The Role of Donor-Derived Eosinophils on Lung Allograft Ischemia Reperfusion Injury

PROJECT SUMMARY/ ABSTRACT Despite advances in organ recovery a large number of lung transplant recipients suffer from primary graft dysfunction associated with ischemia-reperfusion injury (IRI) of the donor graft. Such injury can result in an increased risk of both acute and chronic rejection and substantially decrease survival. Translational research focusing on cellular mechanism/s of injury can set the foundation for therapeutic intervention. In this proposal we expand on a novel finding that donor-derived eosinophils contribute to lung allograft damage during organ storage and after reperfusion. Depletion of eosinophils from the donor lung prior to engraftment decreases IRI and improves pulmonary function. This finding is in direct contrast to discoveries made during the previous cycle of this grant, where we uncovered that recipient-derived eosinophils limit both cellular and humoral rejection. Thus, our data indicate that eosinophils can be beneficial or deleterious to graft survival based on the context and local environment. The aims outlined in this grant test our central hypothesis that organ storage and reperfusion lead to activation of donor-derived eosinophils that results in graft damage. Such damage may be mitigated by blocking eosinophils and eosinophil activation. To explore this in greater detail in Aim #1 we will focus on stress ligands and components of organ preservation solution that activate eosinophils. In Aim #2 we will evaluate mechanism/s of how eosinophils can mediate organ damage and in Aim #3 we will explore clinically relevant methodology to either prevent eosinophil activation or mediate their depletion during the process of organ preservation. Our data will both provide novel insight into cellular immune responses contributing to ischemia-reperfusion injury and set the stage for translational protocols to improve outcomes.