Dissecting the Role of Donor CCR2- Macrophages During Acute Cellular Rejection After Heart Transplantation

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Project Abstract End-stage heart failure is a leading cause of death worldwide and costs the United States over $30 billion annually. Heart transplant remains the only curative therapy but its success is threatened when the donor heart does not work properly. Current immunosuppressive treatments focus on targeting immune cells in the recipient's heart. These therapies confer a significant risk of infections and malignancy and are only modestly effective. Targeting the donor-recipient interaction may provide a novel therapeutic pathway. Several distinct immune cell types reside within the donor heart with macrophages comprising the majority of myeloid cells. The mouse and human heart contain at least two populations of macrophages that can be distinguished based on the expression of C-C chemokine receptor 2 (CCR2). CCR2+ macrophages participate in inflammatory responses whereas CCR2- macrophages promote tissue repair. The PI has established that donor CCR2- and donor CCR2+ macrophages have opposing roles after heart transplant. Depletion of donor CCR2- macrophages accelerates rejection while depletion of donor CCR2+ macrophages prolong allograft survival. In this proposal, the PI will decipher the mechanisms by which donor CCR2- macrophages prevent rejection through their modulation of other immune cell populations and signaling pathways. The scientific goals of this research award are to identify novel immune populations that can be exploited to understand the mechanisms of rejection and can be therapeutically targeted to improve outcomes. By the end of the award period, the PI will understand how donor CCR2- macrophages effect donor CCR2+ macrophage activation and whether this activation is necessary for allograft rejection (SA1). The PI will investigate how CCR2- macrophages become activated and whether this activation is required for allograft protection (SA2). In completing these aims, the PI will gain technical expertise in flow cytometry, intravital imaging, bulk and single cell RNA sequencing, antigen presentation, phagocytosis, and alloreactivity assays. The career development goal of this proposal is to develop the PI into an independent physician-scientist in the field of cardiovascular research. The PI has previously obtained a PhD training in biology and has obtained additional training in basic and translational cardiovascular research during his post-doctoral fellowship. The PI has completed clinical training in Internal Medicine, Clinical Cardiology, and Advanced Heart Failure and Cardiac Transplantation Fellowship. The proposed 5-year career development plan will provide the PI with formal training in immunology and bioinformatics and ongoing laboratory training in the study of cardiac transplantation and macrophage biology. The PI will meet regularly with his mentors and advisory committee which is composed of senior scientists who are experts in immunology, transplantation, cellular imaging, bioinformatics, and career development. At the conclusion of this award period, the PI will have acquired the skills necessary to become an independent and successful physician-scientist.