Strategies to Optimize Pig-to-Primate Kidney Xenograft Survival

University Of Minnesota, Minneapolis MN

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Abstract

PROJECT SUMMARY/ABSTRACT With thousands of patients now on the waiting list for a kidney transplant, it is obvious that there is a critical shortage of available donor organs. Xenotransplantation represents a promising solution. This effort is of paramount importance as a significant number of patients are more likely to die waiting rather than receive a life- saving kidney transplant. The major limitation to the clinical translation of xenotransplantation has been the cross-species differences in cell surface carbohydrates/glycans and proteins that serve as targets for recipient- derived antibodies resulting in antibody mediated rejection. We have observed a bimodal distribution of rejection in the first year after pig to NHP kidney transplant with ~50% of recipients treated with our standard anti-CD154 containing immunosuppression regimen experiencing rejection early (<100 days, MST 53 days, n=17) while the majority of the remaining animals survive between 1 and 4.5 years (MST 422 days, n=17). Early graft loss is secondary to antibody mediated rejection directed mostly at glycan related antigens. Late failure has features of chronic antibody mediated rejection and we have shown that this is directed mostly at SLA class II molecules. For kidney xenotransplantation to have clinical utility we need to consistently prevent early antibody rejection while graft survival of at least 3 years in patients to achieve equipoise. In the current proposal we plan to study and address both early and late kidney xenograft failure. As antibody failure remains the most important problem we will address this through data driven genetic engineering to remove known xenoantigens and test novel, clinically relevant strategies to control immune cells responsible for antibody production. We have identified additional glycan xenoantigens that likely contribute to early antibody mediated rejection and have already produced a new pig- GGTA1-/-/B4GALNT2-/-/B3GNT5-/- that we will test in our pig to primate kidney xenotransplant model. We will test whether the elimination of additional candidate antigens will reduce/eliminate the early rejection we see in the first 100 days after transplant and provide consistency towards long-term survival. Late failure in our pig to NHP kidney transplant model is caused by chronic antibody mediated rejection with antibody directed at SLA class II molecules being a major driver. In aim #2 we will use our already generated SLA class II molecule knock out pigs to evaluate the role of SLA DQ and SLA DR in late xenograft rejection. In aim #3 we will target the cells responsible for antibody production using cutting-edge, clinically relevant therapies including a novel anti-CD19 depleting antibody and CD20 and CD19 specific NHP CAR T cell therapeutics to test whether broader and deeper depletion of B cell subsets will prevent early antibody mediated rejection, reset the B cell repertoire, and prevent late antibody mediated injury to the kidney xenograft. The proposed studies address an important clinical problem-- the adequate supply of donor organs as well as critical scientific questions- including what pathways/molecules are essential for the immune response to xenogeneic tissues.