Severe systemic autoimmunity occurs after syngeneic or autologous bone marrow transplantation (BMT) and treatment with cyclosporine (CsA) and has been termed syngeneic graft-versus-host disease (GVHD). Preliminary studies in syngeneic BMT recipients suggest that CsA alters T-cell differentiation in the thymus as indicated by changes in phenotypic cell surface markers and by a germ line configuration of the T-cell receptor gene. In addition, subsets of cells with phenotypic markers characteristic of early thymocytes with an apparent germ line configuration of the T-cell receptor gene can be detected in the peripheral blood of syngeneic BMT recepients treated with CsA. These data suggest that syngeneic GVHD is the result of altered thymic differentiation. A host autoregulatory system also appears to be essential for the induction of this systemic autoimmune syndrome. The general aim of this proposal is to define the immunological mechanisms which account for syngeneic GVHD. Specifically, determine if the syngeneic GVHD syndrome is the result of altered T-cell differentiation, augmentation of a normal component of T-cell differentiation and/or a loss of autoregulatory mechanisms. Adoptive transfer experiments will be performed in an attempt to identify the precursor effector cell and the mature effector cell of syngeneic GVHD. To demonstrate if there is host autoregulatory mechanisms which control the development of autogression, putative regulatory suppressor T-cells will be adoptively transferred together with the precursor and/or mature effector cell of syngeneic GVHD. Furthermore, the role of the cytotoxic T-cell recognizing Class II major histocompatibility (MHC) determinants associated with syngeneic GVHD will be assessed by adoptive transfer experiments, and in vitro using an organ explant system. In addition, T-cell receptor gene rearrangement will be assessed in thymocytes, the peripheral blood immature T-cells and the Class II specific cytotoxic T-cells in an effort to determine if CsA inhibits normal T-cell differentiation at the molecular level. If CsA results in the inhibition of T-cell differentation with the subsequent release of early thymocytes into the peripheral blood, we will attempt to determine if these cells can be induced to differentiate in vitro upon exposure to Class II MHC antigens utilizing thymic epithelial cultures. Such studies will increase our understanding of self versus non-self discrimination.
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