Regulatory immune cell therapy, promotion of tolerance and underlying mechanisms in NHP renal transplantation

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Our objective in this U19 is to develop a safe and effective therapeutic approach to promote organ transplant tolerance in a clinically-relevant, nonhuman primate model. Two promising complementary but interactive approaches to adoptive immune cell therapy for transplant tolerance,- regulatory dendritic cells (DCreg) and regulatory T cells (Treg) and their combination, comprise this U19 application. Work already completed during the award shows that, using a minimal immunosuppressive (IS) drug regimen of tapering calcineurin inhibition (tacrolimus) combined with co-stimulation blockade (CTLA4Ig), MHC-mismatched renal allograft graft survival can be prolonged using either cell therapy alone. Thus, administration of donor-derived DCreg a week before transplant, or delayed administration of Treg commencing 7 weeks post-transplant, prolongs median kidney graft survival time in rhesus macaques, although transplant tolerance is not induced. As in the original funded award, we hypothesize that, using the same immunosuppressive drug regimen, incorporation of the combined immunomodulatory functions of adoptively-transferred DCreg before transplant and Treg post-transplant will promote IS drug-free, donor-specific tolerance. In this type-4 Extension, we will complete mechanistic studies (delayed as the result of institutional restrictions imposed in response to the COVID-19 pandemic) designed to improve understanding of the in vivo fate of each cell product and how each cell therapy affects anti-donor immune reactivity, with emphasis on their impact on immune effector and regulatory cell functions. In addition, the Extension will allow us perform the delayed combined cell therapy transplant experiments proposed in our funded award, in which we will (in Project 1) test the combined DCreg + Treg approach and (in Project 2) the potential of the anti-inflammatory agent anti-IL-6 receptor antibody to potentiate the therapeutic effect of the combined cell therapy regimen. In both projects, mechanistic studies will be performed on peripheral blood and lymph node mononuclear cells and graft biopsies to elucidate underlying mechanisms. The proposed studies will take advantage of the success we have achieved during the U19 award in expanding highly-suppressive, donor-alloreactive rhesus Treg (arTreg) ex vivo. The Aims of the two Projects for the Extension are: Project 1 Aim 1: To complete mechanistic studies concerning the influence of pre-or post-transplant infusion of donor-derived DCreg on rhesus renal allograft survival Aim 2: To perform combined pre-transplant DCreg infusion with delayed post-transplant arTreg infusion on rhesus renal allograft survival and accompanying mechanistic studies Project 2 Aim 1: To complete mechanistic studies concerning the impact of IL-6R blockade on kidney graft survival and the therapeutic efficacy of ex vivo-expanded arTreg Aim 2: To determine the impact of IL-6R blockade on kidney allograft survival in conjunction with combined cell therapy and underlying mechanisms In addition to highly-interactive, mechanistic studies, both Projects will assess novel biomarker (eomesodermin) expression by alloreactive Tmem as a potential predictor of transplant outcome/tolerance. The Projects will be supported by the Administrative and Biostatistics Core (Core A) and the Transplant Pathology and Tissue Imaging Core (Core B) and will utilize agents from the NIAID NHP Reagent Resource.