Early and late inflammatory events controlling lung allograft homeostasis

PROJECT SUMMARY/ ABSTRACT Despite improved surgical techniques and safer intraoperative management, lung transplant recipients suffer the highest rates of acute and chronic allograft rejection when compared to other organs. At least some aspects of such poor outcomes can be attributed to the unique immunologic milieu of the lung as a mucosal barrier organ. Other grafts (such as hearts, kidneys, and livers) are not in constant and direct contact with the external environment. Unlike the case for other organ grafts, where downregulation of inflammation facilitates acceptance, tolerance induction and maintenance in the lung allograft depends on unique inflammatory mediators. During the previous funding period we identified that CD8+ T cells, eosinophils, as well as IFN-γ and IL-1β to play a unique and counterintuitive role in facilitating the engraftment and long-term stability of the lung allograft. In this proposal we plan to explore the role the cytokine IL-33 and eosinophils in both establishing and maintaining lung allograft tolerance. In Aim 1 we plan to test: 1) the role of ST2 (the IL-33 receptor) on regulatory T cells specific signaling and; 2) the physiologic significance of continuous IL-33 production on allograft tolerance. Aim 2 is based on new and surprising data that eosinophils prevent the development of chronic lung allograft rejection (CLAD). Through three non-mutually exclusive sub-aims we plan to determine how eosinophils ameliorate CLAD by either alteration of the cytokine milieu (Aim 2.1), production of amphiregulin and/or osteopontin (Aim 2.2), or through modulation of eotaxin levels in the graft (Aim 2.3). The data generated as part of this proposal will both expand our understanding of lung alloimmunity and provide a rationale for therapeutic avenue/s to ameliorate both acute and chronic lung allograft dysfunction.