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

The process of graft-versus-host disease (GVHD) elicited by small bowel semi-syngeneic grafts in Lewis rats was studied by an immunohistochemical staining technique for analysis of MHC (major histocompatibility complex) class II antigen expression and of T-cell subpopulations in different organs. Specimens from the graft, native bowel, brain, testis, liver, kidney, and skin were taken on days 5, 10, and 15. All the investigated organs displayed strong class II antigen induction during the course of GVHD. In the native bowel of semi-syngeneically transplanted animals, only discrete morphological changes were noted, whereas the graft displayed a generalized serosal reaction with large infiltrates of rounded and polygonal cells expressing class II antigens. This was not observed in the graft of syngeneically transplanted animals. In the lamina propria of the semisyngeneic graft, 'free' lymphocyte-like cells were depleted and, at the same time, localized aggregates of these cells were observed. Crypt cell class II expression in the native bowel, and to some extent in the graft, was increased during GVHD. However, pronounced intraindividual variations in MHC class II antigen expression were noted, and class II expression was therefore not considered to be a good marker for GVHD.
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PMID:Immunomorphology of graft-versus-host disease after small bowel transplantation in the rat. 220 46

We studied the effect of Cyclosporin A on the thymus in rats. A daily subcutaneous injection of Cyclosporin A at a dose of 45 mg/kg body weight in young adult rats resulted in a 100% mortality within two weeks. Daily administration of 15 mg/kg for two weeks was well tolerated. Rats treated at this dose showed whole blood Cyclosporin concentrations around 6 mg/l. The thymus immediately after treatment showed the almost complete disappearance of the medulla, including the microenvironment made by medulla-type epithelium, interdigitating dendritic cells defined by their expression of MHC class II antigen, and lymphocytes with a mature T-cell phenotype. After discontinuation of Cyclosporin treatment, a rapid recovery occurred, with the reappearance of medulla areas after 2 weeks. These areas differed from the normal medulla by the absence of medulla-type epithelium. This cell population recovered in its normal location in about 4 weeks. The reappearance of medullary interdigitating cells was associated with reappearance of lymphocytes with a mature T-cell phenotype. In the regenerating thymus "holes" in the microenvironment were observed that lacked epithelium and interdigitating cells, and that were filled by lymphocytes with an immature cortex phenotype. Peripheral lymphoid organs, of which the spleen was studied in more detail, did not manifest changes in lymphoid and stromal components. Target organs for syngeneic graft-versus-host disease, as described under special conditions after Cyclosporin treatment, did not show any histologic abnormality. The changes in thymus (immuno)histology may be associated with changes in shaping the T-cell repertoire: but, clinical manifestations of such changes require special experimental conditions.
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PMID:Cyclosporin and the rat thymus. An immunohistochemical study. 229 25

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

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

Previously, it has been shown that the lysosomotropic amine, chloroquine, is effective in the prevention of graft-versus-host disease (GVHD) using murine models. Because chloroquine and hydroxychloroquine suppress MHC class II antigen presentation, their mechanism of action is different to other immune suppressant drugs (cyclosporin A) currently used to control GVHD. It is possible that the use of cyclosporin A and chloroquine in combination may have an additive or synergistic effect on T cell responses to antigens presented in the context of MHC class II. We investigated the effects of chloroquine or hydroxychloroquine in combination with cyclosporin A on human T cell responses in vitro to tetanus toxoid, an exogenous protein antigen dependent on MHC class II presentation for proliferative responses. We demonstrate that similar levels of chloroquine and hydroxychloroquine suppress human T cell responses to tetanus toxoid and that the use of either agent in combination with cyclosporin A results in synergistic suppression. Evaluation for a direct effect by the lysosomotropic amines on T cells, in the absence of antigen presenting cells, revealed that there was inhibition of T cell responses but only at high concentrations. No significant decrease or increase was seen in surface MHC II or invariant chain expression or in cytoplasmic invariant chain after exposure to chloroquine. Thus, lysosomotropic amines in combination with cyclosporin A are synergistic in suppression of T cell proliferation. Use of these agents in combination with cyclosporin A may improve control of graft-versus-host disease.
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PMID:Synergy between lysosomotropic amines and cyclosporin A on human T cell responses to an exogenous protein antigen, tetanus toxoid. 887 28

We have recently shown that the lysosomotropic amine, chloroquine, can inhibit the development of graft-versus-host disease (GVHD) secondary to minor histocompatibility (MiHC) differences in mice. In addition, we have shown that both chloroquine and hydroxychloroquine can inhibit T cell responses in vitro to minor and major histocompatibility (MHC) antigens. We review the rationale for the use of lysosomotropic amines, whose primary mechanism of action appears to be inhibition of MHC class II antigen presentation, as therapy for GVHD in humans. Used in low concentrations, these agents appear to have no direct effect on T cells either in vitro or in vivo although they may have a direct effect at higher concentrations. The lysosomotropic amines, at low concentrations, in combination with the T cell-specific agent, cyclosporin A, synergistically suppresses the T cell response to MiHC and MHC in mouse and in human. We present the initial data from the human clinical trials using hydroxychloroquine. We hypothesize that the lysosomotropic amines may have unique beneficial effects on immune reconstitution following bone marrow transplantation. The lysosomotropic amines, hydroxychloroquine and chloroquine, represent agents with unique mechanisms of action that may be used to control GVHD in humans.
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PMID:The lysosomotropic amines, chloroquine and hydroxychloroquine: a potentially novel therapy for graft-versus-host disease. 915 50