A case for the graft-versus-host disease as a model for B cell-mediated autoimmunity (original) (raw)
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2006
1710 articles) Transplantation (4651 articles) Immunobiology Articles on similar topics can be found in the following Blood collections http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub\_requests Information about reproducing this article in parts or in its entirety may be found online at: http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprints Information about ordering reprints may be found online at: http://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtml Information about subscriptions and ASH membership may be found online at: Chronic graft-vs-host disease (GVHD) is a major cause of morbidity and mortality of long-term survivors of allogeneic hematopoietic cell transplantation (HCT). Chronic GVHD can have features of an autoimmune collagen vascular disease with clinical manifestations similar to autoimmune scleroderma and systemic lupus erythematosus (SLE). However, the pathogenesis of chronic GVHD is poorly understood. It is unclear how autoreactive T and B cells are generated in chronic GVHD recipients. We have recently developed a new chronic GVHD model by transplantation of donor DBA/2 (H-2 d ) spleen cells into major histocompatibility complex (MHC)matched but minor antigen-mismatched sublethally irradiated BALB/c (H-2 d ) recipients as well as athymic BALB/c nu/nu and adult-thymectomized BALB/c recipients. Both euthymic and athymic BALB/c recipients developed high levels of serum IgG autoantibodies, sclerodermatous skin damage, and glomerulonephritis. Disease induction required both donor CD25 ؊ CD4 ؉ T and B cells in transplants. In contrast, donor CD25 ؉ CD4 ؉ T regulatory (Treg) cells prevented the disease induction. These results indicate that host thymus is not required for induction of chronic GVHD and that quiescent autoreactive T and B cells in transplants from nonautoimmune donors may be activated and expanded to cause chronic GVHD with autoimmune manifestations in allogeneic recipients, and donor Treg cells can suppress this process. (Blood. 2006;107: 2993-3001)
European Journal of Immunology, 1989
Allosuppression of B cells in vitro by graft-vs.-host reaction-derived T cells is caused by cytotoxic T lymphocytes* An acute graft-vs.-host reaction (GVHR) was induced by i.v. injection of lo8 lymphoid cells from C57BL110 (B10) donors (H-zb") into adult non-irradiated (B10 x DBA/2)FI mice (H-2b'd). Previous experiments have established that spleen cells obtained from such GVHFl mice suppress the primary antibody response of normal F1 spleen cells to sheep red blood cells. This type of suppression was termed "allosuppression", and it was shown to be mediated by Ly-2+ T cells of donor origin that react against H-2 antigens of the host. It was unclear, however, whether the actual mechanism of allosuppression was due to suppressive factors generated by donor T cells or whether the latter killed the F1 B cells. Here, we show that for their suppressive effect GVHFl spleen cells need direct cell contact with F1 spleen cells; no suppressive effect was measured in a double-chamber culture system in which the GVHFl spleen cells were separated from the responding normal F1 spleen cells by a cell-tight membrane filter. The suppressive effect only affected cells expressing the appropriate H-2 class I alloantigen; in mixed cultures of irradiated F1 spleen cells and GVHFl spleen cells with third-party B cells the antibody response of the third-party B cells was not suppressed. GVHFl spleen cells showed cytotoxic T lymphocyte (CTL) activity specific for the allogeneic F1 H-2 antigen. The suppressive effect of the GVHFl spleen cells did not differ from that exerted by cloned CTL specific for MHC class I alloantigens; cloned CTL suppressed the primary antibody response of murine spleen cells without affecting the response of third-party B cells added to the cultures. The combined findings show that "allosuppression" in vitro is not due to suppression of F1 B cells. but to a direct killing of these cells by alloreactive CTL.
Vox Sanguinis, 1995
Posttransfusion graft-versus-host disease (PTGVHD) is known to develop in immunocompetent patients exhibiting clinical symptoms such as erythroderma, fever, liver dysfunction, diarrhea and pancytopenia. It is speculated that transfused blood donors' lymphocytes might recognize the recipients' HLAs as alloantigens. The thus stimulated lymphocytes might proliferate, expand and finally attack the host's immune system or tissues. However, details regarding these expanded donor cells such as: (1) whether they represent one clone or more, (2) the composition of lymphocyte subsets, and (3) the target HLA antigens of recipients, are not clear, since T-cell lines derived from PTGVHD patients have not yet been obtained. The aim of this study is to characterize T-cells responsible for PTGVHD and to identify their target molecules. For that purpose, we attempted to establish T-cell lines derived from a PTGVHD patient. We show that the established T-cell line, proven to be derived from donor lymphocytes, showed a CD4+ phenotype and had cytotoxic activities. Furthermore, we describe that the target of the cytotoxic T-cell line (CTL) is an HLA-DRB1*0405-related molecule of the patient.
Recipient B Cells Are Not Required for Graft-Versus-Host Disease Induction
Biology of Blood and Marrow Transplantation, 2010
Recipient antigen presenting cells (APCs) are required for CD8-mediated graft-versus-host disease (GVHD), and have an important and nonredundant role in CD4-mediated GVHD in mouse major histocompatibility complex-matched allogeneic bone marrow transplantation (alloBMT). However, the precise roles of specific recipient APCs-dendritic cells, macrophages, and B cells-are not well defined. If recipient B cells are important APCs they could be depleted with rituximab, an anti-CD20 monoclonal antibody. On the other hand, B cells can downregulate T cell responses, and consequently, B cell depletion could exacerbate GVHD. Patients with B cell lymphomas undergo allogeneic hematopoietic stem cell transplantation (alloSCT) and many are B-cell-deficient because of prior rituximab. We therefore studied the role of recipient B cells in major histocompatibility complex-matched murine models of CD8-and CD4-mediated GVHD by using recipients genetically deficient in B cells and with antibody-mediated depletion of host B cells. In both CD4-and CD8-dependent models, B cell-deficient recipients developed clinical and pathologic GVHD. However, although CD8-mediated GVHD was clinically less severe in hosts genetically deficient in B cells, it was unaffected in anti-CD20-treated recipients. These data indicate that recipient B cells are not important initiators of GVHD, and that efforts to prevent GVHD by APC depletion should focus on other APC subsets.
Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease
Blood, 2009
Altered B-cell homeostasis and excess BAFF in human chronic http://bloodjournal.hematologylibrary.org/cgi/content/full/113/16/3865 Updated information and services can be found at: (1374 articles) Transplantation (3797 articles) Immunobiology collections: Blood Articles on similar topics may be found in the following http://bloodjournal.hematologylibrary.org/misc/rights.dtl#repub\_requests
Clinical Immunology and Immunopathology, 1990
The induction of a chronic graft-versus-host (cGVH) disease in (Balb/c X A/J)Fl mice by the intravenous injection of either Balb/c or A/J parental lymphoid cells led to the development of two different models of disease. In this paper we compared the clinical aspects and the antigen specificities which recognized the autoantibodies developed by the animals of these two models of cGVH disease. Renal disease, alopecia, and purpura lesions were common in both models, although their frequency and intensity varied between groups. The models were differentiated by two main characteristics. When donor cells were of Balb/c origin, a joint disease similar to rheumatoid arthritis developed in 50% of the animals, and when donor cells were of A/J origin, 25% of the animals developed edema of the front feet, occasionally with loss of the nails, similar to that of scleroderma. Differences among the autoantibodies found in the sera of these two groups of mice were also observed. After the injection of Balb/c lymphoid cells, rheumatoid factors reactive with human and murine IgG were characteristically present (69 and 75%, respectively) and a statistically significant correlation was found between high titers of rheumatoid factor and arthritis (P < 0.001). Antinuclear antibodies (ANAs) were present in all animals. Anti-dsDNA and anti-histones were positive in 50 and 25%, respectively. Anti-snRNP were detected at a low titer in 35% of the animals. When donor ceils were of A/J origin, ANAs were also present in all mice. Anti-dsDNA, anti-histones, and anti-snRNPs antibodies were present in 90, 15, and 65%. respectively. The most outstanding characteristics among anti-snRNPs were the high titers of anti-U I and anti-U3 detected in 50 and 30%, respectively. Rheumatoid factors reactive with human and murine IgG were positive in 15 and 42% of animals, respectively, but no significant correlation was found between these factors and disease. Our results indicate that the graft-versus-host disease induced in the same FI strain of mice can be manifested in different forms of connective tissue disease. depending on whether the cells come from one or the other of the parental strains. Furthermore, in this paper the occurrence of rheumatoid factors in mice with cGVH is described for the first time. B