Regulation of Innate Immune Responses by Alloimmunity in Liver Ischemia-Reperfusion Injury

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PROJECT II – PROJECT SUMMARY/ABSTRACT Ischemia-reperfusion injury (lRI) may lead to poor early graft function, primary non-function and predisposes the graft to acute and/or chronic rejection. The pathophysiology of liver IRI has been investigated in animal models, primarily in the setting of hepatic partial warm ischemia in situ, and cold storage/syngeneic Tx, with mechanistic emphasis on innate immune responses. Clearly, there are major discrepancies between these experimental models and the clinical scenario, which may cause deficiencies in our comprehension of the disease mechanism. In this regard, the question of whether and how allo-antigens (Ag)/adaptive allo-immunity impact tissue inflammatory response and injury against IR is of high significance. We have compared liver IRI between syngeneic and allogeneic transplants in both rat and mouse orthotropic liver transplantation (OLT) models. Results showed unequivocally that allografts developed significantly more severe tissue injuries than isografts under the same preservation condition in the early stage of reperfusion, which were distinctive kinetically from rejection. Lymphocytes and their functional mechanisms involved in the liver IRI of allografts are clearly different from those in isografts. This project focuses on the role of CD4 T cells in liver IRI of allo-, vs. iso-OLTs after extended cold storage. We have found in a liver partial warm ischemia model that the effector memory (TEM) subset (CD44highCD62Llow), but not naïve, CD4 T cells were able to function in Ag non- specific manner via a CD154 dependent, but IFN-γ independent mechanism. In the OLT setting, our recent data specified functions of IFN-γ in liver IRI of allo-, but not iso-grafts. We hypothesize that recipient pre- existing CD4 TEM cells are responding to liver IR immediately post Tx. They function via both Ag-specific and non-specific pathways involving distinctive effector mechanisms. We have documented that liver CD4 TEM expressed CD154 constitutively and enhanced innate inflammatory immune activation via CD40, independent of their Ag-specificities. In allo-OLTs, we propose that donor allo-Ags may, additionally, activate recipient infiltrating alloreactive CD4 TEM cells to produce IFN-γ, which is responsible for the enhanced inflammatory immune activation and hepatocellular damage, as compared with those in iso-OLTs. Thus, CD4 TEM cells may promote liver IRI by Ag-specific reactivation to secrete IFN-γ and Ag non-specific interaction via CD154 with CD40 on innate immune cells. We will address our hypothesis in two specific aims to determine Ag- specificities and effector mechanisms of CD4 T cells in IRI of OLTs. These studies will be the first to specifically address the fundamental immunobiology question of liver IRI in allogeneic vs. syngeneic transplantation. Results will not only fulfill the gap in our understanding of the disease pathogenesis in real clinical setting, but also provide us novel insight into the role of adaptive immunity in regulating tissue innate inflammatory immune responses.