Emergent autoimmunity in graft-versus-host disease

Tivol, Elizabeth; Komorowski, Richard; Drobyski, William R.

doi:10.1182/blood-2004-12-4980

Cited by 112 publications

(82 citation statements)

References 45 publications

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“…T cells from K14 mice that express MHC class II (MHC-II) only on thymic cortical epithelium are also able to induce autologous GVHD, suggesting that the thymic expression of MHC-II in hemopoietic APCs and medulla cells is critical to eliminating host-reactive T cells (43,44). This has been confirmed in HSCT models that inactivation of MHC-II on thymic hemopoietic APCs results in donor T cells with the ability to induce autoimmune colitis (45), autologous GVHD in normal syngeneic mice (42), and chronic GVHD in allogeneic mice with MHC differences (46). In the present study, we found that inflammatory cells caused severe damage to the thymic architecture of mice receiving donor CD8 ϩ T cells.…”

Section: Discussionsupporting

confidence: 81%

CD4+ T Cells Generated De Novo from Donor Hemopoietic Stem Cells Mediate the Evolution from Acute to Chronic Graft-versus-Host Disease

Zhang

Hexner

Frank

et al. 2007

The Journal of Immunology

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Acute and chronic graft-versus-host disease (GVHD) remain the major complications limiting the efficacy of allogeneic hemopoietic stem cell transplantation. Chronic GVHD can evolve from acute GVHD, or in some cases may overlap with acute GVHD, but how acute GVHD evolves to chronic GVHD is unknown. In this study, in a classical CD8+ T cell-dependent mouse model, we found that pathogenic donor CD4+ T cells developed from engrafted hemopoietic stem cells (HSCs) in C57BL/6SJL(B6/SJL, H-2b) mice suffering from acute GVHD after receiving donor CD8+ T cells and HSCs from C3H.SW mice (H-2b). These CD4+ T cells were activated, infiltrated into GVHD target tissues, and produced high levels of IFN-γ. These in vivo-generated CD4+ T cells caused lesions characteristic of chronic GVHD when adoptively transferred into secondary allogeneic recipients and also caused GVHD when administered into autologous C3H.SW recipients. The in vivo generation of pathogenic CD4+ T cells from engrafted donor HSCs was thymopoiesis dependent. Keratinocyte growth factor treatment improved the reconstitution of recipient thymic dendritic cells in CD8+ T cell-repleted allogeneic hemopoietic stem cell transplantation and prevented the development of pathogenic donor CD4+ T cells. These results suggest that de novo-generated donor CD4+ T cells, arising during acute graft-versus-host reactions, are key contributors to the evolution from acute to chronic GVHD. Preventing or limiting thymic damage may directly ameliorate chronic GVHD.

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Section: Discussionsupporting

confidence: 81%

CD4+ T Cells Generated De Novo from Donor Hemopoietic Stem Cells Mediate the Evolution from Acute to Chronic Graft-versus-Host Disease

Zhang

Hexner

Frank

et al. 2007

The Journal of Immunology

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“…It has been shown that GVHD predisposes to autoimmune disorders. [25][26][27][28] In fact, AIHA can even be a presenting sign of cGVHD. 8,29 The mechanism by which allogeneic cellular activation leads to a humoral autoimmune disorder is unclear.…”

Section: Discussionmentioning

confidence: 99%

Autoimmune hemolytic anemia following allogeneic hematopoietic stem cell transplantation in adult patients

Sanz

Arriaga

Montesinos

et al. 2007

Bone Marrow Transplant

138

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Autoimmune hemolytic anemia (AIHA) after allogeneic hematopoietic stem cell transplantation (HSCT) is still not well characterized. The aim of this study was to analyze the incidence and risk factors for the development of AIHA, as well as its prognosis and response to treatment in a series of patients undergoing allogeneic HSCT at a single institution. Between 1996 and 2004, 272 adult patients with a variety of malignant hematopoietic disorders underwent allogeneic HSCT. Direct antiglobulin testing was performed in routine pretransfusion compatibility testing or after clinical suspicion of AIHA. Twelve patients developed AIHA after HSCT at a median time of 147 days (range, 41-170). The 3-year cumulative incidence of AIHA was 4.44%. Eight cold antibodies and four warm antibodies were detected. Multivariate analysis shows that HSCT from unrelated donors (P ¼ 0.02) and the development of chronic extensive graft-versus-host disease (GVHD) (P ¼ 0.0004) were the only independent factors associated with AIHA. Two patients are still alive. AIHA was never the primary cause of death but added morbidity in patients with other concomitant complications. Patients undergoing HSCT from unrelated donors and those who develop chronic extensive GVHD are especially predisposed for this complication.

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“…The development of antidsDNA Abs appears to require a diverse repertoire of CD4 ϩ T cells (46). Donor APC, host APC, and recipient regulatory T cells can influence the timing and severity of GVHD (47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Development and Selection of Edited B Cells in B6.56R Mice

Sekiguchi

Yunk

Gary

et al. 2006

The Journal of Immunology

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Tolerance to dsDNA is broken in mice with a high-affinity anti-DNA H chain transgene, 56R, on the C57BL/6 background (B6.56R). B6.56R produce more anti-dsDNA Abs than BALBc.56R. To investigate how anti-DNA Abs are regulated on the B6 background, phenotypic and genetic studies were performed. B6.56R have reduced numbers of B cells and phenotypically altered B cell subsets, including relative increases in the proportions of IgM-negative bone marrow B cells, cells with a marginal zone phenotype, and cells with a transitional T3 phenotype. The peripheral B cell repertoire in B6.56R is restricted: most B cells express the 56R H chain and use a similar, limited subset of editor L chains. DNA binding is more common in B6.56R because the repertoire is shifted toward L chains that are more permissive for DNA binding. H chain editing is also observed and is increased in spontaneous as compared with LPS hybridomas. A subset of spontaneous hybridomas appears to lack H chain expression.

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Emergent autoimmunity in graft-versus-host disease

Cited by 112 publications

References 45 publications

CD4+ T Cells Generated De Novo from Donor Hemopoietic Stem Cells Mediate the Evolution from Acute to Chronic Graft-versus-Host Disease

CD4+ T Cells Generated De Novo from Donor Hemopoietic Stem Cells Mediate the Evolution from Acute to Chronic Graft-versus-Host Disease

Autoimmune hemolytic anemia following allogeneic hematopoietic stem cell transplantation in adult patients

Development and Selection of Edited B Cells in B6.56R Mice

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