While we have made major strides in our understanding of transplant immunobiology, the ability to safely, reliably, and predictably induce tolerance in a clinical setting remains an elusive goal. The theme of this Program Project Grant has been, and remains, understanding the mechanisms of T cell mediated graft rejection and tolerance, with the view that this knowledge will be critical to develop new strategies to induce, maintain, and monitor tolerance, and to translate them into primates and humans. During the first funding period, our three projects focused on costimulatory pathways (CD28:B7 and CD154:CD40) and cytokines, analyzing their role in graft rejection, the utility of blocking these pathways to induce tolerance, and the mechanisms of tolerance in vivo. In this renewal application, we will build upon our progress during the first period to investigate novel concepts critical to the induction and maintenance phases of transplantation tolerance. Thus our overall goal is to dissect the determinants of T cell destiny during alloimmune responses. Project #1 will investigate the role of newly identified T cell costimulatory pathways (ICOS, CD27, CD134) in the initiation and maintenance of alloimmune T cell responses, and the development of acute and chronic rejection. Project #2 will study how proliferation and priming, as dictated by the availability of costimulatory signals and cytokines influence the development of effector and regulatory T cells, and their susceptibility to tolerance. Project #3 will focus on the activation, function and mechanisms of regulatory T cells. Given the new and exciting possibilities enabled by the use of microarrays for genome profiling, we have proposed a Core to support initial efforts by projects #2 and #3 in these areas. These studies are not aimed at gene discovery, but at genetic fingerprinting of cells with defined functional phenotypes. Ultimately this will enable us to determine the similarities and differences in the genetic programs of cells mediating tolerance by different approaches. Collectively, these studies should lead to the creation of novel tools and strategies to induce, maintain, and monitor tolerance.
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