INDUCTION OF TRANSPLANTATION TOLERANCE BY ORAL ROUTE

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Successful transplantation depends upon the development of a state of tolerance to the incompatible alloantigens of the graft, especially those of the MHC system. The current state in the clinic is one of short tcrm success, but states of tolerance not requiring the use of powerful and toxic immunosuppressive agents are not easily achievable. The intestine has an elaborate immune system which is incompletely understood. Although the oral route can be used for immunization, there are many experimental examples of tolerance induction, including prevention or treatment of autoimmune disease in animal models . There has been little reported with regard to transplantation. Advances in the molecular biology and structure of the molecules of the MHC, as well as improved definition of the functional varieties of effector and regulatory T cells, now make it possible to perform experiments which should lead to knowledge on how to take advantage of the intestinal immune system's abilities to influence immune responses in a negative direction. Synthetic peptides representing the polymorphic regions of rat class II MHC have been shown after oral feeding to partially tolerize T cells in vitro and in vivo in an antigen specific manner. The study will aim to address the questions of the relationship between immunogenicity and tolerogenicity of MHC peptides, the mode of action with regard to T cell anergy versus suppression, the uniqueness of the proliferative responses of the intestinal epithelial T cells and the peptide presenting capacity of epithelial cells, and optimization of oral feeding to the prolongation of allografts. Rat and mouse murine models will be used, including mice tolerized to Mls immunization and T cell receptor transgenic mice. Mechanisms which involve cytokines with potential downregulatory function (e.g., TGFbeta, IL-4,IL-10) will be pursued.