Using trained immunity-inhibiting nanobiologics to achieve tolerance of heart allografts in non-human primates

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SUMMARY – PROJECT 3 Kidney allograft tolerance has been achieved in nonhuman primates (NHPs) and humans by combining nonmyeloablative conditioning and donor bone marrow transplantation resulting in transient mixed hematopoietic chimerism. However, identical protocols have failed to induce tolerance in NHP heart recipients. The reason for this immunological dichotomy is unknown but elucidating its underlying mechanisms could inform new strategies for achieving tolerance of resistant allografts (Aim 1). Despite the immune barriers posed by heart allografts, we have recently developed a novel protocol that has, for the first time, induced long-term tolerance of fully MHC mismatched heart allografts in cynomolgus monkeys. We attained this remarkable result by combining a transient mixed chimerism protocol with donor kidney co-transplantation. The presence of the donor kidney was associated with diminished inflammation and enhanced host regulatory mechanisms. Since sacrificing a kidney allograft simply to achieve tolerance in human heart recipients is untenable, we now seek an effective substitute for kidney co-transplantation (Aim 2). Recently, our team reported that following organ transplantation, macrophages in the allograft display distinct epigenetic signatures associated with the functional state of trained immunity. Trained immunity has been identified as de facto innate immune memory characterized by metabolic and epigenetic changes in innate immune cells, resulting in their hyperresponsiveness. Trained macrophages have heightened inflammatory cytokine responses and upregulated costimulatory molecules, which consequently induce more potent adaptive immune responses. Importantly, our team has designed a myeloid cell-specific nanoimmunotherapy that selectively inhibits trained immunity while promoting regulatory mechanisms and has achieved long-term cardiac allograft survival in mice and, more recently, in monkeys. Based on these findings, we hypothesize that 1) trained immunity contributes to the tolerance resistance of heart versus kidney allografts, and 2) trained immunity-inhibiting nanotherapy will generate an anti-inflammatory/pro- regulatory milieu that will facilitate heart tolerance without the need for kidney co-transplantation. We will test these hypotheses in Project 3. Murine studies in Project 2 will guide Project 3 by providing complementary, in- depth mechanistic analyses of trained immunity in heart and kidney recipients and also identifying new trained immunity-inhibiting targets (developed by Core B) worthy of testing in NHPs. Core C will provide state-of-the-art molecular assays and expertise, to determine mechanistically 1) how trained immunity is induced, 2) the role trained immunity plays in the organ-specific differences observed in tolerance induction, and 3) how our therapies impact trained immunity. We anticipate that together, these highly interactive Projects will generate new and innovative therapeutic strategies to prevent rejection and more effectively achieve immune tolerance. If successful, these studies could impact the entire field of transplantation and provide insights that could also be field-changing for bone marrow transplantation and autoimmune disease.