Myeloid HIFs in cardiac transplantation vasculopathy

Significant progress has been made in the field of heart transplantation to prevent acute rejection with one-year survival rates approaching 85-90%. However, long-term outcomes remain poor, mainly due to complications that arise following chronic immunosuppression, including impaired immunological function and the subsequent immune-driven cardiac allograft vasculopathy (CAV). The disappointing long-term survival of heart transplant recipients drives the need for novel therapeutic strategies that harness the immune system to induce tolerance and free the recipient from detrimental chronic immunosuppression. While recent studies suggest that cells of the innate immune system, including macrophages, have a dual role following transplantation either facilitating graft rejection or promoting tolerance, their role in cardiac transplantation is underappreciated. The observation that innate immune cells can play a protective role in allograft survival highlights the potential for strategies that target specific innate immune pathways to prevent CAV. Critical regulators of innate immunologic activation, tolerance, and vascular homeostasis are hypoxia-inducible factors (HIFs). Our preliminary data suggest that HIFs in innate immune cells are critical for the induction of tolerance and preservation of cardiac allograft survival. We hypothesize that (I) following cardiac transplantation, HIF expression in innate immune cells is required to suppress adaptive immune reactivity to allografts and subsequent rejection and (II) HIF isoforms uniquely regulate innate immune cell function to limit the severity of CAV. Aim I will determine the protective effects of HIF in myeloid cells on alloreactive responses and CAV following cardiac transplantation. Aim II will elucidate the signaling mechanisms whereby phagocyte expression of HIFs inhibits proliferation of vascular smooth muscle cells, which are key mediators of CAV. Aim III will test the potential of targeting HIFs to promote and extend allograft tolerance. These aims will be tested using a murine heterotopic cardiac transplant model and in vitro models of hypoxia and reperfusion. The proposed studies will fill an important knowledge gap regarding the regulation and consequences of HIF function in innate immune cells in a clinically relevant model of cardiac transplantation. Elucidation of mechanisms in these studies will suggest novel therapies to promote cardiac transplant tolerance and likely apply to tolerance of disparate organs.