) for end-stage liver failure because of cGVHD that had developed 22 months after BMT in a 24-year-old male. Re-transplantation was necessary 6 months later because of intrahepatic ischaemic type biliary tract lesions. He is now in excellent condition 10 years after the first transplant. This experience and the review of literature indicate that LT can cure GVHD-related chronic liver failure. Recurrent GVHD in the allograft has not yet been reported. PMID:15612994

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

    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.

  10. Impact of graft-versus-host disease on outcomes after allogeneic hematopoietic cell transplantation for adult T-cell leukemia: a retrospective cohort study.

    Kanda, Junya; Hishizawa, Masakatsu; Utsunomiya, Atae; Taniguchi, Shuichi; Eto, Tetsuya; Moriuchi, Yukiyoshi; Tanosaki, Ryuji; Kawano, Fumio; Miyazaki, Yasushi; Masuda, Masato; Nagafuji, Koji; Hara, Masamichi; Takanashi, Minoko; Kai, Shunro; Atsuta, Yoshiko; Suzuki, Ritsuro; Kawase, Takakazu; Matsuo, Keitaro; Nagamura-Inoue, Tokiko; Kato, Shunichi; Sakamaki, Hisashi; Morishima, Yasuo; Okamura, Jun; Ichinohe, Tatsuo; Uchiyama, Takashi

    2012-03-01

    Allogeneic hematopoietic cell transplantation (HCT) is an effective treatment for adult T-cell leukemia (ATL), raising the question about the role of graft-versus-leukemia effect against ATL. In this study, we retrospectively analyzed the effects of acute and chronic graft-versus-host disease (GVHD) on overall survival, disease-associated mortality, and treatment-related mortality among 294 ATL patients who received allogeneic HCT and survived at least 30 days posttransplant with sustained engraftment. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated that the development of grade 1-2 acute GVHD was significantly associated with higher overall survival (hazard ratio [HR] for death, 0.65; P = .018) compared with the absence of acute GVHD. Occurrence of either grade 1-2 or grade 3-4 acute GVHD was associated with lower disease-associated mortality compared with the absence of acute GVHD, whereas grade 3-4 acute GVHD was associated with a higher risk for treatment-related mortality (HR, 3.50; P < .001). The development of extensive chronic GVHD was associated with higher treatment-related mortality (HR, 2.75; P = .006) compared with the absence of chronic GVHD. Collectively, these results indicate that the development of mild-to-moderate acute GVHD confers a lower risk of disease progression and a beneficial influence on survival of allografted patients with ATL. PMID:22234682

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

    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

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

    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. PMID:26998764

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

    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.)

  14. Predictive Value of Bronchiolitis Obliterans Syndrome Stage 0p in Chronic Graft-versus-Host Disease of the Lung

    Abedin, Sameem; Yanik, Gregory A.; Braun, Thomas; Pawarode, Attaphol; Magenau, John; Goldstein, Steven C.; Levine, John E.; Kitko, Carrie L.; Couriel, Daniel R.

    2016-01-01

    Bronchiolitis obliterans syndrome (BOS) is a significant post-transplant complication with low survival. BOS stage 0p (BOS 0p) is a parameter detected on pulmonary function tests (PFTs) after lung transplantation to identify patients at risk to develop BOS. We performed a retrospective study on 442 patients who underwent allogeneic stem cell transplant from 2007 to 2011 to evaluate whether development of BOS 0p is a risk factor in this population for BOS. Patients who met criteria for BOS 0p were significantly more likely to develop BOS (hazard ratio [HR], 3.22; P HR, 2.48; P =.001) and chronic graft-versus-host disease (GVHD) outside the lung post-transplant (HR, 23; P < .001). Finally, BOS 0p criteria were adequately sensitive in predicting BOS (85%), with a high negative predictive value (98%). Our findings suggest a routine PFT screening strategy with the intent of detecting BOS 0p, especially among patients with prior lung disease and who developed chronic GVHD, could suitably identify an at-risk population for the development of BOS. PMID:25687798

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

    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 (rs =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.)

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

    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.)

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

    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. PMID:26806586

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

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

    2015-10-15

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

  19. Fecal calprotectin as a biomarker of intestinal graft versus host disease after allogeneic hematopoietic stem cell transplantation.

    Lorenz, Fryderyk; Marklund, Stefan; Werner, Mårten; Palmqvist, Richard; Wahlin, Björn Engelbrekt; Wahlin, Anders

    2015-01-01

    The diagnosis of gastrointestinal graft versus host disease (GI-GVHD) is based on clinical symptoms and histological findings. In clinical practice, it is often difficult to decide whether abdominal symptoms in an allogeneic transplant recipient are caused by GVHD or other disorders. Endoscopic biopsies are helpful in establishing the diagnosis, but endoscopy is not always possible to perform due to poor general condition of the patients. No biomarkers are routinely used to predict GVHD. The aim of fecal calprotectin and alpha-1 antitrypsin testing in our study was to find out whether determination of the concentrations of these proteins may be used as a screening method for enteric GVHD. We studied prospectively 51 patients, 8 of whom developed GI-GVHD. Our data demonstrate that elevated fecal calprotectin levels were significantly associated with presence of GI-GVHD. We found a positive association between high F-calprotectin and severe gastrointestinal GVHD. In bivariate analysis, only calprotectin but not alpha-1 antitrypsin was independently associated with GI-GVHD. Testing for fecal calprotectin after allogeneic stem cell transplantation may be a useful screening tool. PMID:25605402

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

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

    2014-01-01

    BACKGROUND: Rampant caries is an advanced and severe dental disease that affects multiple teeth. This case describes the management of rampant caries in a young teenager suffering from chronic oral graft versus host disease after allogeneic bone marrow transplantation. CASE PRESENTATION: A 14-year-old Chinese boy suffering from beta-thalassemia major was referred to the dental clinic for the management of rampant dental caries. An oral examination revealed pale conjunctiva, bruising of lips, ...

  1. Voriconazole-Induced Phototoxicity Masquerading as Chronic Graft-versus-Host Disease of the Skin in Allogeneic Hematopoietic Cell Transplant Recipients

    Patel, Asha R.; Turner, Maria L.; Baird, Kristin; Gea-Banacloche, Juan; Mitchell, Sandra; Pavletic, Steven Z.; Wise, Barbara; Cowen, Edward W.

    2009-01-01

    Systemic fungal infections pose a significant risk to patients following allogeneic hematopoietic cell transplantation (alloHCT). Voriconazole (Vfend®, Pfizer) is an oral second-generation triazole antifungal agent that offers broad spectrum of coverage against fungal species and is frequently utilized in the post-HCT setting. Herein, we describe five patients who were initially believed to be experiencing a flare of cutaneous chronic graft-versus-host disease (cGvHD), but who were actually e...

  2. IL-17 Gene Ablation Does Not Impact Treg-Mediated Suppression of Graft-Versus-Host Disease after Bone Marrow Transplantation

    Colonna, Lucrezia; Florek, Mareike; Leveson-Gower, Dennis B.; Sega, Emanuela I.; Baker, Jeanette; Smith, Aaron T.; Negrin, Robert S.

    2013-01-01

    Regulatory T cell (Treg) immunotherapy is a promising strategy for the treatment of graft rejection responses and autoimmune disorders. Our and other laboratories have shown that the transfer of highly purified CD4+CD25+Foxp3+ natural Treg can prevent lethal graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation across both major and minor histocompatibility barriers. However, recent evidence suggests that the Treg suppressive phenotype can become unstable, a phe...

  3. Xenogeneic Graft-versus-Host-Disease in NOD-scid IL-2Rγnull Mice Display a T-Effector Memory Phenotype

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

    2012-01-01

    The occurrence of Graft-versus-Host Disease (GvHD) is a prevalent and potentially lethal complication that develops following hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic-GvHD based upon immunodeficient strains injected with human peripheral blood mononuclear cells (PBMC; "Hu-PBMC mice") are important tools to study human immune function in vivo. The recent introduction of targeted deletions at the interleukin-2 common gamma chain (IL-2Rγ(null)), notably the N...

  4. Graft-versus-Host Disease after HLA-Matched Sibling Bone Marrow or Peripheral Blood Stem Cell Transplantation: Comparison of North American Caucasian and Japanese Populations.

    Kanda, Junya; Brazauskas, Ruta; Hu, Zhen-Huan; Kuwatsuka, Yachiyo; Nagafuji, Koji; Kanamori, Heiwa; Kanda, Yoshinobu; Miyamura, Koichi; Murata, Makoto; Fukuda, Takahiro; Sakamaki, Hisashi; Kimura, Fumihiko; Seo, Sachiko; Aljurf, Mahmoud; Yoshimi, Ayami; Milone, Giuseppe; Wood, William A; Ustun, Celalettin; Hashimi, Shahrukh; Pasquini, Marcelo; Bonfim, Carmem; Dalal, Jignesh; Hahn, Theresa; Atsuta, Yoshiko; Saber, Wael

    2016-04-01

    The risk of acute graft-versus-host disease (GVHD) after HLA-matched sibling bone marrow transplantation (BMT) is lower in Japanese than in Caucasian patients. However, race may have differential effect on GVHD dependent on the graft source. North American Caucasian and Japanese patients receiving their first allogeneic BMT or peripheral blood stem cell transplantation from an HLA-matched sibling for leukemia were eligible. BMT was performed in 13% of the Caucasian patients and in 53% of the Japanese patients. On multivariate analysis, the interaction term between race and graft source was not significant in any of the models, indicating that graft source does not affect the impact of race on outcomes. The risk of grade III or IV acute GVHD was significantly lower in the Japanese patients compared with the Caucasian patients (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57 to 0.96), which resulted in lower risk of nonrelapse mortality in the Japanese patients (HR, 0.69; 95% CI, 0.54 to 0.89). The risk of relapse was also lower in this group. The lower risks of nonrelapse mortality and relapse resulted in lower overall mortality rates among the Japanese patients. In conclusion, our data indicate that irrespective of graft source, the risk of severe acute GVHD is lower in Japanese patients, resulting in a lower risk of nonrelapse mortality. PMID:26762681

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

    2016-04-14

    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. 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.

    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). PMID:26729448

  7. Factors Predicting Graft-versus-Host Disease-Free, Relapse-Free Survival after Allogeneic Hematopoietic Cell Transplantation: Multivariable Analysis from a Single Center.

    Solh, Melhem; Zhang, Xu; Connor, Katelin; Brown, Stacey; Solomon, Scott R; Morris, Lawrence E; Holland, H Kent; Bashey, Asad

    2016-08-01

    The ideal outcome of allogeneic hematopoietic cell transplantation (allo-HCT) is based on survival that is free of morbidity. The most common causes of treatment failure and morbidity after HCT are relapse, graft-versus-host disease (GVHD), and nonrelapse death. A composite endpoint that measures survival free of clinically significant negative events may be a useful way to determine the success of allo-HCT. We assessed GVHD and relapse-free survival (GRFS) where the events were acute GVHD grades III to IV, chronic GVHD requiring immunosuppression, relapse, or death in 531 consecutive adult patients who received an allo-HCT between 2006 and 2014 at our center. Median follow-up of living patients was 46 months (range, 12 to 123). HLA matched related donor (MRD, n = 198, 37%), matched unrelated donor (MUD, n = 205, 39%), and haploidentical donor with post-transplant cyclophosphamide (HID, n = 128, 24%) were used. Thirty-six percent of patients had a high/very-high Dana Farber disease risk index (DRI). Estimated rates of GRFS at 1 and 2 years after MRD, MUD, and HID transplantations were 34% and 26%, 26% and 17%, and 33% and 31%, respectively, with MRD recipients having a better GRFS than MUD (P disease risk, stem cell source, and donor type. Importantly, MUDs produce inferior GRFS to MRDs, whereas HIDs do not. PMID:27095692

  8. Mechanisms of cyclic nucleotide phosphodiesterases in modulating T cell responses in murine graft-versus-host disease.

    Weber, Michael; Lupp, Corinna; Stein, Pamela; Kreft, Andreas; Bopp, Tobias; Wehler, Thomas C; Schmitt, Edgar; Schild, Hansjörg; Radsak, Markus P

    2013-01-01

    Graft-versus-host disease (GvHD) is a key contributor to the morbidity and mortality after allogeneic hematopoetic stem cell transplantation (HSCT). Regulatory Foxp3(+) CD4(+) T cells (Treg) suppress conventional T cell activation and can control GvHD. In our previous work, we demonstrate that a basic mechanism of Treg mediated suppression occurs by the transfer of cyclic adenosine monophosphate (cAMP) to responder cells. Whether this mechanism is relevant for Treg mediated suppression of GvHD is currently unknown. To address this question, bone marrow and T cells from C57BL/6 mice were transferred into lethally irradiated BALB/c recipients, and the course of GvHD and survival were monitored. Transplanted recipients developed severe GvHD that was strongly ameliorated by the transfer of donor Treg cells. Towards the underlying mechanisms, in vitro studies revealed that Treg communicated with DCs via gap junctions, resulting in functional inactivation of DC by a metabolic pathway involving cAMP that is modulated by the phosphodiesterase (PDE) 4 inhibitor rolipram. PDE2 or PDE3 inhibitors as well as rolipram suppressed allogeneic T cell activation, indirectly by enhancing Treg mediated suppression of DC activation and directly by inhibiting responder T cell proliferation. In line with this, we observed a cooperative suppression of GvHD upon Treg transfer and additional rolipram treatment. In conclusion, we propose that an important pathway of Treg mediated control of GvHD is based on a cAMP dependent mechanism. These data provide the basis for future concepts to manipulate allogeneic T cell responses to prevent GvHD. PMID:23483980

  9. IL4RA on lymphatic endothelial cells promotes T cell egress during sclerodermatous graft versus host disease

    Urso, Katia; Alvarez, David; Cremasco, Viviana; Tsang, Kelly; Grauel, Angelo; Lafyatis, Robert; von Andrian, Ulrich H.; Ermann, Joerg; Aliprantis, Antonios O.

    2016-01-01

    Systemic sclerosis (SSc) is a potentially fatal autoimmune disorder with limited therapeutic options. Sclerodermatous graft versus host disease (sclGvHD), induced by transfer of B10.D2 splenocytes into BALB/c Rag2−/− mice, models an inflammatory subset of SSc characterized by a prominent IL13-induced gene expression signature in the skin. Host mice deficient in IL4RA, a subunit of the type II IL4/IL13 receptor, are protected from sclGvHD. While IL4RA has a well-established role in Th2 differentiation and alternative macrophage activation, we report here a previously unappreciated function for IL4RA in lymphatic endothelial cells (LECs): regulation of activated T cell egress. Seven days after splenocyte transfer, Il4ra−/− hosts had increased numbers of activated graft CD4+ T cells in skin draining lymph nodes (dLNs) but fewer T cells in efferent lymph, blood, and skin. Sphingosine-1 phosphate (S1P), master regulator of lymphocyte egress from LNs, was lower in dLNs of Il4ra−/− hosts with a corresponding decrease of S1P kinase 1 (Sphk1) expression in LECs. Bypassing the efferent lymphatics via i.v. injection of CD4+ T cells from dLNs of Il4ra−/− sclGvHD mice restored clinical GvHD in secondary Il4ra−/− recipients. These results identify a role for IL4RA and suggest that modulation of lymphocyte egress from LNs may be effective in SSc and GvHD.

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

    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. Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease.

    Koreth, John; Kim, Haesook T; Jones, Kyle T; Lange, Paulina B; Reynolds, Carol G; Chammas, Marie J; Dusenbury, Katherine; Whangbo, Jennifer; Nikiforow, Sarah; Alyea, Edwin P; Armand, Philippe; Cutler, Corey S; Ho, Vincent T; Chen, Yi-Bin; Avigan, David; Blazar, Bruce R; Antin, Joseph H; Ritz, Jerome; Soiffer, Robert J

    2016-07-01

    Chronic graft-versus-host disease (cGVHD) is associated with inadequate reconstitution of tolerogenic CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs). Previous phase 1 studies identified a low daily dose of interleukin-2 (IL-2) that was well tolerated, did not exacerbate alloimmunity, augmented Treg in vivo, and was associated with improvement of active cGVHD. In the current phase 2 study, 35 adults with steroid-refractory cGVHD received daily IL-2 (1 × 10(6) IU/m(2)) for 12 weeks. Median time from transplantation and cGVHD onset was 616 days (range, 270-2145 days) and 317 days (range, 28-1880 days), respectively. Two patients withdrew and 5 required IL-2 dose reductions due to side effects. Twenty of 33 evaluable patients (61%) had clinical responses at multiple cGVHD sites (liver, skin, gastrointestinal tract, lung, joint/muscle/fascia). Three patients (9%) had progressive cGVHD. Compared with pretreatment levels, Treg and natural killer cell counts rose >fivefold (P fourfold (P fivefold (P < .001). Clinical responders initiated IL-2 earlier (508 vs 917 days after transplantation, P = .005; 249 vs 461 days after cGVHD onset; P = .03). Treg:Tcon ratios ≥0.07 at baseline and ≥0.2 at week 1 also predicted clinical response (P = .003; P = .0003, respectively). After a 4-week treatment hiatus, clinical responders were eligible to continue IL-2 therapy indefinitely. During 2 years of extended IL-2 therapy, clinical and Treg immune responses persisted, while Tcon count and Treg:Tcon ratio gradually normalized. Low-dose IL-2 provides durable clinical improvement in active cGVHD and extended therapy is well-tolerated. PMID:27073224

  12. Concise Review: Mechanisms Behind Apoptotic Cell-Based Therapies Against Transplant Rejection and Graft versus Host Disease.

    Morelli, Adrian E; Larregina, Adriana T

    2016-05-01

    The main limitations to the success of transplantation are the antigraft response developed by the recipient immune system, and the adverse side effects of chronic immunosuppression. Graft-versus-host disease (GVHD) triggered by donor-derived T lymphocytes against the recipient tissues is another serious obstacle in the field of hematopoietic stem cell transplantation. Several laboratories have tested the possibility of promoting antigen (Ag)-specific tolerance for therapy of graft rejection, GVHD, and autoimmune disorders, by developing methodologies that mimic the mechanisms by which the immune system maintains peripheral tolerance in the steady state. It has been long recognized that the silent clearance of cells undergoing apoptosis exerts potent immune-regulatory effects and provides apoptotic cell-derived Ags to those Ag-presenting cells (APCs) that internalize them, in particular macrophages and dendritic cells. Therefore, in situ-targeting of recipient APCs by systemic administration of leukocytes in early apoptosis and bearing donor Ags represents a relatively simple approach to control the antidonor response against allografts. Here, we review the mechanisms by which apoptotic cells are silently cleared by phagocytes, and how such phenomenon leads to down-regulation of the innate and adaptive immunity. We discuss the evolution of apoptotic cell-based therapies from murine models of organ/tissue transplantation and GVHD, to clinical trials. We make emphasis on potential limitations and areas of concern of apoptotic cell-based therapies, and on how other immune-suppressive therapies used in the clinics or tested experimentally likely also function through the silent clearance of apoptotic cells by the immune system. Stem Cells 2016;34:1142-1150. PMID:26865545

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

    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.

  14. Prognostic Factors on the Graft-versus-Host Disease-Free and Relapse-Free Survival after Adult Allogeneic Hematopoietic Stem Cell Transplantation

    Yao-Chung Liu

    2016-01-01

    Full Text Available The cure of hematologic disorders by allogeneic hematopoietic stem cell transplantation (HSCT is often associated with major complications resulting in poor outcome, including graft-versus-host disease (GVHD, relapse, and death. A novel composite endpoint of GVHD-free/relapse-free survival (GRFS in which events include grades 3-4 acute GVHD, chronic GVHD requiring systemic therapy, relapse, or death is censored to completely characterize the survival without mortality or ongoing morbidity. In this regard, studies attempting to identify the prognostic factors of GRFS are quite scarce. Thus, we reviewed 377 adult patients undergoing allogeneic HSCT between 2003 and 2013. The 1- and 2-year GRFS were 40.8% and 36.5%, respectively, significantly worse than overall survival and disease-free survival (log-rank p 2 (p 2 (p<0.001, being male (p=0.028, and hematologic malignancy (p=0.010 were significant for poor outcome. The events between 1-year GRFS and 2-year GRFS predominantly increased in relapsed patients. With prognostic factors of GRFS, we could evaluate the probability of real recovery following HSCT without ongoing morbidity.

  15. GVHD (Graft-Versus-Host Disease): A Guide for Patients and Families After Stem Cell Transplant

    ... 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 ...

  16. Chronic graft-versus-host disease and late effects after hematopoietic stem cell transplantation.

    Sanders, Jean E

    2002-08-01

    Late effects following HSCT are related to either the transplant process or to the transplant preparative regimen. Problems related to the transplant process include delayed recovery of the immune system and chronic GVHD. Chronic GVHD presents between 3-14 months post-HSCT in approximately 20% of matched sibling transplants and 40% of matched unrelated donor recipients. Most commonly involved sites are skin, mouth, liver, gastrointestinal tract, and eye. Patients with platelet count Problems related to the transplant preparative regimen include those involving the endocrine system, eyes, lungs, bone, and development of secondary malignancies. Endocrine deficiencies include growth failure with growth hormone (GH) deficiency, overt hypothyroidism, primary gonadal failure, Type 1 or Type 2 diabetes, and exocrine pancreatic insufficiency. These problems develop at any time post-HSCT, but usually occur within the first few years and should be treated with appropriate hormone supplementation. Eye problems are primarily related to development of cateracts secondary to total body irradiation (TBI) or prolonged corticosteroid use. Cateracts developing after fractionated frequently do not require removal. Pulmonary problems may be due to bronchiolitis obliterans (BO) or to restrictive lung disease. BO may be associated with chronic GVHD and may respond to chronic GVHD therapy. Restrictive lung disease does not occur for many years after HSCT. There is not therapy for this problem. Development of decreased bone mineral density (BMD) is related to GH deficiency and/or corticosteroid therapy. Treatment includes withdrawal of corticosteroids, administration of GH and calcium, Vitamin D and antiresorptive agents. All malignant disease survivors are at risk for development of secondary malignancies, including survivors of HSCT. Recipients of TBI are at highest risk as are children. All pediatric and adult survivors of HSCT should be followed for their life-time for development of

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

    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

  18. CTL-Promoting Effects of IL-21 Counteract Murine Lupus in the Parent→F1 Graft-versus-Host Disease Model.

    Nguyen, Vinh; Rus, Horea; Chen, Ching; Rus, Violeta

    2016-02-15

    IL-21 promotes B cell and CTL responses in vivo, conferring IL-21 with a role in both humoral and cellular responses. Because CTL can target and eliminate autoreactive B cells, we investigated whether IL-21R signaling in CD8 T cells would alter the expansion of autoreactive B cells in an autoimmune setting. We addressed this question using the parent→F1 murine model of acute and chronic (lupus-like) graft-versus-host disease (GVHD) as models of a CTL-mediated or T-dependent B cell-mediated response, respectively. Induction of acute GVHD using IL-21R-deficient donor T cells resulted in decreased peak donor CD8 T cell numbers and decreased CTL effector function due to impaired granzyme B/perforin and Fas/Fas ligand pathways and a phenotype of low-intensity chronic GVHD with persistent host B cells, autoantibody production, and mild lupus-like renal disease. CTL effector maturation was critically dependent on IL-21R signaling in Ag-specific donor CD8, but not CD4, T cells. Conversely, treatment of DBA/2J→F1 chronic GVHD mice with IL-21 strongly promoted donor CD8 T cell expansion and rescued defective donor anti-host CTLs, resulting in host B cell elimination, decreased autoantibody levels, and attenuated renal disease, despite evidence of concurrently enhanced CD4 help for B cells and heightened B cell activation. These results demonstrate that, in the setting of lupus-like CD4 T cell-driven B cell hyperactivity, IL-21 signaling on Ag-specific donor CD8 T cells is critical for CTL effector maturation, whereas a lack of IL-21R downregulates CTL responses that would otherwise limit B cell hyperactivity and autoantibody production. PMID:26792801

  19. Human mesenchymal stromal cells attenuate graft-versus-host disease and maintain graft-versus-leukemia activity following experimental allogeneic bone marrow transplantation1

    Auletta, Jeffery J.; Eid, Saada K.; Wuttisarnwattana, Patiwet; Silva, Ines; Metheny, Leland; Keller, Matthew D.; Guardia-Wolff, Rocio; Liu, Chen; Wang, Fangjing; Bowen, Theodore; Lee, Zhenghong; Solchaga, Luis A; Ganguly, Sudipto; Tyler, Megan; Wilson, David L.

    2015-01-01

    We sought to define the effects and underlying mechanisms of human, marrow-derived mesenchymal stromal cells (hMSCs) on graft-versus-host disease (GvHD) and graft-versus-leukemia (GvL) activity. Irradiated B6D2F1 mice given C57BL/6 BM and splenic T-cells and treated with hMSCs had reduced systemic GvHD, donor T-cell expansion, and serum TNFα and IFNγ levels. Bioluminescence imaging demonstrated that hMSCs redistributed from lungs to abdominal organs within 72h; and target tissues harvested fr...

  20. Unraveling graft-versus-host disease and graft-versus-leukemia responses using TCR Vβ spectratype analysis in a murine bone marrow transplantation model1

    Fanning, Stacey L.; Zilberberg, Jenny; Stein, Johann; Vazzana, Kristin; Berger, Stephanie A.; Korngold, Robert; Friedman, Thea M.

    2012-01-01

    The optimum use of allogeneic blood and marrow transplantation (BMT) as a curative therapy for hematological malignancies lies in the successful separation of mature donor T cells that are host-reactive and induce graft-versus-host disease (GVHD) from those that are tumor-reactive and mediate graft-versus-leukemia (GVL) effects. To study whether this separation was possible in an MHC-matched murine BMT model (B10.BR→CBA) with a CBA-derived myeloid leukemia line, MMC6, we used TCR Vβ CDR3-size...

  1. The Use of Hyperbaric Oxygen Therapy in the Treatment of Non-healing Ulcers Secondary to Graft-versus-host Disease

    Heyboer, Marvin; Taylor, Justin; Morgan, Monica; Mariani, Peter; Jennings, Shane

    2014-01-01

    We present the case of a 69 year-old gentleman with non-healing ulcers of the bilateral medial malleoli as a result of graft-versus-host disease (GvHD). The patient discussed was diagnosed with stage IV mantle cell lymphoma. Over the course of 4 years the patient was treated with autologous stem cell transplant, later reduced-intensity allogeneic stem cell transplant, and finally donor lymphocyte infusion due to recurrence. Following these therapies, the patient developed extensive GvHD that ...

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

    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.

  3. Heterogeneity in Studies of Mesenchymal Stromal Cells to Treat or Prevent Graft-versus-Host Disease: A Scoping Review of the Evidence.

    Rizk, Mina; Monaghan, Madeline; Shorr, Risa; Kekre, Natasha; Bredeson, Christopher N; Allan, David S

    2016-08-01

    Effective treatments are lacking for the treatment of steroid-refractory graft-versus-host disease (GVHD), a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Mesenchymal stromal cells (MSCs) have demonstrated promise but there is uncertainty regarding their clinical effectiveness. A systematic scoping review of the literature was performed to characterize the heterogeneity of published studies and identify opportunities for standardization. Thirty studies were identified, including 19 studies (507 patients) addressing the treatment of acute or chronic GVHD and 11 prevention studies (277 patients). Significant heterogeneity was observed in the age and diagnoses of study subjects, intensity and specifics of the conditioning regimens, degree of HLA matching, and source of hematopoietic cells. MSCs were derived from bone marrow (83% of studies), cord blood (13%), or adipose tissue (3%) and were cryopreserved from third-party allogeneic donors in the majority of studies (91% of prevention studies and 63% of treatment studies). Culture conditions and media supplements were highly variable and characterization of MSCs did not conform to all International Society for Cellular Therapy criteria in any study. MSCs were harvested from cell culture at passage 1 to 7 and the dosage of MSCs ranged from 0.3 to 10 × 10(6)/kg, using varying schedules of administration. Treatment response criteria were not standardized and effectiveness in controlled treatment studies (5 studies) was unconvincing. Details of actively recruiting trials suggest heterogeneity still persists with only 53% of registered trials describing the use of standard GVHD response criteria and few detailing methods of MSC manufacturing. Future studies will need to make substantial coordinated efforts to reduce study heterogeneity and clarify the role of MSCs in GVHD. PMID:27130504

  4. Expression of SOCS1 and SOCS3 genes in human graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

    Lee, Tae Hyang; Lee, Ji Yoon; Park, Sohye; Shin, Seung Hwan; Yahng, Seung-Ah; Yoon, Jae-Ho; Lee, Sung-Eun; Cho, Byung-Sik; Kim, Yoo-Jin; Lee, Seok; Min, Chang-Ki; Kim, Dong-Wook; Lee, Jong-Wook; Min, Woo-Sung; Park, Chong-Won

    2013-01-01

    Background Suppressor of cytokine signaling genes (SOCS) are regarded as pivotal negative feedback regulators of cytokine signals, including the interferon-gamma (IFN-γ), granulocyte-colony stimulating factor, and interleukin families, released by T cells. A detailed understanding of the involvement of SOCS genes in graft-versus-host disease (GVHD) is critical to effectively manage GVHD, yet their expression patterns among recipients remain largely unexplored. Methods Expression levels of SOCS1 and SOCS3 were determined by real-time quantitative reverse transcription PCR (qRT-PCR) in patients with acute GVHD (aGVHD) and chronic GVHD (cGVHD), in a severity-dependent manner, after allogeneic hematopoietic stem cell transplantation (HSCT). A total of 71 recipients with AML (N=40), ALL (N=12), myelodysplastic syndromes (MDS; N=10), chronic myelogenous leukemia (CML; N=2), severe aplastic anemia (SAA; N=5), or others (N=2), who received allogeneic HSCT from human leukocyte antigen-identical siblings or unrelated donors between 2009 and 2011, were included in the present study. Results Overall, the expression levels of SOCS1 decreased in recipients with grade II to IV aGVHD and cGVHD when compared to normal donors and non-GVHD recipients. Interestingly, the expressions of SOCS1 decreased significantly more in cGVHD than in aGVHD recipients (P=0.0091). In contrast, SOCS3 expressions were similarly reduced in all the recipients. Conclusion This is the first study to show that SOCS1 and SOCS3 are differentially expressed in recipients following allogeneic HSCT, suggesting a prognostic correlation between SOCS genes and the development of GVHD. This result provides a new platform to study GVHD immunobiology and potential diagnostic and therapeutic targets for GVHD. PMID:23589790

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

    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

  6. Characterization and Risk Factor Analysis of Osteoporosis in a Large Cohort of Patients with Chronic Graft-versus-Host Disease.

    Pirsl, Filip; Curtis, Lauren M; Steinberg, Seth M; Tella, Sri Harsha; Katić, Mašenjka; Dobbin, Marnie; Hsu, Jennifer; Hakim, Fran T; Mays, Jacqueline W; Im, Annie P; Pulanić, Dražen; Mitchell, Sandra A; Baruffaldi, Judy; Masuch, Licia; Halverson, David C; Gress, Ronald E; Barsony, Julianna; Pavletic, Steven Z

    2016-08-01

    The National Institutes of Health Chronic Graft-versus-Host Disease (cGVHD) Consensus Project Ancillary and Supportive Care Guidelines recommend annual assessment of bone mineral density (BMD) to monitor bone health. The study of osteoporosis in patients with cGVHD has been limited to small numbers of patients, and the guidelines are based on experience with other chronic diseases and expert opinion. We hypothesized that the prevalence of osteoporosis is high in a cohort of 258 patients with moderate to severe cGVHD because of prolonged exposure to risk factors for osteoporosis after allogeneic hematopoietic stem cell transplantation. We defined osteoporosis using BMD criteria (T-score ≤-2.5) at 3 anatomic sites-the femoral neck (FN), lumbar spine (LS), and total hip (TH)-and characterized risk factors through univariate and multivariate analyses. We found that low body weight (FN, P transplantation. PMID:27118572

  7. 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

    Paulo José Lorenzoni; Rosana Herminia Scola; Ana Lucila Moreira Carsten; Ana Paula Trentin; Hélio A.G. Teive; Ricardo Pasquini; Lineu C. Werneck

    2007-01-01

    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 demyelinatin...

  8. Treatment of severe neutropenia with high-dose pyridoxine in a patient with chronic graft versus host disease and squamous cell carcinoma: a case report

    Rauf Mariam

    2011-08-01

    Full Text Available Abstract Introduction The differential diagnosis of neutropenia includes medications, infections, autoimmune diseases, and deficiencies of Vitamin B12 and folate. The association of Vitamin B6 deficiency with severe neutropenia is a rare finding. Case presentation A 51-year-old Caucasian woman presented with fever and profound neutropenia (48 neutrophils/uL. Her clinical history included non-Hodgkin lymphoma, in remission following treatment with allogeneic bone marrow transplantation, quiescent chronic graft-versus-host disease, and squamous cell carcinoma of the skin metastatic to cervical lymph nodes. Medications included atenolol, topical clobetasol, Ditropan (oxybutynin, prophylactic voriconazole, prophylactic valganciclovir, Soriatane (acitretin, and Carac (fluorouracil cream. The bone marrow was hypocellular without metastatic cancer or myelodysplasia. Neutropenia did not respond to stopping medications that have been associated with neutropenia (valganciclovir, voriconazole and Soriatane or treatment with antibiotics or granulocyte colony stimulating factor. Blood tests revealed absence of antineutrophil antibodies, normal folate and B12 levels, moderate zinc deficiency and severe Vitamin B6 deficiency. Replacement therapy with oral Vitamin B6 restored blood vitamin levels to the normal range and corrected the neutropenia. Her cervical adenopathy regressed clinically and became negative on scintography following Vitamin B6 therapy and normalization of the blood neutrophil count. Conclusion Severe pyridoxine deficiency can lead to neutropenia. Screening for Vitamin B6 deficiency, along with folate and Vitamin B12 levels, is recommended in patients with refractory neutropenia, especially those with possible malabsorption syndromes, or a history of chronic-graft-versus host disease. Severe neutropenia may facilitate progression of squamous cell carcinoma.

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

    Elad, Sharon; Jensen, Siri Beier; Raber-Durlacher, Judith E; Mouradian, Nancy; Correa, Elvira M P; Schubert, Mark M; Blijlevens, Nicole M A; Epstein, Joel B; Saunders, Deborah P; Waltimo, Tuomas; Yarom, Noam; Zadik, Yehuda; Brennan, Michael T

    2015-01-01

    GVHD patients, diagnostic and evaluation methods in their practice, preferred treatment strategies for mucosal and salivary gland involvement, and preventive measures. RESULTS: Twelve responders, representing 12 sites, stated that they treat oral cGVHD patients on a regular basis. This fraction of responders...... was confirmed by another online survey. Eleven out of the 12 providers were dentists. Seventy-five percent of the providers did not use biopsy in order to diagnose oral cGVHD. The NIH scale for the clinical assessment was used sporadically. The first-line topical treatment for oral mucosal cGVHD was......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...

  10. Combination Therapy for Graft-versus-Host Disease Prophylaxis with Etanercept and Extracorporeal Photopheresis: Results of a Phase II Clinical Trial.

    Kitko, Carrie L; Braun, Thomas; Couriel, Daniel R; Choi, Sung W; Connelly, James; Hoffmann, Sandra; Goldstein, Steven; Magenau, John; Pawarode, Attaphol; Reddy, Pavan; Schuler, Charles; Yanik, Gregory A; Ferrara, James L; Levine, John E

    2016-05-01

    Reduced-intensity conditioning (RIC) regimens minimize early toxicity after allogeneic hematopoietic cell transplantation (HCT) by placing greater reliance on establishing a graft-versus-leukemia effect (GVL). Because graft-versus-host disease (GVHD) and GVL are tightly linked, inhibition of T cell populations that cause GVHD may lead to an unintended increased risk of relapse in the RIC setting. Although not completely understood, etanercept and extracorporeal photopheresis (ECP) are thought to ameliorate GVHD without direct T cell inhibition. We hypothesized that adding these 2 agents to a standard GVHD prophylaxis regimen of tacrolimus and mycophenolate mofetil (MMF) would improve survival by reducing GVHD-related mortality without increasing relapse rates. Therefore, we conducted a prospective phase II clinical trial that incorporated tacrolimus, MMF, etanercept, and ECP as GVHD prophylaxis in 48 patients undergoing RIC unrelated donor transplantation. The preferred RIC was fludarabine 160 mg/m(2) + busulfan 6.4 mg/kg to 12.8 mg/kg ± total body irradiation 200 cGy. Etanercept .4 mg/kg (maximum dose, 25 mg) was given subcutaneously twice weekly for 8 weeks after HCT and ECP was given for 12 treatments, starting weekly on day 28 weekly and tapering off by day 180. The median age of the study patients was 60 (range, 18 to 71) years. Donors were 7/8 (n = 14, 29%) or 8/8 (n = 34, 71%) HLA matched. All patients engrafted neutrophils at a median of 12 days. The cumulative incidence of grades II to IV acute GVHD at day 100 was 46%, but it was typically sensitive to initial steroid treatment (84% day 56 complete response/partial response rate). Overall survival at 1 year in this older, frequently mismatched unrelated donor setting was excellent (73%) because of low rates of nonrelapse mortality (21%) and relapse (19%). However, this strategy was not effective at preventing a high incidence of chronic GVHD and late deaths led to a drop in 2-year

  11. Expression and significance of CD4+ CD25+ Foxp3+ T cells in the acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation%骨髓或外周血中CD4+CD25+Foxp3+调节性T淋巴细胞与aGVHD的关系

    王晓娟; 车传珍; 周昱男; 刘仲萍; 黄士昂

    2009-01-01

    目的 研究患者异基因造血干细胞移植(allo-HSCT)前后骨髓或外周血单个核细胞中CD4+CD25+Foxp3+调节性T淋巴细胞(以下简称CD4+CD25+Foxp3+T细胞)的比率、Foxp3 mRNA和Foxp3蛋白的表达与急性移植物抗宿主病(aGVHD)的关系.方法 选择37例行HIA相合异基因造血干细胞移植(allo-HSCT))的患者作为研究对象.采用流式细胞术检测患者allo-HSCT前7天(-7 d)、移植当天(0 d)、移植后30天(+30d)、+60 d和+90 d时骨髓或外周血单个核细胞中CD4+CD25+Foxp3+T细胞所占的比率;定量聚合酶链反应(PCR)检测Foxp3 mRNA相对表达量;蛋白印迹(Western blot)法检测Foxp3的蛋白表达水平.结果 37例患者存移植后100 d内发生aGVHD 13例(aGVHD组),未发生aGVHD 24例(无aGVHD组).CD4+CD25+Foxp3+T细胞的比率在0 d时最低,与-7、+30、+60、+90d时比较.差异均有统计学意义(P<0.01);与aGVHD组比较,无aGVHD组患者的CD4+CD25+Foxp3+T细胞的比率明显升高,差异有统计学意义(P<0.01).aGVHD组患者移植后Foxp3的表达水平逐渐升高,但明显低于无aGVHD组,尤其在+60和+90 d时的差异有统计学意义(P<0.01).Western blot法检测结果 表明,aGVHD组受者的Foxp3蛋白表达也明显低于无aGVHD组.结论 CD4+CD25+Foxp3+T细胞对防止发生aGVHD具有重要作用,监测患者骨髓或外周血中CD4+CD25+Foxp3+T细胞的比率可以预测aGVHD的发生.%Objective To investigate the expression and significance of CD4+ CD25+ Foxp3+ T Cells, Foxp3 mRNA and Foxp3 protein in the acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods Thirty-seven donor grafts and their respective clinical characteristics were evaluated. Flow cytometric analysis was performed to assess the percentage of CD4+ CD25+ Foxp3+ T cells in the recipients before, and 0, 30, 60, and 90 days after allo-HSCT. The relative expression of Foxp3 mRNA was detected by real time reverse transcription-polymerase chain

  12. Granulocyte colony-stimulating factor affects the distribution and clonality of TRGV and TRDV repertoire of T cells and graft-versus-host disease

    Xuan Li

    2011-12-01

    Full Text Available Abstract Background The immune modulatory effect of granulocyte colony-stimulating factor (G-CSF on T cells resulted in an unexpected low incidence of graft-versus-host disease (GVHD in allogeneic peripheral blood stem cell transplantation (allo-PBSCT. Recent data indicated that gamma delta+ T cells might participate in mediating graft-versus-host disease (GVHD and graft-versus-leukemia (GVL effect after allogeneic hematopoietic stem cell transplantation. However, whether G-CSF could influence the T cell receptors (TCR of gamma delta+ T cells (TRGV and TRDV repertoire remains unclear. To further characterize this feature, we compared the distribution and clonality of TRGV and TRDV repertoire of T cells before and after G-CSF mobilization and investigated the association between the changes of TCR repertoire and GVHD in patients undergoing G-CSF mobilized allo-PBSCT. Methods The complementarity-determining region 3 (CDR3 sizes of three TRGV and eight TRDV subfamily genes were analyzed in peripheral blood mononuclear cells (PBMCs from 20 donors before and after G-CSF mobilization, using RT-PCR and genescan technique. To determine the expression levels of TRGV subfamily genes, we performed quantitative analysis of TRGVI~III subfamilies by real-time PCR. Results The expression levels of three TRGV subfamilies were significantly decreased after G-CSF mobilization (P = 0.015, 0.009 and 0.006, respectively. The pattern of TRGV subfamily expression levels was TRGVII >TRGV I >TRGV III before mobilization, and changed to TRGV I >TRGV II >TRGV III after G-CSF mobilization. The expression frequencies of TRGV and TRDV subfamilies changed at different levels after G-CSF mobilization. Most TRGV and TRDV subfamilies revealed polyclonality from pre-G-CSF-mobilized and G-CSF-mobilized samples. Oligoclonality was detected in TRGV and TRDV subfamilies in 3 donors before mobilization and in another 4 donors after G-CSF mobilization, distributed in TRGVII, TRDV1

  13. Clinical significance of autoantibodies in a large cohort of patients with chronic graft-versus-host disease defined by NIH criteria.

    Kuzmina, Zoya; Gounden, Verena; Curtis, Lauren; Avila, Daniele; Rnp, Tiffani Taylor; Baruffaldi, Judy; Cowen, Edward W; Naik, Haley B; Hasni, Sarfaraz A; Mays, Jacqueline W; Mitchell, Sandra; Baird, Kristin; Steinberg, Seth M; Pavletic, Steven Z

    2015-02-01

    There is an unmet need for identifying new clinical biomarkers in chronic Graft-versus-Host-disease (cGVHD) suitable for diagnosis and disease monitoring. Circulating autoantibodies represent an ongoing immune response and suggest a pathogenic role for B cells in cGVHD. Autoantibodies could be useful markers of cGVHD disease activity, severity, or organ specificity; however, their clinical utility is not established. The focus of this study was to determine the incidence and associations of a broad array of clinical autoantibodies with cGVHD manifestations in a large patient cohort characterized by NIH criteria. A panel of 21 circulating antibodies commonly used in clinical medicine was tested in 280 cGVHD patients (70% severe) enrolled in a cross-sectional prospective natural history study. Median cGVHD duration was two years. Patients with circulating autoantibodies (62%) had significantly higher levels of IgM (P antibodies were detected in 35% of patients. Prior rituximab therapy (n = 66) was associated with reduced presence of autoantibodies (48 vs. 66% P = 0.01). Only oral cGVHD was significantly associated with presence of autoantibodies in this study (P = 0.028). No significant associations were found between cGVHD activity and severity, and presence of autoantibodies. Circulating autoantibodies are common in patients with advanced cGVHD. Their presence is associated with better quantitative immunologic reconstitution but does not have utility as a clinical biomarker of cGVHD. PMID:25363867

  14. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: III. The 2014 Biomarker Working Group Report.

    Paczesny, Sophie; Hakim, Frances T; Pidala, Joseph; Cooke, Kenneth R; Lathrop, Julia; Griffith, Linda M; Hansen, John; Jagasia, Madan; Miklos, David; Pavletic, Steven; Parkman, Robertson; Russek-Cohen, Estelle; Flowers, Mary E D; Lee, Stephanie; Martin, Paul; Vogelsang, Georgia; Walton, Marc; Schultz, Kirk R

    2015-05-01

    Biology-based markers to confirm or aid in the diagnosis or prognosis of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation or monitor its progression are critically needed to facilitate evaluation of new therapies. Biomarkers have been defined as any characteristic that is objectively measured and evaluated as an indicator of a normal biological or pathogenic process, or of a pharmacologic response to a therapeutic intervention. Applications of biomarkers in chronic GVHD clinical trials or patient management include the following: (1) diagnosis and assessment of chronic GVHD disease activity, including distinguishing irreversible damage from continued disease activity; (2) prognostic risk to develop chronic GVHD; and (3) prediction of response to therapy. Sample collection for chronic GVHD biomarkers studies should be well documented following established quality control guidelines for sample acquisition, processing, preservation, and testing, at intervals that are both calendar and event driven. The consistent therapeutic treatment of subjects and standardized documentation needed to support biomarker studies are most likely to be provided in prospective clinical trials. To date, no chronic GVHD biomarkers have been qualified for use in clinical applications. Since our previous chronic GVHD Biomarkers Working Group report in 2005, an increasing number of chronic GVHD candidate biomarkers are available for further investigation. This paper provides a 4-part framework for biomarker investigations: identification, verification, qualification, and application with terminology based on Food and Drug Administration and European Medicines Agency guidelines. PMID:25644957

  15. Umbilical cord blood-derived mesenchymal stem cells ameliorate graft-versus-host disease following allogeneic hematopoietic stem cell transplantation through multiple immunoregulations.

    Wu, Qiu-Ling; Liu, Xiao-Yun; Nie, Di-Min; Zhu, Xia-Xia; Fang, Jun; You, Yong; Zhong, Zhao-Dong; Xia, Ling-Hui; Hong, Mei

    2015-08-01

    Although mesenchymal stem cells (MSCs) are increasingly used to treat graft-versus-host disease (GVHD), their immune regulatory mechanism in the process is elusive. The present study aimed to investigate the curative effect of third-party umbilical cord blood-derived human MSCs (UCB-hMSCs) on GVHD patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their immune regulatory mechanism. Twenty-four refractory GVHD patients after allo-HSCT were treated with UCB-hMSCs. Immune cells including T lymphocyte subsets, NK cells, Treg cells and dendritic cells (DCs) and cytokines including interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNF-α) were monitored before and after MSCs transfusion. The results showed that the symptoms of GVHD were alleviated significantly without increased relapse of primary disease and transplant-related complications after MSCs transfusion. The number of CD3(+), CD3(+)CD4(+) and CD3(+)CD8(+) cells decreased significantly, and that of NK cells remained unchanged, whereas the number of CD4(+) and CD8(+) Tregs increased and reached a peak at 4 weeks; the number of mature DCs, and the levels of TNF-α and IL-17 decreased and reached a trough at 2 weeks. It was concluded that MSCs ameliorate GVHD and spare GVL effect via immunoregulations. PMID:26223913

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

    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.

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

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

  18. Subclinical pulmonary function defects following autologous and allogeneic bone marrow transplantation: relationship to total body irradiation and graft-versus-host disease

    Pulmonary function results pre- and post-transplant, to a maximum of 4 years, were analyzed in 98 patients with haematological disorders undergoing allogeneic (N = 53) or autologous bone marrow transplantation (N = 45) between 1982 and 1988. All received similar total body irradiation based regimens ranging from 9.5 Gy as a single fraction to 14.4 Gy fractionated. FEV1/FVC as a measure of airway obstruction showed little deterioration except in patients experiencing graft-versus-host disease in whom statistically significant obstructive ventilatory defects were evident by 6 months post-transplant (p less than 0.01). These defects appeared to be permanent. Restrictive ventilatory defects, as measured by reduction in TLC, and defects in diffusing capacity (DLCO and KCO) were also maximal at 6 months post-transplant (p less than 0.01). Both were related, at least in part, to the presence of GVHD (p less than 0.01) or use of single fraction TBI with absorbed lung dose of 8.0 Gy (p less than 0.05). Fractionated TBI resulted in less marked restricted ventilation and impaired gas exchange, which reverted to normal by 2 years, even when the lung dose was increased from 11.0 Gy to between 12.0 and 13.5 Gy. After exclusion of patients with GVHD (30% allografts) there was no significant difference in pulmonary function abnormalities between autograft and allograft recipients

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

    Lucas Sacchini Del Lama

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

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

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

    2013-01-01

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

  1. Transduction and selection of human T cells with novel CD34/thymidine kinase chimeric suicide genes for the treatment of graft-versus-host disease.

    Rettig, Michael P; Ritchey, Julie K; Meyerrose, Todd E; Haug, Jeffrey S; DiPersio, John F

    2003-07-01

    Clinical trials evaluating the herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV) suicide gene therapy system for the control of graft-versus-host disease (GVHD) have been limited by low transduction efficiencies and inefficient selection procedures. In this study, we designed and evaluated a novel chimeric suicide gene consisting of the extracellular and transmembrane domains of human CD34 and full-length HSV-tk (DeltaCD34-tk). High-efficiency transfer of DeltaCD34-tk to primary human T cells was accomplished after a single exposure to VSV-G-pseudotyped, Moloney murine leukemia virus-based retrovirus 48 h after activation of human PBMCs with anti-CD3 and anti-CD28 antibodies immobilized on magnetic beads. Using an optimized 5-day transduction and selection procedure, transduction efficiencies averaged 71%, with isolation purities greater than 95% and yields exceeding 90%. The immunoselected T cells were selectively eliminated by GCV (IC(50) approximately 3 nM), maintained a normal subset composition, exhibited a polyclonal TCR Vbeta family repertoire, and contained 5 or 6 vector copies per transduced cell when optimally transduced. No increase in GCV sensitivity was observed upon incorporation of highly active mutant HSV-tk enzymes into the DeltaCD34-tk suicide gene. T cells modified with the DeltaCD34-tk gene using the optimized protocol should improve the overall efficacy of the HSV-tk/GCV suicide gene therapy method of GVHD control. PMID:12842426

  2. Anti-CD13 antibodies in children with extensive chronic graft-versus-host disease and their relation to soluble CD13 after allogeneic blood and marrow transplantation from a Children's Oncology Groups Study, ASCT0031

    Cuvelier, Geoff D.E.; Kariminia, Amina; Fujii, Hisaki; Aslanian, Soudabeh; Wall, Donna; Goldman, Fred; Grupp, Stephan A.; Dunn, Sandra E.; Krailo, Mark; Shapiro, Linda H.; Gilman, Andrew; Schultz, Kirk R.

    2010-01-01

    Our group previous demonstrated a strong association between elevated plasma soluble CD13 enzyme activity and newly diagnosed extensive chronic graft-versus-host disease (cGVHD) in children. Since cytotoxic anti-CD13 antibodies have been documented after blood and marrow transplant in association with cytomegalovirus infection and cGVHD, we hypothesized soluble CD13 contributes to cGVHD pathogenesis by induction of CD13 reactive antibodies and that anti-CD13 antibodies could be additional bio...

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

    Antonio Velasco-Guardado; Lucía López-Corral; Alberto Álvarez-Delgado; Teresa Flores-Corral; Fernando Geijo-Martínez; Dolores Caballero-Barrigón; Antonio Rodríguez-Pérez

    2012-01-01

    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 sen...

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

    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

  5. Papel das citocinas na imunopatogênese da doença do enxerto contra o hospedeiro Role of cytokines in the immunopathogenesis of Graft-versus-Host Disease

    Silvana L. Vizoni

    2008-04-01

    Full Text Available O transplante de células progenitoras hematopoéticas é o tratamento de escolha para muitas doenças hematológicas e imunodeficiências primárias. A doença do enxerto contra o hospedeiro (DECH é ainda uma grave complicação após o transplante alogênico e a principal causa de mortalidade e morbidade. O estudo da patogênese da DECH auxilia no desenvolvimento de medidas preventivas da doença, assim como na escolha de terapias imunossupressoras adequadas de tratamento. Este estudo discute os principais componentes imunológicos envolvidos na patogênese da DECH aguda e crônica, com ênfase à participação das citocinas e seu controle.Stem cell transplantation is the first line treatment of many hematological diseases and primary immunodeficiencies. Graft-versus-host disease (GVHD is still a severe complication after allogeneic transplantation and the main cause of mortality and morbidity. The study of the pathogenesis of GVHD may help to develop ways to prevent the disease, as well as to choose adequate immunosuppressant therapies. This study discusses the main immunological components involved in the pathogenesis of acute and chronic GVHD, with emphasis on the participation of cytokines and their control.

  6. Human mesenchymal stromal cells attenuate graft-versus-host disease and maintain graft-versus-leukemia activity following experimental allogeneic bone marrow transplantation.

    Auletta, Jeffery J; Eid, Saada K; Wuttisarnwattana, Patiwet; Silva, Ines; Metheny, Leland; Keller, Matthew D; Guardia-Wolff, Rocio; Liu, Chen; Wang, Fangjing; Bowen, Theodore; Lee, Zhenghong; Solchaga, Luis A; Ganguly, Sudipto; Tyler, Megan; Wilson, David L; Cooke, Kenneth R

    2015-02-01

    We sought to define the effects and underlying mechanisms of human, marrow-derived mesenchymal stromal cells (hMSCs) on graft-versus-host disease (GvHD) and graft-versus-leukemia (GvL) activity. Irradiated B6D2F1 mice given C57BL/6 BM and splenic T cells and treated with hMSCs had reduced systemic GvHD, donor T-cell expansion, and serum TNFα and IFNγ levels. Bioluminescence imaging demonstrated that hMSCs redistributed from lungs to abdominal organs within 72 hours, and target tissues harvested from hMSC-treated allogeneic BMT (alloBMT) mice had less GvHD than untreated controls. Cryoimaging more precisely revealed that hMSCs preferentially distributed to splenic marginal zones and regulated T-cell expansion in the white pulp. Importantly, hMSCs had no effect on in vitro cytotoxic T-cell activity and preserved potent GvL effects in vivo. Mixed leukocyte cultures containing hMSCs exhibited decreased T-cell proliferation, reduced TNFα, IFNγ, and IL-10 but increased PGE2 levels. Indomethacin and E-prostanoid 2 (EP2) receptor antagonisms both reversed while EP2 agonism restored hMSC-mediated in vitro T-cell suppression, confirming the role for PGE2 . Furthermore, cyclo-oxygenase inhibition following alloBMT abrogated the protective effects of hMSCs. Together, our data show that hMSCs preserve GvL activity and attenuate GvHD and reveal that hMSC biodistribute to secondary lymphoid organs wherein they attenuate alloreactive T-cell proliferation likely through PGE2 induction. PMID:25336340

  7. Spontaneous autologous graft-versus-host disease in plasma cell myeloma autograft recipients: flow cytometric analysis of hematopoietic progenitor cell grafts.

    Lazarus, Hillard M; Sommers, Scott R; Arfons, Lisa M; Fu, Pingfu; Ataergin, S A; Kaye, N M; Liu, F; Kindwall-Keller, Tamila L; Cooper, Brenda W; Laughlin, Mary J; Creger, Richard J; Barr, Paul M; Gerson, Stanton L; Kaplan, David

    2011-07-01

    Nine plasma cell myeloma patients spontaneously developed histologically proven autologous graft-versus-host disease (GVHD) limited predominantly to the gastrointestinal tract within 1 month of initial autologous hematopoietic cell transplantation (AHCT) using high-dose melphalan conditioning. All recipients responded promptly to systemic and nonabsorbable oral corticosteroid therapy. All patients previously received systemic therapy with thalidomide, lenalidomide, or bortezomib before AHCT. Using enzymatic amplification staining-enhanced flow cytometry, we evaluated expression of selected transcription regulators, pathway molecules, and surface receptors on samples of the infused hematopoietic cell grafts. We demonstrated significantly enhanced expression of GATA-2, CD130, and CXCR4 on CD34(+) hematopoietic progenitor cells of affected patients compared with 42 unaffected AHCT controls. These 3 overexpressed markers have not been previously implicated in autologous GVHD. Although we did not specifically evaluate T cells, we postulate that exposure over time to the various immunomodulating therapies used for induction treatment affected not only the CD34(+) cells but also T cells or relevant T cell subpopulations capable of mediating GVHD. After infusion, the affected hematopoietic progenitor cells then encounter a host that has been further altered by the high-dose melphalan preparative regimen; such a situation leads to the syndrome. These surface markers could be used to develop a model to predict development of this syndrome. Autologous GVHD potentially is a serious complication of AHCT and should be considered in plasma cell myeloma patients with otherwise unexplained gastrointestinal symptoms in the immediate post-AHCT period. Prompt recognition of this condition and protracted treatment with nonabsorbable or systemic corticosteroids or the combination may lead to resolution. PMID:21440080

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

    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.

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

    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.

  10. Translation, Cross-Cultural Adaptation, and Validation of the Lee Chronic Graft-versus-Host Disease Symptom Scale in a Brazilian Population.

    Vasconcellos de Souza, Clarissa; Vigorito, Afonso Celso; Miranda, Eliana C M; Garcia, Celso; Rensi Colturato, Vergílio Antonio; Mauad, Marcos Augusto; Rodrigues Moreira, Maria Cláudia; da Silva Bouzas, Luis Fernando; Lermontov, Simone; Hamerschlak, Nelson; Rodrigues, Morgani; Carlos de Almeida Barros, Jose; Chiattone, Ricardo; Lee, Stephanie J; Flowers, Mary E D

    2016-07-01

    The Lee Chronic Graft-versus-Host Disease (GVHD) Symptom Scale is a patient-reported instrument developed and validated in English to measure the symptoms and functional impact of cGVHD. This tool has not yet been validated in a Latin American population, however. The Brazil-Seattle Chronic GVHD Consortium conducted a multicenter study at 5 Brazilian institutions to validate the Lee cGVHD Symptom Scale in adults with cGVHD. Study objectives included the translation and validation of the instrument in Brazilian Portuguese and evaluation of the correlation with other quality of life (QoL) tools, including the Medical Outcomes Study Short Form 36 (SF-36) and Functional Assessment of Chronic Illness Therapy with Bone Marrow Transplant subscale (FACT-BMT). Translation and validation were done according to the American Association of Orthopedic Surgeons Outcome Committee guidelines. Spearman's correlation coefficient was used to measure construct validity. Reliability was assessed using Cronbach's α and intraclass correlation coefficients. Between April 2011 and August 2012, 47 patients with cGVHD based on the 2005 National Institutes of Health criteria (29 males [62%], 18 females [38%]; median age, 48 years; range, 23 to 69 years) were enrolled in this study. The reliability of the Lee cGVHD Symptom Scale was adequate (Cronbach's α = 0.62 to 0.83). The correlations between similar domains of the Lee cGVHD Symptom Scale, SF-36, and FACT-BMT were moderate to high. Our data indicate that the Brazilian Portuguese version of the Lee cGVHD Symptom Scale is valid and reliable and can be used in clinical trials of cGVHD in Brazil. PMID:27058616

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

    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

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

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

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

    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.

    2014-01-01

    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 leuk...

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

    Perz, Jolanta B.; Gürel, Selma; Schonland, Stefan O.; Hegenbart, Ute; Ho, Anthony D.; Dreger, Peter

    2012-01-01

    Background. The therapeutic efficacy of allogeneic hemopoietic stem cell transplantation (HSCT) largely relies on the graft-versus-leukemia (GVL) effect. Uncontrolled graft-versus-host disease (GVHD) is a feared complication of HSCT. Regulatory T cells (Treg) are a subset of CD4+ T-helper cells believed to maintain tolerance after HSCT. It remains unclear whether low peripheral blood Treg have an impact on the risk for acute (aGVHD) and chronic GVHD (cGVHD). Methods. In this paper we enumerated the CD4+CD25highCD127low Treg in the peripheral blood of 84 patients after at least 150 days from HSCT and in 20 healthy age-matched controls. Results. Although similar mean lymphocyte counts were found in patients and controls, CD3+CD4+ T-cell counts were significantly lower in patients. Patients also had significantly lower Treg percentages among lymphocytes as compared to controls. Patients with cGVHD had even higher percentages of Treg if compared to patients without cGVHD. In multivariate analysis, Treg percentages were not an independent factor for cGVHD. Conclusions. This paper did not show a relation between deficient peripheral blood Treg and cGVHD, therefore cGVHD does not seem to occur as a result of peripheral Treg paucity. PMID:22666141

  15. 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.

    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.

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

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

  17. Graft-Versus-Host-Disease

    ... to 20-year friendship Supporter stories Valerie Sun - bone marrow transplant patient advocate Jeff and Kim take their life- ... transplant and other treatment options What is a bone marrow transplant How a bone marrow transplant works Transplant process ...

  18. MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice.

    Wu, Yongxia; Heinrichs, Jessica; Bastian, David; Fu, Jianing; Nguyen, Hung; Schutt, Steven; Liu, Yuejun; Jin, Junfei; Liu, Chen; Li, Qi-Jing; Xia, Changqing; Yu, Xue-Zhong

    2015-09-10

    MicroRNAs (miRs) play important roles in orchestrating many aspects of the immune response. The miR-17-92 cluster, which encodes 6 miRs including 17, 18a, 19a, 20a, 19b-1, and 92-1, is among the best characterized of these miRs. The miR-17-92 cluster has been shown to regulate a variety of immune responses including infection, tumor, and autoimmunity, but the role of this cluster in T-cell response to alloantigens has not been previously explored. By using major histocompatibility complex (MHC)-matched, -mismatched, and haploidentical murine models of allogeneic bone marrow transplantation (allo-BMT), we demonstrate that the expression of miR-17-92 on donor T cells is essential for the induction of graft-versus-host disease (GVHD), but dispensable for the graft-versus-leukemia (GVL) effect. The miR-17-92 plays a major role in promoting CD4 T-cell activation, proliferation, survival, and Th1 differentiation, while inhibiting Th2 and iTreg differentiation. Alternatively, miR-17-92 may promote migration of CD8 T cells to GVHD target organs, but has minimal impact on CD8 T-cell proliferation, survival, or cytolytic function, which could contribute to the preserved GVL effect mediated by T cells deficient for miR-17-92. Furthermore, we evaluated a translational approach and found that systemic administration of antagomir to block miR-17 or miR-19b in this cluster significantly inhibited alloreactive T-cell expansion and interferon-γ (IFNγ) production, and prolonged the survival in recipients afflicted with GVHD while preserving the GVL effect. Taken together, the current work provides a strong rationale and demonstrates the feasibility to target miR-17-92 for the control of GVHD while preserving GVL activity after allo-BMT. PMID:26138686

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

    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.

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

    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

  1. CD103 deficiency prevents graft-versus-host disease but spares graft-versus-tumor effects mediated by alloreactive CD8 T cells.

    Kechang Liu

    Full Text Available BACKGROUND: Graft-versus-host disease (GVHD remains the main barrier to broader application of allogeneic hematopoietic stem cell transplantation (alloSCT as a curative therapy for host malignancy. GVHD is mediated by allogeneic T cells directed against histocompatibility antigens expressed by host tissues. Based on previous studies, we postulated that the integrin CD103 is required for CD8-mediated GVHD, but not for graft-versus-tumor effects (GVT. METHODOLOGY/PRINCIPAL FINDINGS: We herein provide evidence in support of this hypothesis. To circumvent the potentially confounding influence of donor CD4 T cells, we developed an alloSCT model in which GVHD mortality is mediated by purified CD8 T cells. In this model, host-reactive CD8 T cells receive CD4 T cell help at the time of initial activation but not in the effector phase in which mature CD8 T effectors migrate into host tissues. We show that donor CD8 T cells from wild-type BALB/c mice primed to host alloantigens induce GVHD pathology and eliminate tumors of host origin in the absence of host CD4 T cells. Importantly, CD103 deficiency dramatically attenuated GVHD mortality, but had no detectable impact on the capacity to eliminate a tumor line of host origin. We provide evidence that CD103 is required for accumulation of donor CD8 T cells in the host intestinal epithelium but not in the tumor or host lymphoid compartments. Consistent with these data, CD103 was preferentially expressed by CD8 T cells infiltrating the host intestinal epithelium but not by those infiltrating the tumor, lamina propria, or lymphoid compartments. We further demonstrate that CD103 expression is not required for classic CD8 effector activities including cytokine production and cytotoxicity. CONCLUSIONS/SIGNIFICANCE: These data indicate that CD103 deficiency inhibits GVHD pathology while sparing anti-tumor effects mediated by CD8 T cells, identifying CD103 blockade as an improved strategy for GVHD prophylaxis.

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

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

    2016-09-01

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

  3. Differential Effect of MyD88 Signal in Donor T Cells on Graft-versus-Leukemia Effect and Graft-versus-Host Disease after Experimental Allogeneic Stem Cell Transplantation

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

    2015-01-01

    Despite the presence of toll like receptor (TLR) expression in conventional TCRαβ T cells, the direct role of TLR signaling via myeloid differentiation factor 88 (MyD88) within T lymphocytes on graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect after allogeneic stem cell transplantation (allo-SCT) remains unknown. In the allo-SCT model of C57BL/6 (H-2b) → B6D2F1 (H-2b/d), recipients received transplants of wild type (WT) T-cell-depleted (TCD) bone marrow (BM) and splenic ...

  4. 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

    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

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

    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

  6. 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

    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

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

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

    1987-01-01

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

  8. Doença enxerto versus hospedeiro aguda A- GVHD Acute graft-versus-host disease

    Wellington Azevedo

    2010-01-01

    A doença enxerto contra hospedeiro aguda (A-GVHD) é síndrome sistêmica que acomete pacientes transplantados de medula óssea que recebem linfócitos imuno-competentes. A fisiopatologia do fenômeno é complexa e envolve uma série de respostas de diversos efetores imunológicos a estímulos antigênicos naturais ou que são expressos devido ao dano tecidual provocado pela doença ou pelo condicionamento. A ocorrência desta complicação é frequente em transplantes de medula óssea e determina, em grande p...

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

    2016-03-09

    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

  10. Cyclophosphamide for Prevention of Graft-Versus-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation in Patients With Hematological Malignancies

    2015-08-04

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Myeloid Leukemia in Remission; Adult Erythroleukemia (M6a); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Pure Erythroid Leukemia (M6b); Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Erythroleukemia (M6); Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Megakaryocytic Leukemia (M7); 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 Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Philadelphia Chromosome Negative Chronic Myelogenous Leukemia; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell

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

    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.

  12. Inhibition of calcineurin abrogates while inhibition of mTOR promotes regulatory T cell expansion and graft-versus-host disease protection by IL-2 in allogeneic bone marrow transplantation.

    Atsushi Satake

    Full Text Available Regulatory T cells (Tregs attenuate excessive immune responses, making their expansion beneficial in immune-mediated diseases including allogeneic bone marrow transplantation (BMT-associated graft-versus-host disease (GVHD. We have recently reported that Treg expansion does not require phospholipase Cγ activation when IL-2 is provided. As such, the combination of IL-2 and a calcineurin inhibitor (Cyclosporine A; CsA expands Tregs while inhibiting Tconv proliferation and protects against a mouse model of multiple sclerosis. However, CsA inhibits Treg proliferation in the presence of a TCR stimulus, suggesting that CsA may negatively impact Treg proliferation when they receive strong allogeneic MHC-mediated TCR signals. In this study, we show that CsA inhibits Treg proliferation and inducible Treg generation in allogeneic but not in syngeneic BMT when IL-2 is provided. In contrast to CsA, the mTOR inhibitor (Rapamycin almost completely suppressed IL-2-mediated Treg proliferation. However, CsA and Rapamycin inhibited Treg proliferation to a similar extent when TCR stimulation was provided. Furthermore, Rapamycin promoted Treg expansion and inducible Treg generation in allogeneic BMT recipients treated with IL-2. Consistent with these observations, CsA abrogated while Rapamycin promoted the protective effect of IL-2 on allogeneic BMT-induced GVHD. These results suggest that while CsA permits IL-2-induced Treg proliferation in the syngeneic setting (absence of strong TCR signals, CsA in combination with IL-2 may be detrimental for Treg proliferation in an allogeneic setting. Thus, in allogeneic settings, an mTOR inhibitor such as Rapamycin is a better choice for adjunct therapy with IL-2 in expansion of Tregs and protection against allogeneic BMT-induced GVHD.

  13. Mycophenolate Mofetil and Cyclosporine in Reducing Graft-Versus-Host Disease in Patients With Hematologic Malignancies or Metastatic Kidney Cancer Undergoing Donor Stem Cell Transplant

    2016-03-01

    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 Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; 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 Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Childhood Renal Cell Carcinoma; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Clear Cell Renal Cell Carcinoma; 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 Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; 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 Immunoblastic Large Cell

  14. 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

    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.

  15. Metagenomic Analysis of the Stool Microbiome in Patients Receiving Allogeneic Stem Cell Transplantation: Loss of Diversity Is Associated with Use of Systemic Antibiotics and More Pronounced in Gastrointestinal Graft-versus-Host Disease

    Holler, Ernst; Butzhammer, Peter; Schmid, Karin; Hundsrucker, Christian; Koestler, Josef; Peter, Katrin; Zhu, Wentao; Sporrer, Daniela; Hehlgans, Thomas; Kreutz, Marina; Holler, Barbara; Wolff, Daniel; Edinger, Matthias; Andreesen, Reinhard; Levine, John E.; Ferrara, James L.; Gessner, Andre; Spang, Rainer; Oefner, Peter J.

    2016-01-01

    Next-generation sequencing of the hypervariable V3 region of the 16s rRNA gene isolated from serial stool specimens collected from 31 patients receiving allogeneic stem cell transplantation (SCT) was performed to elucidate variations in the composition of the intestinal microbiome in the course of allogeneic SCT. Metagenomic analysis was complemented by strain-specific enterococcal PCR and indirect assessment of bacterial load by liquid chromatography-tandem mass spectrometry of urinary indoxyl sulfate. At the time of admission, patients showed a predominance of commensal bacteria. After transplantation, a relative shift toward enterococci was observed, which was more pronounced under antibiotic prophylaxis and treatment of neutropenic infections. The shift was particularly prominent in patients that developed subsequently or suffered from active gastrointestinal (GI) graft-versus-host disease (GVHD). The mean proportion of enterococci in post-transplant stool specimens was 21% in patients who did not develop GI GVHD as compared with 46% in those that subsequently developed GI GVHD and 74% at the time of active GVHD. Enterococcal PCR confirmed predominance of Enterococcus faecium or both E. faecium and Enterococcus faecalis in these specimens. As a consequence of the loss of bacterial diversity, mean urinary indoxyl sulfate levels dropped from 42.5 ± 11 µmol/L to 11.8 ± 2.8 µmol/L in all post-transplant samples and to 3.5 ± 3 µmol/L in samples from patients with active GVHD. Our study reveals major microbiome shifts in the course of allogeneic SCT that occur in the period of antibiotic treatment but are more prominent in association with GI GVHD. Our data indicate early microbiome shifts and a loss of diversity of the intestinal microbiome that may affect intestinal inflammation in the setting of allogeneic SCT. PMID:24492144

  16. 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

    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.

  17. Treatment of severe neutropenia with high-dose pyridoxine in a patient with chronic graft versus host disease and squamous cell carcinoma: a case report

    Rauf Mariam; Gleason Charise; Nooka Ajay K; Husman Abbie; Waller Edmund K

    2011-01-01

    Abstract Introduction The differential diagnosis of neutropenia includes medications, infections, autoimmune diseases, and deficiencies of Vitamin B12 and folate. The association of Vitamin B6 deficiency with severe neutropenia is a rare finding. Case presentation A 51-year-old Caucasian woman presented with fever and profound neutropenia (48 neutrophils/uL). Her clinical history included non-Hodgkin lymphoma, in remission following treatment with allogeneic bone marrow transplantation, quies...

  18. Prevention of graft-versus-host disease by treatment of bone marrow with gliotoxin in fully allogeneic chimeras and their cytotoxic T cell repertoire

    Gliotoxin, a secondary fungal metabolite, at nanomolar concentrations, irreversibly inhibits murine T cell proliferation to mitogen. Treatment of allogeneic spleen cells with gliotoxin allows their transfer into sublethally irradiated recipients without inducing a GVH reaction. Gliotoxin treatment of bone marrow allows the establishment of fully allogenic bone marrow chimeras free of GVH disease. The cytotoxic T cell repertoire against influenza virus in these animals is restricted to both host- and donor-type MHC. However, their immune competence is severely compromised by their lack of host MHC-type stimulator cells

  19. Suppression of graft-versus-host disease and retention of graft-versus-tumour reaction by murine genetically engineered dendritic cells following bone marrow transplantation.

    Huang, Yihong; Feng, Saran; Xu, Yujie; Chen, Wanru; Wang, Shuhua; Li, Depeng; Li, Zhenyu; Lu, Qunxian; Pan, Xiuying; Xu, Kailin

    2015-05-01

    The effect of infusion of lentiviral vector‑mediated, genetically engineered dendritic cells (DCs) following allogeneic bone marrow transplantation (allo‑BMT) on graft‑versus‑host disease (GVHD) and graft‑versus‑leukemia (GVL) was investigated in a mouse model. Lentivirus‑mediated expression of soluble tumor necrosis factor receptor 1 (sTNFR1) converted immature DCs (imDCs) from BABL/c mice into engineered DCs in vitro. An EL4 leukemia allo‑BMT model of BABL/c to C57BL/6 mice was established. Engineered DCs with donor bone marrow cells and splenocytes were subsequently transplanted into myeloablatively irradiated recipients. The average survival duration in the sTNFR1‑ and pXZ9‑imDC groups was significantly prolonged compared with that of the allo‑BMT group (PGVL effects during allo‑BMT. PMID:25529231

  20. A subset of asialo GM1+ cells play a protective role in the occurrence of graft-versus-host disease in mice

    In three different murine models of bone marrow (BM) transplantation the capacity of asialo GM1+ cells to suppress graft-vs-host disease (GVHD) was investigated. In a first model, total lymphoid irradiation (TLI)-treated BALB/C mice were given 1 mg of anti-asialo GM1 antibody. This led to the disappearance of functional suppressor cells after TLI. Injections of anti-asialo GM1 into TLI-treated BALB/C mice before infusion of 30 x 10(6) fully allogeneic (C3H) BM cells, led to a significantly decreased survival rate as compared to TLI-treated mice injected with control serum before BM transplantation (survival 29 and 83%, respectively, at 120 days after transplantation, p = 0.0032 log rank). The mortality of the former group was due to GVHD as 1 degree all dying animals showed clinical and histologic signs of GVHD, 2 degrees all animals were chimeric and 3 degrees mice receiving no or syngeneic BALB/C BM had excellent survival rates excluding BM aplasia or increased susceptibility for infections as reason for the mortality of the allogeneic BM recipients. In a second model, asialo GM1+ cells were removed in vitro from the C3H BM inoculum before injection into lethally irradiated (9 Gy) BALB/C recipients. In mice kept in specific pathogen-free conditions, this procedure resulted into a significant mortality (12/12) as compared to mice receiving BM pretreated with control serum (1/12, p = 0.0001 log rank). When kept in conventional housing, GVHD occurred in both groups but much earlier in the group receiving anti-asialo GM1-treated BM (median survival time 6 vs 46 days for the control mice, p = 0.001 log rank). No animal receiving anti-asialo GM1 and treated with syngeneic BM died, thus excluding toxicity, increased susceptibility to infections, or decreased graft take as a cause of mortality

  1. Attenuation of murine graft-versus-host reactivity by azathioprine

    Shand, F.L.

    1980-07-01

    The therapeutic effects of azathioprine were evaluated in a murine graft-versus-host (GVH) model. A single high dose (200 mg/kg) of azathioprine, administered to FI recipients 2 to 3 days after the injection of parental spleen cells, abrogated the ensuing GVH reaction. Lower doses of the drug, even when injected over an extended period of time (14 days), were found to be ineffective. However, high doses of azathioprine failed to protect when FI recipients were sublethally irradiated or injected with cyclophosphamide before GVH induction, and even the transfer of syngeneic FI spleen cells immediately after irradiation failed to alter this outcome. Further analysis of the changes that occurred in sublethally irradiated recipients revealed that the protective effect of azathioprine on CBA leads to (CBA x C57BL)FI GVH reaction was totally abrogated by doses of irradiation as low as 200 rad. Further experiments in which death was used as an indicator of GVH disease showed that lethality could not be reversed in sublethally irradiated FI recipients by the transfer of syngeneic FI spleen cells unless approximately 10 days were allowed to elapse between syngeneic reconstitution and GVH induction. Since syngeneic FI cells from spleen, lymph node, or bone marrow all behaved similarly, it seems likely that the increased severity of GVH reaction induced by prior immunosuppression may not be attributable to a simple cell deletion event.

  2. Attenuation of murine graft-versus-host reactivity by azathioprine

    The therapeutic effects of azathioprine were evaluated in a murine graft-versus-host (GVH) model. A single high dose (200 mg/kg) of azathioprine, administered to FI recipients 2 to 3 days after the injection of parental spleen cells, abrogated the ensuing GVH reaction. Lower doses of the drug, even when injected over an extended period of time (14 days), were found to be ineffective. However, high doses of azathioprine failed to protect when FI recipients were sublethally irradiated or injected with cyclophosphamide before GVH induction, and even the transfer of syngeneic FI spleen cells immediately after irradiation failed to alter this outcome. Further analysis of the changes that occurred in sublethally irradiated recipients revealed that the protective effect of azathioprine on CBA leads to (CBA x C57BL)FI GVH reaction was totally abrogated by doses of irradiation as low as 200 rad. Further experiments in which death was used as an indicator of GVH disease showed that lethality could not be reversed in sublethally irradiated FI recipients by the transfer of syngeneic FI spleen cells unless approximately 10 days were allowed to elapse between syngeneic reconstitution and GVH induction. Since syngeneic FI cells from spleen, lymph node, or bone marrow all behaved similarly, it seems likely that the increased severity of GVH reaction induced by prior immunosuppression may not be attributable to a simple cell deletion event

  3. Differential Effect of MyD88 Signal in Donor T Cells on Graft-versus-Leukemia Effect and Graft-versus-Host Disease after Experimental Allogeneic Stem Cell Transplantation.

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

    2015-11-01

    Despite the presence of toll like receptor (TLR) expression in conventional TCRαβ T cells, the direct role of TLR signaling via myeloid differentiation factor 88 (MyD88) within T lymphocytes on graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect after allogeneic stem cell transplantation (allo-SCT) remains unknown. In the allo-SCT model of C57BL/6 (H-2(b)) → B6D2F1 (H-2(b/d)), recipients received transplants of wild type (WT) T-cell-depleted (TCD) bone marrow (BM) and splenic T cells from either WT or MyD88 deficient (MyD88KO) donors. Host-type (H-2(d)) P815 mastocytoma or L1210 leukemia cells were injected either subcutaneously or intravenously to generate a GVHD/GVL model. Allogeneic recipients of MyD88KO T cells demonstrated a greater tumor growth without attenuation of GVHD severity. Moreover, GVHD-induced GVL effect, caused by increasing the conditioning intensity was also not observed in the recipients of MyD88KO T cells. In vitro, the absence of MyD88 in T cells resulted in defective cytolytic activity to tumor targets with reduced ability to produce IFN-γ or granzyme B, which are known to critical for the GVL effect. However, donor T cell expansion with effector and memory T-cell differentiation were more enhanced in GVHD hosts of MyD88KO T cells. Recipients of MyD88KO T cells experienced greater expansion of Foxp3- and IL4-expressing T cells with reduced INF-γ producing T cells in the spleen and tumor-draining lymph nodes early after transplantation. Taken together, these results highlight a differential role for MyD88 deficiency on donor T-cells, with decreased GVL effect without attenuation of the GVHD severity after experimental allo-SCT. PMID:26552489

  4. T Cells in Predicting Acute Graft-Versus-Host Disease in Patients Undergoing Donor Stem Cell Transplant

    2016-06-22

    Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

  5. 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

    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

  6. 桂附地黄丸干预主要组织相容性复合物半相合移植小鼠慢性移植物抗宿主病的效应%Effect of Guifu rehmaniae bolus on preventing chronic graft versus host disease in major histocompatibilty complex halpo-identical bone marrow transplantation mice

    吴顺杰; 梁凯雯; 吴远彬; 周健; 涂三芳

    2012-01-01

    BACKGROUND: At present, the method for the treatment of chronic graft versus host disease is not ideal due the adverse reactions, founding the traditional Chinese medicine for effective intervention and treatment of chronic graft versus host disease is one of the common focuses of attention for the transplant scholars. OBJECTIVE: To observe effect of Guifu rehmaniae bolus on preventing chronic graft versus host disease in major histocompatibilty complex halpo-identical bone marrow transplantation mice. METHODS: Transplantation models of major histocompatibilty complex halpo-identical hematopoietic stem cells transplantation mice were established by transplanting the hematopoietic stem cells of male Balb/cH-2d mice to female (Balb/cxC57BL/6) F1 H-2d/b (CB6F1) mice. After transplantation, 24 recipient mice were divided into two groups: Guifu rehmaniae bolus group and blank group, mice in the Guifu rehmaniae bolus group were lavaged from the first day after transplantation with 0.2 mL Guifu rehmaniae bolus liquid twice per day; mice in the blank group were lavaged with the same dose of normal saline and lasted for 100 days. RESULTS AND CONCLUSION: Five mice died in the Guifu rehmaniae bolus group, and all mice died in the blank group at 86 days after transplantation (P=0.004). The mice in the blank group depressed at 35 days after transplantation and the mice in the Guifu rehmaniae bolus group depressed at 45 days after transplantation, and the clinical score in the blank group was significantly higher than that in the Guifu rehmaniae bolus group (P < 0.05). Pathological observation showed that the mice with chronic graft versus host disease in Guifu rehmaniae bolus group mostly classified from 0 to 1 grade. Compared with blank group, the liver, skin and small intestine tissue of the mice in Guifu rehmaniae bolus group were improved. Guifu rehmaniae bolus can relieve symptoms of chronic graft versus host disease in major histocompatibilty complex halpo-identical bone

  7. 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

    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

  8. 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

    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

  9. 非清髓性造血干细胞移植后并发移植物抗宿主病的相关因素分析%Related factor analysis of graft-versus-host disease post nonmyeloablative stem cell transplantation

    李庆山; 毛平; 王顺清; 莫文健; 张玉平; 应逸; 邓婷芬

    2008-01-01

    目的 探讨和分析非清髓性造血干细胞移植(NST)后并发移植物抗宿主病(GVHD)的相关因素.方法 选择34例血液病患者,其中重型再生障碍性贫血(SAA)15例,重型β-地中海贫血(TM)1例,肿瘤性血液病18例;进行无关供者脐带血造血干细胞移植(UCBT)11例,同胞供者骨髓联合外周血干细胞移植7例,外周血造血干细胞移植(PBSCT)16例.移植前采用以抗胸腺细胞球蛋白(ATG)、抗淋巴细胞球蛋白(ALG)或者氟达拉滨强效免疫抑制为基础的非清髓性预处理方案.GVHD的预防采用短程的甲氨蝶呤(MTX)联合环孢素A(CsA).观察非清髓性造血干细胞移植后的临床特点以及急、慢性移植物抗宿主病的发生情况;分析发生慢性移植物抗宿主病(cGVHD)的相关因素.结果 NST的植入率为91.2%.移植后7例肿瘤性血液病患者形成了供、受者造血细胞混合嵌合体(MC),给予供者淋巴细胞输注(DLI)2~9次后,例由MC转变为供者造血细胞完全嵌合体(FDC).随访12(3~96)个月,共发生Ⅰ~Ⅱ度急性移植物抗宿主病(aGVHD)5例,GVHD 15例.经统计学分析,发现年龄大的肿瘤性血液病患者经以ATG为基础的NST后,再给予DLI,其cGVHD的发生率高,且合并感染,对治疗的反应差;而以氟达拉滨为基础的NST患者发生cGVHD后治疗反应较好.移植100 d前后患者分别死亡3例和5例,其中3例死于广泛性cGVHD.结论 患者的年龄大、有合并症、以ATG为基础的预处理方案、肿瘤性血液病是NST后患者并发cGVHD的危险因素.%Objective To explore and analyze the related factors of graft-versus-host disease (GVHD) post nonmyeloablative stem cell transplantation (NST) for haematologic diseases.Methods Thirty-four patients including severe aplastic anemia (SAA) (n=15),halassemia major (TM) (n=1) and malignant haematologie diseases (n=18) underwent unrelated umbilical cord blood transplantation (UCBT) (n=11) and sibling donor bone and peripheral

  10. Blockade of interleukin-23 signaling results in targeted protection of the colon and allows for separation of graft-versus-host and graft-versus-leukemia responses

    Das, Rupali; Komorowski, Richard; Hessner, Martin J; Subramanian, Hariharan; Huettner, Claudia S.; Cua, Daniel; Drobyski, William R.

    2010-01-01

    Allogeneic stem cell transplantation is the most potent form of effective adoptive immunotherapy. The graft-versus-leukemia (GVL) effect mediated by the allogeneic graft, however, is typically coexpressed with graft-versus-host disease (GVHD), which is the major complication of allogeneic stem cell transplantation. In this study, we used genetic and antibody-based strategies to examine the effect that blockade of interleukin 23 (IL-23) signaling had on GVH and GVL reactivity in murine transpl...