Our overall goal is to meticulously evaluate the proposition that immune deviation from the Th1 format, a format usually noted during acute rejection to a Th2 format at various stages of the allograft response will produce permanent engraftment/tolerance. In the process we will also test a second hypothesis, contrary to the first, stating that neither IL-2 or IL-4 inherently produces tolerance but both of these T-cell growth factors are barriers to tolerance albeit IL-2 poses a greater barrier than IL-4 for tolerance induction. Deriving from this reasoning, we believe that Th1- Th2 immune deviation will prove far more effective in promoting tolerance in situations in which a limited T-cell clone size is engaged in the allograft response (i.e. exemplified by donor specific transfusions (DST) and transplantation across minor but not major histocompatibility barriers). In order to test these hypotheses we will utilize long-lived cytokine proteins, anti- cytokine mAbs and 1) islet allograft models employing transplantation across (I) MHC + minor barriers and (ii) minor barriers only; 2) tolerizing as well as suboptimal immunosuppressive protocols; and 3) a DST induced model of cardiac allograft tolerance.
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