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)

Administration of the immunosuppressive drug cyclosporine after autologous bone marrow transplantation induces a systemic autoimmune syndrome resembling graft-versus-host disease (GVHD). This syndrome termed autologous GVHD has significant antitumor activity. Associated with autologous GVHD is the development of T lymphocytes that recognize major histocompatibility complex (MHC) class II determinants, including self. The present studies attempted to characterize and define the molecular specificity of the effector T lymphocytes in autologous GVHD induced in patients with metastatic breast cancer. The results suggest that the effector cells associated with human autologous GVHD are CD8+ T lymphocytes expressing the alpha/beta T-cell receptor. Additional studies show that the effector T cells recognize MHC class II antigens in association with a peptide from the invariant chain (CLIP). Pretreatment of autologous lymphoblast target cells with anti-CLIP antibody completely blocked lysis mediated by autologous GVHD effector T cells. On the other hand, force loading this peptide markedly enhanced the susceptibility of the target cells to recognition by the autoreactive T cells. The recognition of the MHC class II CLIP complex may account for the novel specificity of the effector T cells associated with human autologous GVHD. Moreover, identification of the target peptide may allow for the development of novel immunotherapeutic strategies to enhance the antitumor efficacy of autologous GVHD.
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PMID:Specificity of effector T lymphocytes in autologous graft-versus-host disease: role of the major histocompatibility complex class II invariant chain peptide. 905 45

Administration of the immunosuppressive drug cyclosporine after syngeneic or autologous bone marrow transplantation elicits a T-lymphocyte-dependent autoimmune syndrome similar to graft-versus-host disease (GVHD). The onset of this autoaggression syndrome, termed syngeneic GVHD, is associated with the development of a highly restricted repertoire of CD8+ autoreactive T cells that recognize a peptide from the invariant chain, termed CLIP, presented by major histocompatibility complex (MHC) class II molecules. Clonal analysis reveals 2 distinct subsets of autoreactive T cells defined by their activation requirement for either the N-terminal or the C-terminal flanking regions of CLIP and by their cytokine profile. The studies here reveal that the autoreactive T-cell clones requiring the N-terminal flanking region of CLIP produce type 1 cytokines (interferon [IFN]-gamma, interleukin [IL]-2, and tumor necrosis factor-alpha). In contrast, the autoreactive T-cell clones that require the C-terminal flanking region of CLIP produce type 2 cytokines (IL-4, IL-10, transforming growth factor-beta). As assessed in a local graft-versus-host reaction assay, the N-terminal flanking-restricted clones mediate changes consistent with acute GVHD, whereas the clones responsive to the C-terminal flanking region do not. Moreover, the autoreactive T-cell clones restricted by the C-terminal flanking region of CLIP ameliorate the pathogenic potential of the cells responsive to the N-terminal flanking region of CLIP. The mechanism accounting for this regulatory affect appears to be the downregulation of mRNA message for type 1 cytokines (IFN-gamma and IL-2). The C-terminal-restricted autoreactive T-cell clones, however, could manifest disease with dermal changes similar to those seen in chronic syngeneic GVHD, provided that IFN-gamma was present. Consistent with these observations was the demonstration that type 1 cytokines are preferentially detected during the acute phase of syngeneic GVHD, whereas type 2 cytokines dominate during the chronic phase. The results suggest that acute and chronic syngeneic GVHD is mediated by distinct autoreactive T cells, which are separated by their fine specificity for the CLIP-MHC class II complex and by their cytokine profiles.
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PMID:Complexity of effector mechanisms in cyclosporine-induced syngeneic graft-versus-host disease. 1070 95

Administration of cyclosporine after autologous bone marrow transplantation elicits a T-lymphocyte autoaggression syndrome with remarkable similarity to graft-versus-host disease (GVHD). This syndrome, termed syngeneic GVHD (SGVHD), with both acute and chronic phases, is mediated by a restricted repertoire of autoreactive T cells that promiscuously recognize major histocompatibility complex (MHC) class II determinants in association with a peptide from the invariant chain (MHC class II-invariant chain peptide; CLIP). This study evaluated and compared antigen-specific autoreactive T cells during acute and chronic SGVHD ex vivo isolated with a soluble MHC class II immunoglobulin molecular construct. This approach allows for the direct assessment of the functional behavior of the effector T cells without potential modification by in vitro culture. Two major subsets were detected that had overlapping specificity recognizing the MHC class II-binding domain of CLIP but that were differentially dependent on the N- and C-terminal flanking domains of this peptide. The N- and C-terminal subsets were primarily associated with acute and chronic SGVHD, respectively. The cytokine profiles of the CLIP-reactive T cells, however, were most informative and closely correlated with the onset and progression of disease. Levels of type 1 cytokine, particularly interferon-gamma, messenger RNA (mRNA) production, assessed by quantitative polymerase chain reaction, were dominant during acute SGVHD, whereas chronic SGVHD was associated with type 2 cytokine mRNA production. Although there was a dramatic polarization with respect to cytokine production, only subtle changes in antigen specificity could be detected. Unexpectedly, the functional behavior within the antigen-specific effector cell populations is not fixed and seems to change as the disease progresses to the chronic phase. Concordant with the evolution of the effector T-cell response is a differential loss in B7.1 mRNA expression in the N-terminal CLIP-reactive T-cell subset that may reflect the regulation of this autoimmune response. Of additional interest, autoreactive T cells producing interleukin-10 mRNA were detected in both acute and chronic SGVHD, suggesting that this cytokine may play an important but perhaps paradoxical role in both the onset and progression of this experimental autoaggression syndrome.
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PMID:Functional divergence of antigen-specific T-lymphocyte responses in syngeneic graft-versus-host disease. 1531 71

Administration of cyclosporine (CyA) following autologous bone marrow transplantation elicits a T-lymphocyte autoaggression syndrome with remarkable similarity to acute and chronic graft-versus-host disease (GVHD). This syndrome termed syngeneic (S) GVHD is mediated by a restricted repertoire of autoreactive T cells that promiscuously recognize major histocompatibility complex (MHC) class II determinants in association with a peptide from the invariant chain (CLIP). The present studies evaluated and compared antigen-specific autoreactive T cells during acute and chronic SGVHD isolated ex vivo with a soluble MHC class II-immunoglobulin (sMHC class II-Ig) molecular construct. Two major subsets were detected that had overlapping specificity recognizing the MHC class II binding domain of CLIP but were differentially dependent on the N- and C-terminal flanking domains of this peptide. Both subsets were detected in acute and chronic SGVHD. Interestingly, the cytokine profiles of the CLIP-reactive T cells closely correlated with the onset and progression of disease. Levels of type 1 cytokines, particularly IFN-gamma mRNA production assessed by quantitative polymerase chain reaction (PCR), were dominant during acute SGVHD, whereas chronic SGVHD was associated with type 2 cytokine mRNA production. Although there was a dramatic polarization with respect to cytokine production, only subtle changes in antigen specificity were detected. Of additional interest, autoreactive T cells producing IL-10 mRNA were detected in both acute and chronic SGVHD, suggesting that this cytokine may play an important but perhaps paradoxical role in both the onset and progression of this experimental autoaggression syndrome.
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PMID:Antigen-specific T-lymphocyte responses in acute and chronic syngeneic graft-versus-host disease. 1580 45

The immune system undergoes rapid reconstitution after autologous or syngeneic bone marrow transplantation with the re-establishment of tolerance to self-antigens. Administration of drugs such as cyclosporine that inhibit thymic-dependent clonal deletion disrupts the reconstitution of the immune system. In the absence of a peripheral regulatory T cells eliminated by the preparative regimen, systemic autoimmunity with pathology similar to graft-versus-host disease often develops. Moreover, the resolution of autoaggression is dependent on the reconstitution of CD4+ regulatory T cells. This study examined the specificity and function of this regulatory population assessed ex vivo that plays a critical role in down-regulating the autoreactive T lymphocyte response in cyclosporine-induced syngeneic graft-versus-host disease. The results suggest that both the antigen-specific regulatory and pathogenic effector T cells recognize a common peptide antigen framework (CLIP, a peptide derived from the invariant chain) presented by major histocompatibility complex class II molecules. Analysis of the CD4+ T-cell compartment revealed two subsets of CLIP-reactive T cells that differentially require the N- and C-terminal flanking domain of this peptide. Regulatory function is associated with the cells that require the C-terminal flanking domain. This population expresses the Foxp3 nuclear transcription factor and plays a critical role in re-establishing tolerance to self-major histocompatibility complex class II antigens. In addition to suppressing the production of type 1 cytokines, these regulatory T cells can direct the apoptotic death of the pathogenic autoreactive lymphocytes. This study also suggests that the development of functional regulatory activity is an active response initiated by the presence of autoreactive lymphocytes that can present the target antigen (major histocompatibility complex class II CLIP) to the regulatory T cells. Moreover, this process can be mimicked by peptide antigen in the absence of the pathogenic effector lymphocytes leading to the development of functional regulatory T-cell activity.
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PMID:Immune tolerance to self-major histocompatibility complex class II antigens after bone marrow transplantation: role of regulatory T cells. 1663 87