Monocytic-MDSCs as resolution mediators of post-transplant lung ischemia-reperfusion injury

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PROJECT SUMMARY Post-lung transplant ischemia reperfusion injury is an unavoidable insult that occurs early in the post-transplant period and can cause significant dysfunction in an otherwise healthy graft. This injury is characterized by a robust inflammatory response that when unresolved, can lead to both short- and long-term mortality, ultimately hindering success rates of lung transplantation. The mechanisms that facilitate the resolution of inflammation, and specifically the resolution of this sterile insult, are not well characterized, and thus represent an attractive research opportunity that could uncover therapeutic targets. Recently, transplant research has focused on the therapeutic potential of innate cells that suppress immune response, referred to as Myeloid-Derived Suppressor Cells (MDSCs). This is a heterogeneous population of cells made up of granulocytic-like (G-MDSC) and monocytic-like (M-MDSCs) immature myeloid cells with potent immunosuppressive properties. Their role as master immunosuppressive regulators has been extensively elucidated in cancer settings, with findings translatable, but not confirmed, in transplantation. The proposed F31 NRSA application will use an experimental lung IRI model, a murine orthotopic lung transplant model, and in vitro methods to test the overall hypothesis that the M-MDSC subset facilitates the resolution of post-lung transplant ischemia reperfusion injury. In Aim 1, I will test the hypothesis that M-MDSC facilitate the resolution of lung IRI in an experimental hilar-ligation induced lung injury model through modulation of specific immune cell activation. In Aim 2, I will test the hypothesis that M-MDSCs act in an immunosuppressive manner to reduce lung injury in a murine orthotopic lung transplant model. This project will reveal insights into the actions of M-MDSCs in the lung which is crucial to understanding their full potential as a cellular therapy in the induction of graft tolerance.