Cyclosporine (CsA) is a potent immunosuppressive drug that paradoxically elicits a T-lymphocyte dependent autoimmune disease when administered after syngeneic/autologous bone marrow transplantation (BMT). This autoaggression syndrome which develops after withdrawal of CsA treatment was termed syngeneic graft-vs-host disease (SGVHD) because of its similarity (histologically, target organs) to GVHD occurring after allogeneic BMT. Two important factors responsible for the pathogenesis of this autoimmune syndrome have been identified: the enhanced production of CD4+ and CD8+ MHC class II specific autoreactive T cells by the thymus and the elimination of a T-lymphocyte dependent peripheral host resistance mechanism. Both CD8+ and CD4+ SGVHD autoreactive T lymphocytes promiscuously recognize MHC class II antigens and express the V beta 8.5 T-cell receptor determinant. Preliminary studies reveal that the peptide from the invariant chain plays a critical role in the recognition of MHC class II antigens in SGVHD. The studies proposed in this application plan to characterize the autoreactive and regulatory effector T cells. The T-cell receptor repertoire with respect to a Valpha and Vbeta gene usage and the cytokine profile of the autoreactive T-cell subsets will be assessed in vitro by the reverse transcriptase polymerase chain reaction in clones from limiting dilution cultures. These results will be confirmed by in situ hybridization and immunoperoxidase analysis of the target tissue and by adoptive transfer studies with established autoclones. Structure function studies with modified CLIP peptides will be evaluated in order to identify the regions that allow autoimmune recognition in SGVHD. Thirdly, mechanisms by which CsA inhibits the clonal deletion or promotes selection of these autoreactive T cells in the thymus will be defined assessing if CsA inhibits clonal deletion of the MHC class II reactive T cells. Finally, studies will be performed to evaluate the mechanism by which the regulatory T cells recognize and inactivate the autoreactive T cells. Specifically, the ability of the autoregulatory T cells to recognize V beta T-cell receptor peptides presented by MHC class II determinants will be assessed. These studies will define some of the immunobiological mechanisms involved in this unique autoaggression syndrome.
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