Despite marked success and progress in clinical organ transplantation over the last 30 years, transplant recipients are plagued with side effects resulting from generalized immunosuppression. Further, current immunosuppressive agents have not produced significant improvements in the transplant half-life over the last decade. Given these discouraging long-term results, a primary goal of transplant immunology is to define mechanisms of immunologic tolerance and apply these mechanisms in the clinical setting, to avoid the inevitable complications of immunosuppression and ultimate allograft failure. The development of immuno- logic tolerance to transplanted organs is a complex, likely multifactorial alteration of numerous cellular signaling pathways. Surprisingly, in a number of preclinical models of transplantation tolerance, the presence of the Thl cytokines IL-2 and IFN-gamma are required to facilitate long-term allograft survival, implicating these cytokines in critical immunomodulatory roles. The objectives outlined in this application examine the mechanisms by which IFN- gamma functions as a regulatory cytokine in the induction of islet cell allograft tolerance. This series of experiments utilizes an islet cell transplant model system in genetically manipulated mice to study the mechanisms of IFN-gamma-facilitated tolerance. Specifically, anti-adhesion therapy using the monoclonal antibody anti-LFA-1 induces islet cell allograft tolerance that is IFN-gamma dependent. Given that the CD8 T cell is the primary effecter cell in islet cell rejection, and its ability to mediate rejection is enhanced in the absence of IFN-gamma, the experiments described herein will determine if the nature of IFN-gamma regulation is at the level of the CD8 cell versus other lymphocytes or innate immune cells. This application will define the critical cellular producers and responders of IFN-gamma in the induction of tolerance, with complementary in vitro studies determining the mechanisms involved in IFN- gamma regulation. These results will ultimately lead to a greater under- standing of how specific cytokines can deviate an immune response, and poten- tially will lead to more directed therapies aimed at inhibiting the known pro- inflammatory properties of IFN-gamma while promoting the protective actions of IFN-gamma.
