# Innate-Adaptive Immunoregulation in Liver Transplant Ischemia/Reperfusion Injury

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $1,674,502

## Abstract

OVERALL – SUMMARY/ABSTRACT
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-γ 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 C...

## Key facts

- **NIH application ID:** 9975685
- **Project number:** 5P01AI120944-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Jerzy W Kupiec-Weglinski
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,674,502
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975685

## Citation

> US National Institutes of Health, RePORTER application 9975685, Innate-Adaptive Immunoregulation in Liver Transplant Ischemia/Reperfusion Injury (5P01AI120944-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9975685. Licensed CC0.

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