Apoptotic Donor Leukocytes to Promote Kidney Transplant Tolerance

项目二总结

PROJECT 2 SUMMARY We demonstrated that two peritransplant infusions of apoptotic donor leukocytes (ADLs) and transient immunosuppression (TIS) with α-CD40, rapamycin, sTNFR, and α-IL-6R induced long-term (>1 year) tolerance to islet allografts in 5 of 5 nonsensitized, 1 MHC-II DRB allele-matched nonhuman primates (NHPs). Project 2 will examine the efficacy and mechanisms of the ADL+TIS regimen in a kidney transplant model and apply high- dimensional immune profiling to guide protocol refinements, with the PRINCIPAL OBJECTIVE of developing a safe, effective, and clinically translatable protocol for inducing stable tolerance in living donor kidney transplantation. WE HYPOTHESIZE that the ADL+TIS regimen, with modifications deemed necessary to facilitate successful translation to a solid organ transplant setting and with refinements informed by results of the overall U19 program, promotes long-term graft survival in living donor kidney transplant models in NHPs through operational tolerance. To test this hypothesis and facilitate the clinical translation of ADL+TIS, we propose two SPECIFIC AIMS: AIM #1: To determine the efficacy and mechanisms of ADL infusions combined with transient immunosuppression in inducing and maintaining tolerance in a NHP renal transplant model Studies determining the efficacy of the ADL+TIS protocol in achieving operational tolerance of renal allografts in NHPs will be accompanied by deep immune profiling of blood, graft, spleen, and urine to investigate the effects of the protocol on the abundance and activation profiles of distinct effector, exhausted, and regulatory immune cell subsets in various compartments and their spatial organization within graft and spleen. AIM #2: To study the efficacy and mechanisms of inflammasome inhibition and IL-1b antagonism to promote renal transplant tolerance induced by ADL infusions and transient immunosuppression in NHPs Studies in this Aim will determine the ability of strategies inhibiting the inflammasome and its products to synergize with ADL+TIS in promoting operational tolerance in a renal transplant model in NHPs. Mechanistic studies will investigate how inflammasome inhibition and IL-1b antagonism modify the effects of ADLs + TIS on frequencies and activation profiles of myeloid and lymphoid cell subsets in blood, urine, and spleen and their recruitment to and spatial interaction within coordinated immune regulation domains in the renal allograft. The SIGNIFICANCE & INNOVATION of the proposal lie in the efficacy of the ADL+TIS protocol to deplete and exhaust allospecific T cells and to create potent immune regulation. The prospects for tolerance induction to renal transplants in NHPs are high, based on documented tolerance to renal transplants in rodents and islet transplants in NHPs and opportunities for rational refinements of the strategy created by system-level immune profiling.