Murine Models for Graft‐Vs.‐Host Disease

Korngold, Robert; Friedman, Thea M.

doi:10.1002/9780470987070.ch26

Cited by 4 publications

(3 citation statements)

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“…It is not known whether human aGVHD or cGVHD is caused by CD4 or CD8 T cells. In mice, aGVHD can be caused by CD4 and/or CD8 T cells [20]. Our data strongly suggest that it is also the case in humans (Tables 3-5).…”

Section: Discussionsupporting

confidence: 69%

Immune Cell Subset Counts Associated with Graft-versus-Host Disease

Podgorny

Liu

Dharmani‐Khan

et al. 2014

Biology of Blood and Marrow Transplantation

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Graft-versus-host disease (GVHD) is a major transplantation complication. The purpose of this study was to measure immune cell subsets by flow cytometry early after transplantation (before median day of GVHD onset) to identify subsets that may play a role in GVHD pathogenesis. We also measured the subsets later after transplantation to determine which subsets may be influenced by GVHD or its treatment. We studied 219 patients. We found that acute GVHD (aGVHD) was preceded by high counts of CD4 T cells and CD8 T cells. It was followed by low counts of total and naive B cells, total and cytolytic NK cells, and myeloid and plasmacytoid dendritic cells. Chronic GVHD (cGVHD) was preceded by low counts of memory B cells. In conclusion, both CD4 and CD8 T cells appear to play a role in the pathogenesis of aGVHD. Generation of B cells, NK cells, and dendritic cells may be hampered by aGVHD and/or its treatment. Memory B cells may inhibit the development of cGVHD.

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Section: Discussionsupporting

confidence: 69%

Immune Cell Subset Counts Associated with Graft-versus-Host Disease

Podgorny

Liu

Dharmani‐Khan

et al. 2014

Biology of Blood and Marrow Transplantation

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“…Patients with GVHD develop a wide range of symptoms, including skin rash, diarrhea, liver disease, erythema, and weight loss, which eventually result in death. [1][2][3][4][5][6][7] Immunosuppressive drug treatment or mature T-cell-depleted bone marrow transplantation (TCD BMT) have been used as effective strategies to prevent GVHD. 8,9 However, these strategies can also lead to engraftment failure, a prolonged state of immunodeficiency, and various types of opportunistic infections.…”

Section: Introductionmentioning

confidence: 99%

Prevention of graft-versus-host disease by anti–IL-7Rα antibody

Chung

Dudl

Min

et al. 2007

Blood

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Graft-versus-host disease (GVHD) continues to be a serious complication that limits the success of allogeneic bone marrow transplantation (BMT). Using IL-7-deficient murine models, we have previously shown that IL-7 is necessary for the pathogenesis of GVHD. In the present study, we determined whether GVHD could be prevented by antibody-mediated blockade of IL-7 receptor ␣ (IL- 7R␣ IntroductionGraft-versus-host disease (GVHD) continues to be a limiting factor in the use of clinical hematopoietic stem-cell transplantation (HSCT). GVHD occurs when donor T cells recognize host antigenic disparities expressed on antigen-presenting cells (APCs), resulting in activation of alloreactive T cells and destruction of host tissues. Patients with GVHD develop a wide range of symptoms, including skin rash, diarrhea, liver disease, erythema, and weight loss, which eventually result in death. [1][2][3][4][5][6][7] Immunosuppressive drug treatment or mature T-cell-depleted bone marrow transplantation (TCD BMT) have been used as effective strategies to prevent GVHD. 8,9 However, these strategies can also lead to engraftment failure, a prolonged state of immunodeficiency, and various types of opportunistic infections. Therefore, developing a therapeutic strategy to suppress GVHD without compromising the immune system will be ideal for allogeneic BMT recipients.IL-7 and Kit ligand (KL; stem-cell factor [SCF]) are the major lymphopoietic cytokines produced in the thymus and BM compartment. 10-13 IL-7 induces proliferation, differentiation, and survival of immature T lymphocytes. During normal T-cell development in the thymus, IL-7 produced by thymic epithelial cells (TECs) binds to the cognate IL-7 receptor (IL-7R). The IL-7R is composed of IL-7R␣ and common ␥ subunits and expressed on the surface of immature T-lymphoid progenitor cells. Mutations of the IL-7, IL-7R␣, and ␥ c genes result in defective thymopoiesis and impaired ability to produce T lymphocytes. 14-18 Previously we and others have shown that administration of recombinant human IL-7 following histocompatible BMT in murine recipients corrects thymopoietic defects and enhances immune reconstitution, further suggesting the importance of IL-7 in the development of T lymphocytes. 19 Besides its thymopoietic effects, IL-7 also promotes expansion and survival of mature naive and memory CD4 ϩ and CD8 ϩ T cells. Recent studies have shown that IL-7-IL-7R interactions in concert with low-affinity interactions between T-cell receptors (TCRs) and self-peptide ligands bound to major histocompatibility complex (MHC) allow proliferation of mature T cells in the periphery. [20][21][22][23][24][25][26] In addition, IL-7 enhances the survival of alloreactive donor T cells in allogeneic BMT recipients and plays a crucial role in the development and exacerbation of GVHD. [27][28][29][30][31] Based on the effects of IL-7 on mature T cells, we investigated whether GVHD could be prevented by a blockade of IL-7R␣ with an anti-IL-7R␣ monoclonal antibody. Similar to earlier experimental results ...

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“…11 Autoreactive T helper (Th) clones can be isolated. 12 One minor mismatch model mimics human scleroderma with skin and lung fibrosis, a process that can be blocked by anti-transforming growth factor ␤ (TGF-␤) antibody treatment. 13 Another murine model mimics systemic lupus erythematosis with splenomegaly, B-cell expansion, autoantibodies, and glomerulonephritis.…”

Section: Rodent Modelsmentioning

confidence: 99%

New approaches for preventing and treating chronic graft-versus-host disease

Lee

2005

Blood

127

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Despite improvements in the practice of allogeneic hematopoietic stem cell transplantation (HCT) over the last 25 years, chronic graft-versus-host disease (GVHD) remains a substantial problem with little change in the incidence, morbidity, and mortality of this complication. In fact, with increased use of peripheral blood, transplantation of older patients, and less immediate transplantation-related mortality, the prevalence of chronic GVHD may increase. One of the difficulties in combating chronic GVHD is a lack of understanding about the pathophysiology of the syndrome. IntroductionChronic graft-versus-host disease (GVHD) is the most serious and common long-term complication of allogeneic hematopoietic stem cell transplantation (HCT), occurring in 20% to 70% of people surviving more than 100 days. 1,2 Approximately half of affected people have 3 or more involved organs, and treatment typically requires immunosuppressive medications for a median of 1 to 3 years. Because of higher treatment-related (nonrelapse) mortality, chronic GVHD remains the major cause of late death despite its association with a lower relapse rate. 3,4 In addition, secondary malignancies are more common in people with chronic GVHD, particularly of commonly involved tissues such as mouth and skin, suggesting that chronic inflammation, prolonged exposure to immunosuppressive medications, or immune dysregulation facilitates the development of new cancers. 5 Finally, the functional consequences of chronic GVHD organ involvement are major determinants of the health and quality of life of survivors. 6,7 Despite the well-recognized adverse effects of chronic GVHD on the long-term success of allogeneic transplantation, its pathophysiology is poorly understood, and management strategies beyond systemic corticosteroids have not been established.While there are some lessons that can be translated from basic and clinical studies of acute GVHD, several lines of evidence suggest that chronic GVHD is not simply a continuation of acute GVHD, and that separate approaches will be required for its prevention and management. First, except for T-cell depletion and use of umbilical cord blood, the major innovations that have improved acute GVHD rates do not seem to have affected chronic GVHD incidence. Second, while there is significant overlap between the organs involved in acute and chronic GVHD, the distribution of affected organs in chronic GVHD is much broader. Fully evolved chronic GVHD is largely an inflammatory and fibrotic process, while acute GVHD is more likely to reflect apoptosis and necrosis. Although traditionally the boundary between acute and chronic GVHD has been set at 100 days after transplantation, more recent definitions hinge on different clinical manifestations rather than time of onset. Third, while acute GVHD is highly associated with subsequent chronic GVHD, approximately 25% to 35% of chronic GVHD is de novo without any preceding acute manifestations, while 20% to 30% of people who had acute GVHD do not go on to develop chronic GVH...

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Murine Models for Graft‐Vs.‐Host Disease

Cited by 4 publications

References 59 publications

Immune Cell Subset Counts Associated with Graft-versus-Host Disease

Immune Cell Subset Counts Associated with Graft-versus-Host Disease

Prevention of graft-versus-host disease by anti–IL-7Rα antibody

New approaches for preventing and treating chronic graft-versus-host disease

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