Orthotopic liver transplantation (OLT) is the gold standard of care in patients with end-stage liver disease and those with tumors of hepatic origin. However, the organ shortage has prompted the use of extended criteria livers, which are particularly susceptible to ischemia-reperfusion injury (IRI), an inflammation/tissue damage response, which is inevitable during organ procurement and preservation. We propose the overarching hypothesis that liver IRI results from impaired regulation between innate (e.g., macrophage-dependent) and adaptive (T cell-driven) immune mechanisms. Complementary skills and expertise of the team well-versed in the study of organ IRI, basic immunology, liver immunobiology, and organ transplantation, both experimental and clinical, are melded in this PPG initiative to better appreciate molecular mechanisms that operate at the hepatic innate - adaptive immune interface. Project I focuses on a newly discovered TIM-3 ? CEACAM1 negative checkpoint regulation of innate ? adaptive immune interface in IR-stressed iso-OLT.
Aim 1 will elucidate mechanisms by which CEACAM1 ? TIM-3 signaling on host circulating CD4+ T cells promotes T cell dysfunction phenotype via exhaustion-like mechanism in IRI?OLT.
Aim 2 will investigate mechanisms by which hepatocellular-specific CEACAM1 expression may discriminate between sterile inflammation/liver hepatocellular damage vs. cytoprotection in IR-stressed iso-OLT. Project II will define mechanisms by which allo-specific CD4 T cells during the host rejection response influence liver IRI in clinically-relevant allogeneic OLT settings. Studies focus on a subset of pre-existing effector memory CD4 T cells (TEM), which respond to allograft challenge via Ag-dependent vs. Ag non-dependent pathways, involving reactivation to secrete IFN-? or to promote CD154 - CD40 signaling.
Aim 1 will analyze the Ag-dependence of CD4 TEM, while Aim 2 will ascertain the role of costimulatory molecules in IR-stressed allo-OLT. Project III examines reciprocal regulation of innate/adaptive immune responses and determines the contribution of alloimmune memory on the incidence and severity of hepatic IRI in human OLT.
Aim 1 will determine the role of DAMPs/PRR signaling in the activation of innate and adaptive immunity in human liver grafts under IR-stress.
Aim 2 will delineate the pathological signature of IRI in human OLT via transcriptomic profiling of IRI biopsies and characterize the acute and long-term pro-inflammatory profile of IRI.
Aim 3 will determine the molecular basis for crosstalk between innate and adaptive immune networks in human OLT that suffer from IR-damage (synergy: Project I and II). These 3 Projects will be supported by an Administrative Core (Core A); Liver Microsurgery Core (Core B; supports Project I and II); and Computational/Biostatistics Core (Core C; supports all 3 Projects). Relevance: The ultimate shared goal of these well-integrated and interdependent Projects and Cores is to unravel clinically relevant mechanisms that regulate hepatic IRI in OLT recipients. These should identify molecules as targets for a possible therapeutic intervention against IR-stress, and promote cytoprotection in liver transplant patients.

Public Health Relevance

OVERALL ? NARRATIVE Ischemia-reperfusion injury (IRI) limits the success of orthotopic liver transplantation in patients with end-stage liver disease and those with tumors of hepatic origin. By using established mouse models of IRI, and by analyzing human liver transplants suffering from IRI, this Program Project seeks to address unmet scientific and clinical needs in the field of organ transplantation. The results have the potential to alter clinical paradigms by identifying the continuum of innate immune phenotypes that can be used to select, monitor, and refine the practice of therapeutic interventions against IRI in transplant patients.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1)
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Kehn, Patricia J
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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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