| Transplantation is an accepted intervention for patients with end-stage organ disease. Current immunosuppressive regimens achieve good short-term allograft survival but long-term outcomes are less than adequate. With advances in the field of immunology, promising new therapies have arisen that could eliminate life-long drug therapy and promote indefinite acceptance of the donor tissue. Recent data has shown that the blockade of T cell costimulatory pathways, in particular CD28-B7 and CD40-CD154 interactions, effectively promotes graft acceptance, although it does not lead to indefinite graft survival.; The most robust strategy to induce transplantation tolerance involves the creation of hematopoietic chimerism, a state in which donor and recipient blood cells co-exist. Unfortunately, regimen-associated toxicities have limited the use of this strategy in clinical organ transplantation. In the first series of experiments we describe the development of a non-myelosuppressive strategy to induce stable mixed chimerism. This strategy was designed with the intent of potential clinical utility. To facilitate the introduction of such a protocol into pre-clinical and clinical trials we continued our studies by testing the compatibility of the tolerance regimen with several conventional immunosuppressive agents.; A variety of strategies have been devised to promote long-term allograft acceptance without chronic immunosuppression in rodent models. However these protocols have proven to be markedly less effective when tested in primates or in man. One major distinction between SPF mice and non-human primates or human patients is their exposure to pathogens and resultant immune history. In the third set of experiments we provide evidence that immune history is an under-appreciated barrier to tolerance induction in transplantation. We show that a heterologous immune response, specifically virally-induced allo-reactive memory, is a potent barrier to allograft tolerance. We identify CD8 + “central” memory T cells as the principal mediators of rejection and develop a strategy to promote antigen specific tolerance of memory.; The final experiments extend the use of costimulation blockade to the primate model. Although strict tolerance has yet to be achieved in a non-human primate model, the introduction of costimulation blockade reagents as potent immunosuppressive agents may facilitate their clinical introduction paving the way for future tolerance studies in patients. |
