T cell costimulation in allograft acceptance and rejection

Over the past ten years, significant progress has been made in the understanding of T cell activation pathways and the mechanisms involved in the aggressive immunologic response to transplanted organs. In particular, T cell costimulatory pathways have been shown to play a critical role in T cell activation during immune responses. Four series of complementary experiments are reported here which further define the role of costimulation on T cell dependent alloimmune responses and the induction of donor-specific transplantation tolerance.; In the first set of experiments, we investigated the role of the CD40 pathway on T cell dependent macrophage activation during alloimmune responses. Our studies demonstrated that CD40 signals were not critical as previously hypothesized, but functionally overlapping with TNF$a$ signals. Thus, during T dependent immune responses, the CD40 pathway provides a redundant signal for macrophage activation.; Next, we investigated bone graft transplantation as a strategy to induce long term hematopoietic chimerism and transplantation tolerance in the absence of a pre-conditioning regimen. We demonstrated that hematopoietic cells within a bone graft migrated to the thymus and influenced selection of developing T cells. Furthermore, bone graft transplantation in recipients treated with costimulation blockade resulted in donor-specific hyporesponsiveness in vitro and acceptance of donor-specific skin grafts. Thus, bone graft transplantation provides a novel strategy for induction of hematopoietic chimerism and tolerance without the need for a pre-conditioning regimen.; Next, we studied the response of T cells to well-healed skin and cardiac allografts. We demonstrated that in the absence of detectable inflammation, allografts were rejected by transferred T cells and newly emerging thymic emigrants. Thus, peripheral tolerance mechanisms are not sufficient to inhibit allograft rejection, even in the absence of inflammation.; Finally, we investigated the role of the CD40 and CD28 pathways on alloimmune responses by CD4+ T cells. Our studies demonstrated that the CD40 pathway but not the CD28 pathway was critical for CD4 mediated skin allograft rejection. In contrast, CD28 blockade was more effective than CD40L blockade in inhibiting CD4 cell activation, priming, and proliferative responses. These results provide new insights into the mechanisms of action of costimulation blockade in transplantation.