Studying and regulating trained immunity in mouse transplant models

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SUMMARY – PROJECT 2 Transplantation has revolutionized the lives of patients suffering from organ failure. However, the associated immunosuppressive therapies induce significant side effects and display suboptimal success rates. Achieving a state of operational tolerance would lead to indefinite graft survival without chronic immunosuppression and its associated morbidity. This P01’s investigators have revealed pronounced organ-specific differences in tolerance induction, preserved across species. For example, kidney and liver allografts are easier to tolerize than heart and lung allografts. Moreover, co-transplanting a kidney promotes tolerance of heart allografts. These phenomena indicate an underappreciated mechanism regulating allograft tolerance, which might be therapeutically leveraged to turn “tolerant resistant” into “tolerance prone” organs. This P01’s investigators have also demonstrated that trained immunity plays a critical role in allograft rejection. Trained immunity is a long-term (>several months) increased functional responsiveness of innate immune cells mediated through epigenetic mechanisms at the level of hematopoietic progenitors in the bone marrow, resulting in enhanced production of hyperresponsive myeloid cells. We demonstrated that transplantation induces trained immunity and that the ensuing ‘trained’ myeloid cells promote graft rejection. Project 2’s premise is 1) that the difference between organs’ susceptibility to acute rejection stems from different degrees or modes of trained immunity of trained immunity and that 2) therapeutically inhibiting trained immunity early post-transplantation will prolong graft survival. In line with this, we have developed bone marrow-avid nanotherapeutics which inhibit the trained immunity regulator mTOR and effectively promote allograft survival without continuous immunosuppressive therapy. Here, we propose studying and therapeutically inhibiting trained immunity in mouse transplant models. Aim 1 will longitudinally assess the (innate) immune response to rejecting heart and spontaneously accepting kidney transplantation, using in vivo immuno-PET imaging and ex vivo (multi-omics) analyses. We will strive to maximize the obtained mechanistic insights using relevant knockout models and syngeneic controls. In parallel, Aim 2 will therapeutically inhibit trained immunity-related metabolic and epigenetic pathways and similarly study the effects on the immune system and graft survival. This Project will unravel the mechanisms behind transplantation-induced trained immunity and its role in graft rejection. Furthermore, it will advance an innovative treatment paradigm based on trained immunity-regulating nanobiologics and initiate clinically relevant readouts of trained immunity based on immuno-PET imaging. Project 2, led by Dr. Teunissen, will interface with Projects 1 and 3 by providing mechanistic insights and validating novel therapeutic targets.