The overall goal of this application is to define the mechanisms responsible for long term tolerance of allografts. Treatments and agents discussed in this program project which have been shown by previous work in our group, to prolong allograft survival include Major Histocompatibility Antigens and their peptides, peptides generated from T cell receptors, injection of cells and antigens into the thymus and treatment of animals with antibodies to adhesion molecules. Program #1 will determine mechanisms by which human liver allografts are immunologically accepted. Recipients of liver allografts delete cytotoxic T lymphocyte clones specific for donor HLA antigens, develop autoantibodies to donor reactive T-cell receptors and shed don or HLA antigens into the serum. Proposed studies will examine the mechanisms by which these events lead to specific immunological unresponsiveness. Program #2 will determine the mechanisms by which peptides derived from the TCR or MHC induce prolongation of allograft survival in murine allograft models. These studies will employ Vb8 negative mice, site specific Ld mutants and photocoupling. In addition to Ld, other MHC class I antigens will also be analysed. Program #3 will examine the molecular basis for coupling T cell death to TCR stimulation in mature T cells, determine its role in model of tolerance induction for cardiac allografts. Animals and cells from wild type (C57BL/6) mice and autoimmune, congenic mutants (B6.MRL-lpr and B6.C3H-gld) will be used to understand the role of responding cell suicide during tolerance induction and maintenance. Project #4 will address the mechanisms by which allograft tolerance occurs following intrathymic injection of alloantigens or their peptides in a murine model of cardiac transplantation. It is our aim that the results obtained from the above projects will facilitate the development of strategies for induction and maintenance of allograft tolerance without the need for continued immunosuppressive therapy.
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