LYMPHOCYTES AND HISTOCOMPATIBILITY ANTIGENS

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This proposal focuses on three aspects of the interaction between T lymphocytes and MHC gene products: (i) the cellular basis of specifically induced resistance to GVH disease, (ii) the cellular mechanisms underlying the induction and onset of autoimmune disease in rats undergoing a prolonged course of treatment with cyclosporine A, and (iii) whether common mechanisms based on idiotype-anti-idiotype interactions involving MHC specific T cells and receptor specific regulator T cells underly these two disease models. Previous studies supported by this grant have shown that alloreactive parental strain (A) T cells carry associated marker which behaves like a highly conserved idiotype of anti-MHCb receptors. As an immunogen in adult A/B F1 rats it induces a prolonged and specific T cell mediated state of resistance to GVH disease caused by anti-MHCb T cells from any source. As a tolerogen in newborn A/B F rats it induces an exquisite and specific sensitivity to GVH disease caused by anti-b T cells. The responding F1 T cells include a subset which suppresses alloreactivity-in vivo and is lytic for MLC blasts in vitro. In both cases these "regulator anti-idiotypic T cells do not appear to be MHC restricted. The studies to be performed are designed to explore the possibility that autoreactive T cells (e.g. B anti-b) have the same idiotypic marker found on alloreactive (A anti-b) T cells, and that regulatory, anti-idiotypic T cells control the expression of these idiotypic anti-MHC T cells as part of the ongoing process involved in the maintenance of self tolerance.