Visualizing rejection: Model systems for the study of transplantation tolerance

Organ transplantation is often the only treatment option for diseases such as congestive heart failure, kidney failure, and liver disease. While current immunosuppressive regimens have achieved impressive results in short-term allograft survival, there remain significant areas of improvement in long-term outcomes. Recent advances in the field of immunology have introduced new approaches that could eliminate the need for life-long immunosuppression while establishing tolerance to donor tissues.; Blockade of the T-cell costimulatory pathways CD28-B7 and CD40--CD154 significantly prolongs allograft survival in animal models, but does not lead to indefinite allograft survival. It is therefore important to identify pathways that are synergistic with costimulatory signals during rejection. In the first series of experiments, we explore the role of the IL-2 pathway in costimulation blockade resistant rejection. We find that additional blockade of IL-2 has synergy with costimulation blockade in prolonging graft survival and controlling the alloresponse.; The most effective strategy to date using combined costimulatory blockade has been the establishment of hematopoietic chimerism. This approach yields transplantation tolerance through deletion of alloreactive cells; however, it is unknown whether chimerism is necessary for peripheral tolerance. Current understanding of peripheral tolerance suggests that any cell type which expresses MHC-peptide complexes should tolerize antigen specific T-cells when critical costimulatory interactions are interrupted, but in practice this has not been the case. In the next series of experiments, we assess the tolerogenic potential of donor hematopoietic and parenchymal cells. We find that allogeneic tissues differ profoundly in their ability to promote peripheral tolerance. Hematopoietic chimerism is necessary and sufficient for peripheral tolerance through deletion of donor-reactive cells.; Chimerism, while effective in murine models, has proven elusive in primate models, necessitating the identification of new pathways to facilitate costimulation blockade-based tolerance. Cellular trafficking events are relatively unexplored in transplantation immunology. In the final two series of experiments, we explore the molecules regulating T-cell trafficking to allografts. We have developed a model of intravital videomicroscopy to directly study signals critical to T-cell rolling within the graft. This technique has identified the selectins regulating T-cell migration to allografts that may serve as future targets in clinical transplantation settings.