Despite improvements in early post-transplant survival rates over the last two decades, a relentless annual attrition rate of 3-5 % in recipients of previously successful renal allografts continues to limit longer term outcomes. Long term outcomes with islet transplantation are simply unacceptable with only 10% of recipients remaining insulin free at five years. In islets metabolic exhaustion due to an inadequate islet cell mass may be an important impediment to long term graft function. Late allograft failure, resulting from chronic rejection, infection, drug toxicity, and malignancies emphasizes the limitations of chronically administered immunosuppression in kidney and islet transplantations. Therefore the ultimate goal of transplantation is to achieve long-term engraftment without maintenance immunosuppression. Pilot clinical tolerance protocols are currently being tested in humans, but there remain substantial barriers to achieving true tolerance in humans. The major objective of this Multi-Project grant is to improve the outcome following kidney and islet transplantation by defining the essential conditions for induction of durable tolerance to kidney and islet allografts, and defining the roles of inflammation and memory T cells in being major barriers to tolerance. Our central hypothesis is that the early pro-inflammatory responses due in large measure to ischemia-reperfusion and anoxic injury to the donor tissues incites adverse forms of anti-donor immunity, thereby provoking acute clinical or subclinical rejection and exaggerating the subsequent expansion of pre-existing donor reactive memory, and post transplant development of newly acquired donor reactive memory T cells. Thus, we hypothesize that an adverse balance of pro- to anti-inflammatory cytokines and anti-donor memory responses represent major obstacles to the induction and maintenance of tolerance. We propose novel and inter-related strategies to alter the balance of the alloimmune response to favor regulation and long-term tolerance taking into consideration the inflammatory- and memory-related barriers to tolerance in the context of islet and kidney transplantation. The rationale linking the specific aims of the two interrelated in vivo projects and the mechanistic studies is that we now have the tools to test the relevance and inter-relationship of inflammatory responses to the balance of aggressive and memory responses, T cell regulatory and tolerance induction. It, therefore, should be possible to define and systematically apply the perturbations of the innate and adaptive immune response that lead to tolerance in primate allograft recipients. Moreover, the Program will lead to cross-fertilization and sharing of facets of the best tolerance inducing regimens developing from Project 1 with those of Project 2.