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 nave, CD4 T cells were able to function in Ag non- specific manner via a CD154 dependent, but IFN-? independent mechanism. In the OLT setting, our recent data specified functions of IFN-? 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-?, 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-? 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI120944-04
Application #
9975699
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2017-08-01
Project End
2022-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Kageyama, Shoichi; Nakamura, Kojiro; Fujii, Takehiro et al. (2018) Recombinant relaxin protects liver transplants from ischemia damage by hepatocyte glucocorticoid receptor: From bench-to-bedside. Hepatology 68:258-273
By the Contributors to the C4 Article (Appendix 1) (2018) Current opinions in organ allocation. Am J Transplant 18:2625-2634
Sosa, Rebecca A; Rossetti, Maura; Naini, Bita V et al. (2018) Pattern Recognition Receptor-reactivity Screening of Liver Transplant Patients: Potential for Personalized and Precise Organ Matching to Reduce Risks of Ischemia-reperfusion Injury. Ann Surg :
Kageyama, Shoichi; Hirao, Hirofumi; Nakamura, Kojiro et al. (2018) Recipient HO-1 inducibility is essential for posttransplant hepatic HO-1 expression and graft protection: From bench-to-bedside. Am J Transplant :
Kageyama, Shoichi; Nakamura, Kojiro; Ke, Bibo et al. (2018) Serelaxin induces Notch1 signaling and alleviates hepatocellular damage in orthotopic liver transplantation. Am J Transplant 18:1755-1763
Nakamura, Kojiro; Kageyama, Shoichi; Yue, Shi et al. (2018) Heme oxygenase-1 regulates sirtuin-1-autophagy pathway in liver transplantation: From mouse to human. Am J Transplant 18:1110-1121
Nakamura, Kojiro; Kageyama, Shoichi; Ke, Bibo et al. (2017) Sirtuin 1 attenuates inflammation and hepatocellular damage in liver transplant ischemia/Reperfusion: From mouse to human. Liver Transpl 23:1282-1293
Nakamura, Kojiro; Zhang, Min; Kageyama, Shoichi et al. (2017) Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury. J Hepatol 67:1232-1242