ROLE OF MHC ANTIGEN INDUCTION IN GRAFT REJECTION

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The long-term objective of our proposed study is to better understand the mechanisms of rejection and tolerance of transplanted tissues. This knowledge should be applicable to the maintenance of human allografts, problems in reproductive immunology, the inducibility of immunity to human tumors, and the treatment of autoimmune diseases. The specific aim of this project is to determine the role of major histocompatibility complex (MHC) antigen expression in allograft rejection and tolerance. These studies will follow up on preliminary experiments that demonstrate a relationship between MHC Induction and graft rejection and an inhibition of that expression and its inducibility following culture of thyroid grafts in hyperbaric oxygen. We will first determine the in vitro conditions required to induce and suppress the expression of class I and class II MHC antigens in fresh and oxygen cultured endocrine tissues; secondly, we will determine the influence of MHC expression on the fate of cultured allografts; and thirdly, we will study the effect of tolerance on the expression of MHC antigens. In order to accomplish these goals we will use mouse thyroids and pancreatic islets which will be cultured under different conditions. The expression of MHC antigens on the tissues will be studied by immunohistological techniques. Some of the tissues will be grafted under the kidney capsule of syngeneic or allogeneic recipients. The first goal will be accomplished by experiments that will (a) determine factors or conditions other than hyperbaric oxygen that can inhibit MHC expression and inducibility, and (b) determine the in vitro conditions required to restore MHC inducibility after its loss following culture in hyperbaric oxygen. The second goal will be studied by determining in oxygen cultured endocrine allografts (a) if the lymphocytic infiltration to minor antigens can induce expression of MHC antigens, (b) if the reduction of MHC antigen expression and inducibility after oxygen treatment can partially explain graft acceptance, and (c) if the hyperexpression of allo-MHC antigens on the parenchymal cells can be enough stimulus to induce graft rejection. If MHC induction is necessary but not sufficient to induce rejection of cultured allografts in unimmunized recipients, we will try to determine the complementary factors that are required. The third goal will be approached by experiments using mice that have developed tolerance to cultured allografts. For this purpose we will (a) determine if tolerance affects the expression and inducibility of MHC antigens on the graft, and (b) attempt to determine if serum or cellular factor(s) are present in tolerant mice that can alter MHC antigen induction.