Immune tolerance, the phenomenon by which the allograft is accepted without immunosuppression whilepreserving the recipient's protective immunity, represents a solution to the problems of acute and chronicrejection and the resulting long-term reliance on toxic immunosuppressive therapies. The significant successof transplantation tolerance studies in rodent models has suggested that similar tolerance-inductiontechniques involving bone marrow transplant and hematopoietic chimerism could be achieved in preclinicaland clinical situations, thus revolutionizing solid organ transplantation. Non-human primate models have anumber of important attributes that allow them to serve as critical preclinical models in order to bridge thebasic insights gained in mice and the application of these insights to patient care. Among the mostprominent of the tolerance induction strategies are CD28/CD40 T cell costimulation blockade and mixedchimerism induction. By taking advantage of our ability to induce chimerism using mobilized peripheral bloodstem cells from living Rhesus macaque donors, we propose to perform a systematic analysis of impact of acostimulation blockade and chimerism-based tolerance induction strategy in transplant pairs having varyingdegrees of MHC disparity. These studies also are focused on understanding the immune consequences oftransplant, specifically on evaluating the anti-donor response and the preservation of protective immunity inthe peritransplant period. The unifying purpose of our proposal is to develop clinically applicable protocols forthe induction of tolerance to solid organ allografts while preserving immune competence in the transplantrecipient. Specifically, the aims in this project will address 1) the effectiveness of a CD28/CD40costimulation-blockade-based chimerism/tolerance induction protocol on transplants displaying varyingdegrees of MHC matching between the donor and recipient, 2) the necessary components of theimmunomodulatory strategy for chimerism and tolerance induction, and 3) the efficacy of inhibiting NaturalKiller cell-mediated alloreactivity in order to decrease the need for recipient conditioning and/or donorperipheral blood stem cells to promote tolerance across MHC barriers. We believe the ability to induce stabledonor chimerism and immune tolerance in this transplant setting would have a large impact on the outcomeof transplantation, and holds the promise of relieving many transplant recipients from the requirement forcomplicated life-long immunosuppressive regimens and their attendant toxicities.
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