Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of murine spleen cells (SpC) with L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) depletes L3T4(+) and Lyt2(+) cytotoxic T lymphocyte precursors and the capacity to generate lethal graft-versus-host disease in semiallogeneic class I + II MHC and multiple non-MHC-disparate recipient mice, whereas T helper cell function is preserved. In the present studies the role of Leu-Leu-OMe-sensitive CTL in skin graft rejection was examined. C57BL/6J (B6) mice were serially thymectomized, lethally irradiated, reconstituted with T cell-depleted bone marrow, and treated with intraperitoneal injections of anti-L3T4 and anti-Lyt2 monoclonal antibodies. These adult thymectomized, bone marrow-reconstituted, T cell-depleted (ATXBM, TCD) mice were unable to reject B6xDBA/2F1 (B6D2F1) skin grafts. When such ATXBM, TCD mice were reconstituted with 7 x 10(7) control B6 SpC, acute rejection of B6D2F1 skin was observed. When B6 donor SpC were Leu-Leu-OMe-treated prior to transfer to ATXBM, TCD mice, uniform rejection of B6D2F1 skin grafts was still observed, although a significant delay in the time to rejection was observed. More rigorous T cell depletion of ATXBM, TCD host mice by infusion of antithymocyte globulin did not prevent delayed rejection of B6D2F1 skin initiated by transfer of Leu-Leu-OMe-treated B6 SpC. Despite the lack of complete prevention of skin allograft rejection, Leu-Leu-OMe treatment of B6 donor cells prevented lethal GVHD even in thymectomized B6D2F1 recipients. Precursors of anti-B6D2F1-specific CTL were greatly reduced or undetectable in unreconstituted ATXBM, TCD mice or in irradiated B6D2F1 recipients of Leu-Leu-OMe-treated B6 SpC. By contrast, ATXBM, TCD recipients of Leu-Leu-OMe-treated B6 SpC were found to contain a population of anti-class I MHC-specific CTL precursors of host origin within 28 days of reconstitution. These findings have indicated a number of features of the cells involved in skin graft rejection. First, Leu-Leu-OMe-sensitive CTL play a major role in acute rejection of class I + II MHC and multiple non-MHC antigen-disparate skin grafts. Moreover, the thymus-independent expansion of host-derived CTL precursors in ATXBM, TCD mice reconstituted with syngeneic Leu-Leu-OMe-resistant T helper cells also appears to play a role in mediating rejection of allogeneic skin grafts.
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PMID:The role of leucyl-leucine methyl ester-sensitive cytotoxic cells in skin allograft rejection. 160 89

In a healthy state, the central nervous system (CNS) is believed to be an immunologically privileged site, which does not participate in the immune reactions of the rest of the body, and in which identifiable components of the immune system are rare or non-existent. In this study, an immunohistochemical examination of the CNS of F1 hybrid rats following induction of graft-versus-host disease (GVHD) was carried out to determine whether specific immune reactions in the normal CNS could occur during a systemic immune reaction. The results revealed extensive parenchymal and vascular expression of class I and II major histocompatibility complex (MHC) encoded cell surface molecules. The strongest expressors of class I and II molecules were endothelial cells and parenchymal cells, respectively, the latter being apparently activated microglia, in the cerebrum and cerebellum of rats with GVHD. In addition, occasional scattered lymphocytes were detected in the CNS of GVHD rats without blood-brain barrier disruption. Thus, evidence was obtained for the presence of immune responses such as MHC antigen expression and lymphocyte infiltration in the CNS during a strong systemic immune response such as GVHD, microglia and endothelial cells apparently playing an important role.
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PMID:Major histocompatibility complex expression in brain of rats with graft-versus-host disease. 203 16

Class I and class II (HLA-DR, DP and DQ) MHC antigen expression and the phenotypic nature of the inflammatory infiltrate in gastric and duodenal biopsies in bone marrow transplantation patients with and without graft-versus-host disease were investigated. Increased expression of class I (P less than 0.016) and class II (HLA-DR, DP) antigens (P less than 0.002) was associated with GVHD. The epithelium in two GVHD-positive biopsies was HLA-DP-positive and HLA-DR-negative. None of the tissues expressed HLA-DQ. Association between MHC antigen expression and phenotype of infiltrating cell was then examined. The majority of GVHD biopsies showed an infiltrate composed of CD4+ cells and CD8+ cells. However, the two DP+, DR- biopsies were associated exclusively with CD8+ intraepithelial cells, suggesting sequential events in GVHD, with CD8+ cells infiltrating tissue first associated with HLA-DP expressions, followed by accumulation of CD4+ as well as CD8+ cells in association with expression of HLA-DR.
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PMID:Immunopathology of graft-versus-host disease in the upper gastrointestinal tract. 266 37

To explore the relationship between aberrant MHC antigen expression and tissue injury in acute graft-versus-host disease, we performed a sequential histological and immunohistochemical analysis of multiple tissues in acute GVHD generated across complete MHC and multiple minor H incompatibilities in the rat. Two patterns of MHC antigenic modulation were recognized. Aberrant MHC class I and class II antigen expression occurred simultaneously on the epithelial cells of nonlymphoid target tissues early in acute GVHD. This coincided with a lymphoproliferative phase that preceded nonlymphoid tissue injury. The extent of epithelial class II antigen induction predicted the extent of subsequent histological injury. Changes in MHC class II antigen expression were also seen on nonepithelial cells. Interstitial dendritic cells (IDCs) expressing recipient MHC class II antigens increased in both target and nontarget tissues during early GVHD. Recipient class II antigens were also induced on large numbers of microglialike cells in the brain and Kupffer cells in the liver. However, tissue injury did not follow MHC class II antigen induction on nonepithelial cells. These findings are consistent with a role for aberrant epithelial MHC antigen expression in nonlymphoid tissue injury in acute GVHD.
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PMID:Evidence that nonlymphoid tissue injury in acute graft-versus-host disease is limited to epithelial cells aberrantly expressing MHC antigens. 279 19

Characterization of the effect of immunization of F1 hybrid hosts with low doses of parental cells has shown that the F1 hybrid response to the receptor for the unshared MHC antigen on the immunizing cell induces specific resistance to a GVH challenge from cells of the same parental strain. We have shown that cells from parental rats tolerant to the unshared MHC antigens are capable of inducing GVH resistance in F1 hybrids. Unlike cells from normal parental rats that induce GVH resistance only when given in low immunizing doses of 10(6) cells, 10(6)-10(8) cells from tolerant donors effectively immunize F1 hybrids. This effect does not appear to be the result of passive transfer of suppressor cells from the tolerant donor. An alternative explanation is that tolerant populations contain cells that express the receptor for the tolerated alloantigen. The finding that normal parental populations that have been deleted of receptor-bearing cells by passage through semiallogeneic intermediate hosts do not induce GVH resistance, whereas tolerant cell populations do, confirms that clonal deletion does not adequately account for the functional characteristics of the tolerant cells. Attempts to delete putative receptor-bearing cells from the tolerant population however produced equivocal results.
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PMID:Graft-versus-host resistance induced by tolerant cell populations. Evidence against clonal deletion as a mechanism of transplantation tolerance. 292 1

Graft-versus-host disease (GVHD) caused by T-cell recognition of minor histocompatibility (MiHC) antigens is a major complication of bone marrow transplantation. GVHD therapy has focused on removal or suppression of donor T cells, but modulation of MiHC antigen presentation to CD4+ T cells may represent an alternative approach. Chloroquine is known to inhibit major histocompatibility complex (MHC) class II presentation of antigen in vitro by affecting invariant chain dissociation from MHC class II. The goal of this study was to evaluate the role of chloroquine in abrogating T-cell priming to MiHC and GVHD in mice after transplantation of an MiHC incompatible donor. C57BL/6 mice were treated with phosphate-buffered saline or chloroquine at 400 micrograms intraperitoneally every day for 5 days before priming with BALB.B cells (MiHC-incompatible) followed by weekly injections of chloroquine at 400 micrograms for 4 to 8 weeks. Chloroquine treatment decreased the proliferative T-cell response to MiHC by 67% and the cytolytic T-cell activation by greater than 50%. After bone marrow transplantation (LP/J into C57BL/6; MiHC-incompatible), GVHD was significantly decreased in chloroquine-treated mice (17% with GVHD) as compared with that in controls (92% with GVHD). Chloroquine treatment did not have other effects in vivo on the normal T- and B-cell mitogenic responses, T-cell allogeneic responses, and MHC class II and I surface expression. Chloroquine treatment does decrease the ability of C57BL/6 antigen-presenting cells to stimulate C3H.SW T cells reactive with MiHC expressed on C57BL/6 cells, suggesting an effect on MHC class II presentation of MiHC in vivo. Treatment with chloroquine in vivo appears to result in decreased CD4+ T-cell priming to MiHC and GVHD by decreased class II MHC antigen presentation. Thus, chloroquine treatment may represent an alternative approach to control GVHD.
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PMID:Chloroquine treatment affects T-cell priming to minor histocompatibility antigens and graft-versus-host disease. 749 96

An in vitro skin explant model has been used to predict the severity of acute graft-versus-host disease (GVHD) in 34 HLA-identical bone marrow transplant recipients (correlation coefficient 0.6 p < 0.001). Supernatants from HLA-matched patient/donor mixed lymphocyte cultures (MLCs) were analysed for levels of tumour necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma). High levels of both cytokines correlated with the development of GVHD grades II or above (p < 0.05). The supernatants were also tested for induction of class II MHC antigen expression on third party skin and results correlated with clinical outcome in 17 of 22 cases (77%) (correlation coefficient 0.65, p < 0.001). The results suggest that measurement of both TNF alpha and IFN gamma in HLA-matched MLC supernatants is of predictive value and that the skin explant model is a useful model for studying the aetiology of GVHD in humans.
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PMID:Cytokine involvement in predicting clinical graft-versus-host disease in allogeneic bone marrow transplant recipients. 801 55

Peripheral blood mononuclear cells (PBMC) from 17 patients receiving HLA-identical sibling bone marrow grafts were stimulated with host pretransplant PBMC. Cytotoxic T-cell lines (TCL) with specificity for host pretransplant PBMC were obtained from 9 of these patients, all presenting with severe graft-versus-host disease (GVHD), but from none of the remaining cases lacking evidence of disease. Cytotoxic TCL were specific for host targets and failed to lyse donor cells. Monoclonal antibodies (MoAbs) blocking experiments and donor population screening analyses demonstrated that minor histocompatibility antigen (MiHA)-specific lysis of host targets was restricted by class I major histocompatibility complex (MHC) determinants. Whereas hematopoietic cells such as phytohemagglutinin (PHA) blasts or lymphoblastoid cell lines were susceptible to lysis by MiHA-specific TCL, keratinocytes (K) representing the natural targets of GVHD were quite resistant. Quantitative radioimmunometric measurements indicated very low constitutive expression of class I MHC antigens on K targets, which was readily increased by treatment with interferon-gamma (IFN-gamma). IFN-gamma treatment at the same time rendered these cells susceptible to lysis by MiHA-specific TCL. Host leukemic cells of 3 patients were recognized by MiHA-specific TCL in a chromium release assay and in one experiment host leukemic cells were effectively killed and their growth specifically inhibited in a leukemia colony assay by a clone. These data demonstrate that (1) host-specific cytotoxic TCL are detected exclusively in the PB of patients with acute GVHD grades II through IV after allogeneic matched bone marrow transplantation, and (2) their target antigens are simultaneously expressed on several host cell lines, including lymphoblastoid cell lines, PHA blasts, leukemic cells, and K. We also extend previous findings by showing that, besides the expression of the nominal MiHA, the density of the restricting class I MHC elements also crucially determines the extent of TCL lysis. Because of its capacity to enhance class I MHC antigen expression, IFN-gamma represents a key cytokine for determining the susceptibility of MiHA targets for lysis by TCL and clones, and in one patient an MiHA-specific clone recognized host leukemic cells and also inhibited host leukemic cell growth in a colony inhibition assay.
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PMID:Correlation of minor histocompatibility antigen-specific cytotoxic T lymphocytes with graft-versus-host disease status and analyses of tissue distribution of their target antigens. 847 80