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)

Cyclosporin A (Sandimmun) has gained wide acceptance by most transplant physicians as the immunosuppressant of choice for preventing rejection of solid organ grafts and graft-versus-host disease. The drug has a specific effect on T-lymphocytes in which it seems to prevent the transcription of genes for several lymphokines. The reduction in IL-2 prevents the clonal expansion of T-lymphocytes and their differentiation into effector T-cells. The reduction in IFN-tau interrupts the feedback mechanism between T-cells and macrophages and the aberrant expression of MHC class II molecules. Through these mechanisms Sandimmun exerts an immunosuppressive and anti-inflammatory effect. Considerable evidence has accumulated to suggest that rheumatoid arthritis (RA) is an auto-immune disease. Activated T-lymphocytes interrelate with macrophages, other inflammatory cells and effector cells in joint tissue, leading to symptoms of inflammation accompanied by joint destruction. Immunosuppressive treatment is already well established in this disease and several trials have already taken place using Sandimmun. A total of 224 patients with RA refractory to conventional disease-modifying drugs have participated in 11 published clinical studies. A review of these studies concludes that Sandimmun is efficacious in controlling inflammatory and functional symptoms, although this improvement is no generally accompanied by reductions in ESR and rheumatoid factor. The frequency of adverse events is comparable to that of other treatments but nephropathy remains the principal factor limiting the use of Sandimmun. Recent evidence suggests that with a strict dosage strategy and good monitoring this problem is controllable and reversible. Further studies are under way to confirm these claims.
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PMID:Sandimmun (cyclosporin A): mode of action and clinical results in rheumatoid arthritis. 307 82

Injection of parental strain rat lymphocytes under the kidney capsule of semi-allogeneic F1 recipients causes a local graft-versus-host reaction (GVHR) characterized by a heavy mononuclear cell infiltrate and renal tubular destruction. Since the cellular events involved may have relevance to allogeneic tissue damage in GVH disease and allograft rejection, a detailed analysis of the rat renal GVH reaction was performed. A purified CD4+ lymphocyte subpopulation was as effective in mediating a local GVHR as unfractionated parental lymphocytes, but neither naive CD8+ nor specifically sensitized CD8+ lymphocytes produced a detectable renal GVHR. Mononuclear cells harvested from renal GVHR lesions induced by CD4+ lymphocytes were able to lyse natural killer (NK)-sensitive targets when tested in vitro, but showed no allospecific cell-mediated cytotoxicity. Experiments using recombinant PVG rats demonstrated that the ability of the injected cells to cause a GVHR was dependent upon a disparity in MHC class II antigens and that an isolated disparity of MHC class I antigens alone was not a sufficient stimulus to provoke a response. The use of chimaeric rats demonstrated that F1 MHC alloantigens present on kidney parenchyma (but absent on bone marrow-derived cells) were not sufficient to stimulate injected parental lymphocytes, even in the presence of markedly increased amounts of MHC antigens on vascular endothelium and renal tubular cells following in vivo administration of interferon-gamma (IFN-gamma). These results suggest that the renal GVHR in the rat is mediated principally by the interaction of parental CD4+ lymphocytes recognizing and responding to class II F1 alloantigens on bone marrow-derived cells. The resulting tissue damage is most likely a result of a delayed-type hypersensitivity (DTH) phenomenon.
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PMID:The cellular basis of the local graft-versus-host reaction in rat kidney. 326 45

We studied the expression of major histocompatibility complex (MHC) class II antigens in liver biopsies taken from ten patients with clinical and biochemical evidence of liver damage after bone marrow transplantation. In all six patients who had histologically confirmed graft-versus-host disease, MHC class II antigens were detected on intrahepatic bile ducts. In four patients with no histological features of graft-versus-host disease, MHC class II antigens were not detected. In controls, a positive reaction for bile duct MHC class II antigens was only detected in the patients with primary biliary cirrhosis. Characterisation of the lymphocytes surrounding the bile ducts showed a prevalence of Leu 3+ cells in graft-versus-host disease and primary biliary cirrhosis. We propose that the aberrant expression of class II antigens on bile duct epithelium cells may play a role in the pathogenesis of graft-versus-host disease. A similar pattern in primary biliary cirrhosis may suggest a common pathogenetic mechanism.
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PMID:Expression of major histocompatibility complex class II antigens on bile duct epithelium in patients with hepatic graft-versus-host disease after bone marrow transplantation. 332 Jan 79

Recently we observed the expression of MHC class II antigens on bile duct epithelium in human liver transplantation rejection. In this report we present evidence for the expression of MHC class II antigens on bile duct epithelium in experimental GVHD. These findings support the idea, that the target tissue elements in liver transplantation rejection and GVHD are the bile ducts, on the other hand this is a new experimental model for the analysis of MHC class II antigen expression on epithelial tissue.
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PMID:Expression of MHC class II antigens on bile duct epithelium in experimental graft versus host disease. 404 Apr 46

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

Administration of cyclosporine (CsA) following syngeneic/autologous bone marrow transplantation (BMT) elicits a T lymphocyte-dependent autoimmune disease resembling graft-vs-host disease (syngeneic GVHD). This autoaggression syndrome appears to be due to the autorecognition of self-MHC class II antigens by CD8+ cytolytic T cells and a CD4+ autoreactive T cell subset. The syngeneic GVHD model was used to assess the effectiveness of treatment with monoclonal antibodies to the alpha/beta T cell receptor (TCR) and the CD4 or CD8 determinants on the prevention of autoimmune disease. Nylon wool nonadherent splenic T cells (50 x 10(6)) from Lewis strain rats with active syngeneic GVHD were adoptively transferred into irradiated (1050 rad syngeneic recipients reconstituted with normal marrow (60 x 10(6) cells). Monoclonal antibody (McAb) to the alpha/beta TCR, the CD4 determinant, or the CD8 determinant was administered to secondary recipients on Days 0, 3, 6, 9, and 12 at a dose of 0.1 ml of ascites fluid. Control animals received normal mouse serum on the same schedule. Animals treated with either saline or normal mouse serum developed syngeneic GVHD within 16-20 days. Comparatively, syngeneic GVHD developed much later in the secondary recipients treated with anti-CD4 McAb (onset of syngeneic GVHD, 28-32 days) and was less severe compared to the control group. On the other hand, the recipients treated with McAb's to the alpha/beta TCR or to the CD8 determinant did not develop syngeneic GVHD (monitored over 10 weeks post-therapy). Peripheral blood lymphocytes from these recipients also were analyzed for T cell subsets by phenotypic analysis. There was a pronounced reduction of the total number of cells expressing the alpha/beta TCR and the CD8 determinant after treatment of the recipients with the McAb's to the alpha/beta TCR and to the CD8 determinant, respectively. Recovery to normal levels began to occur 6 weeks after the last dose of McAb. There was a significant reduction of the CD4+ subset after treatment with anti-CD4 McAb, but it was not long lasting with recovery coinciding with the onset of syngeneic GVHD. Studies were also performed to evaluate McAb therapy of established syngeneic GVHD. The McAb's were found to be largely ineffective due in part to pulmonary toxicity. Furthermore, this model was utilized to evaluate the efficacy of treatment with McAb to the target antigen of syngeneic GVHD. Infusion of McAb to a public determinant on class II MHC molecules prevented or significantly delayed the onset of syngeneic GVHD after adoptive transfer of effector cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cyclosporine-induced syngeneic graft-vs-host disease: prevention of autoaggression by treatment with monoclonal antibodies to T lymphocyte cell surface determinants and to MHC class II antigens. 769 18

The immunobiological mechanisms involved in the manifestation of an autoaggressive disease after autologous bone marrow transplantation (BMT) and cyclosporine A (CyA) treatment are still unclear. This disease, which in animals shows clinical and histopathological features in the skin, liver and gut similar to those of graft-versus-host disease (GVHD), is called autologous GVHD and associated with the appearance of CD8+ cells with a lytic specificity for a public epitope on MHC class II. 2 steps are supposed to be essential for the induction of autologous GVHD: firstly, the elimination of a host resistance or an autoregulatory mechanism of self tolerance by high dose chemotherapy including total body irradiation, and secondly, the prevention of clonal deletion of MHC class II-restricted auto-reactive T-cells by CyA. Several experiments describe a possible antitumor effect of this disease in vitro as well as in vivo. The CD8+ cells kill tumor cells in vitro and survival of animals with autologous GVHD challenged with low doses of tumor cells is better than that of animals without autologous GVHD. In an attempt to reduce the relapse rate after autologous BMT, induction of GVHD with CyA treatment was investigated in clinical trials. A syndrome similar to the one described in rats was observed also in humans. However, symptoms were confined to the skin, appeared earlier than in experimental transplantation and were always self-limiting. Further investigations aiming at understanding in more detail the immunobiological mechanisms in human autologous GVHD and phase III clinical trials will have to be completed in order to define the role of this disease in clinical transplantation.
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PMID:Graft-versus-host disease after autologous bone marrow transplantation: a realistic expectation? 776 48

Keratinocytes are activated to express MHC class II and ICAM-1 molecules during cutaneous inflammatory reactions. It is controversial how the interaction between these 'nonprofessional' antigen presenting cells (APC) and infiltrating T cells affects the local inflammatory response. To address this issue we analyzed whether IFN gamma-treated cultured human keratinocytes would activate established Th cell clones in vitro. Three allo DR specific T cell clones were induced to proliferate in a HLA-DR and LFA-1/ICAM-1 dependent fashion upon coculture with intact layers of IFN gamma stimulated keratinocytes. Likewise, keratinocytes also could activate two out of four minor histocompatibility (mH) antigen specific Th cell clones obtained from peripheral blood leukocytes (PBL) of graft versus host disease patients. The T cell activating potential of MHC class II+ keratinocytes was shown to be relatively low compared to specialized APC as PMNC and EBV-BLCL. Most strikingly, measurable allo MHC and mH antigen specific Th cell proliferation was only induced by using adherent keratinocytes at low cell densities, but not by keratinocytes in suspension. The results presented here indicate that in vitro conditions may crucially influence observations regarding the T cell activating potential of MHC class II expressing keratinocytes. Furthermore, our results indicate that, in addition to a tolerizing effect as suggested by previous reports, interaction of primed antigen specific T cells with activated keratinocytes may also result in enhancement of a cutaneous immune response in vivo.
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PMID:Human keratinocytes activate primed major and minor histocompatibility antigen specific Th cells in vitro. 791 50

In order to discover some biological markers of acute graft-versus-host disease (aGVHD), we have studied the percentage of peripheral monocytes and T lymphocytes bearing HLA-DR and HLA-DQ class II molecules. This study included 25 allogeneic BMT in children, either with (n = 10) or without (n = 15) aGVHD. Within 2 months after transplantation, a higher percentage of DQ+ and DR+ monocytes and of DQ+ T lymphocytes was observed in patients without aGVHD compared with patients with aGVHD. The most discriminating marker was the strong increase in the percentage of DQ+ monocytes in patients without aGVHD (P = 0.001). In a sequential study, we observed a low percentage of DQ+ and DR+ peripheral blood mononuclear cells (PBMC) as long as the clinical manifestations of aGVHD continued. We speculate if the modulation of DQ and DR molecules on PBMC after BMT is a consequence of the action of some lymphokines, and if it plays a role in the regulation of the acute GVH reaction. We conclude that MHC class II molecules on peripheral mononuclear cells may be reliable biological markers for the diagnosis of aGVHD.
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PMID:A high percentage of HLA-DQ+ and HLA-DR+ mononuclear cells is associated with a low incidence of acute graft-versus-host disease after allogeneic bone marrow transplantation (BMT) in children. 818 44

The graft-vs.-host reaction (GVHR) results in damage to the epithelial and lymphoid compartments of the thymus and thus in abnormal maturation and function of thymocytes in mice undergoing GVHR. In this report, the effects of GVHR on thymic T cell receptor (TCR) expression and usage have been investigated. GVHR was induced in unirradiated F1 hybrid mice by the intravenous transfer of parental lymphoid cells. Expression of the CD3/TCR complex on thymocyte subsets defined by CD4 and CD8 was studied by three-color flow cytometry. The level of CD3/TCR was decreased on CD4+CD8-, but not CD4-CD8+, mature thymocytes. The lack of upregulation of CD3/TCR on CD4 single-positive thymocytes, but not on their CD8+ counterparts, suggested an abnormality of class II major histocompatibility complex (MHC) expression in the thymuses of mice undergoing GVHR. Immunofluorescence staining of thymic frozen sections revealed that MHC class II expression was dramatically decreased in GVH-reactive mice. GVHR-induced changes in positive and negative selection were evaluated by determining the incidence of specific V beta TCR segment usage in the thymus. In normal mice, thymocyte usage of any given V beta segment was highly consistent between individuals of the same strain and age; however, a marked divergence in the incidence of TCR V beta 6hi and V beta 8hi cells between GVH-reactive littermate mice was observed, suggesting that thymic positive selection had become disregulated in these animals. Furthermore, negative selection was defective; the incidence of phenotypically self-reactive V beta 6hi T cells was significantly greater in the thymuses of GVH-reactive mice bearing the endogenous superantigen Mls-1a than in untreated controls. Thus, mice undergoing GVHR showed defective TCR upregulation on CD4+CD8- thymocytes and changes in TCR usage reflecting aberrant thymic selection, in conjunction with decreased expression of MHC class II. Most abnormalities of TCR expression and usage on CD4+ thymocytes observed in GVH-reactive mice were analogous to those of class II knockout mice.
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PMID:Thymic selection and thymic major histocompatibility complex class II expression are abnormal in mice undergoing graft-versus-host reactions. 839 4


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