# Innate-Adaptive Immune Interface in  Liver Ischemia-Reperfusion Injury

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $382,305

## Abstract

PROJECT I - SUMMARY/ABSTRACT
Ischemia-reperfusion injury (IRI) remains the primary obstacle limiting the success of orthotopic liver
transplantation (OLT) in patients with end-stage liver disease and those with tumors of hepatic origin. Our
group has pioneered the concept that hepatic IRI requires activated CD4+ T cells to facilitate liver tissue
damage. T cell immunoglobulin-3 (TIM-3; encoded by Havcr2 gene) is the central negative regulator of T cell
activation. CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1; encoded by CC1 gene) has
been identified as a new cellular ligand determining TIM-3 function. First, we found that compared with
CEACAM1 proficient (WT) livers, CEACAM1 null-mutation (CC1-/-) exacerbated IRI in OLT. Second, we
discovered that the benefit of recipient CD4+TIM-3+ signaling in IR-stressed OLT (WT→TIM-3Tg) was
completely lost when CEACAM1 KO mice served as organ donors (CC1-/-→TIM-3Tg). These preliminary data
have led us to central hypothesis that 1/ TIM-3 – CEACAM1 negative regulation is essential to control IRI by
imposing exhaustion-like dysfunction in OLT-infiltrating CD4+ T cells; and 2/ CEACAM1 in the donor liver
promotes hepatoprotection. Project I will test this hypothesis through two interlocked specific aims:
Aim 1: Define mechanisms of TIM-3 – CEACAM1 negative T cell regulation in IR-stressed iso-OLT. A panel of
mice available to us for Aim 1 experiments include CD4+ T cell mutants, which are: i/ CEACAM1Tg; ii/ double
TIM-3Tg and CEACAM1-/-; as well as: iii/ TIM-3Tg and TIM-3-/- mice.
 Aim 1.1. Hypothesis: CEACAM1 - TIM-3 signaling on host circulating CD4+ T cells promotes exhaustion-
type phenotype in IRI–OLT.
 Aim 1.2. Hypothesis: Under dominant CAECAM1 signaling, TIM-3+CD4+ exhausted T cells inhibit the
development and progression of IRI in OLT.
Aim 2: Define mechanisms by which hepatocellular CEACAM1 in donor liver regulates IRI in iso-OLT. Gene-
targeted strains for Aim 2 studies include: i/ hepatic CEACAM1 inactivation (loss-of- function; L-CC1-/-); or ii/
forced hepatic CEACAM1 overexpression (gain-of-function; L-CC1Tg).
 Aim 2.1. Hypothesis: Enhancement of hepatocyte-specific CEACAM1 – β-catenin regenerative functions
facilitates hepatoprotection.
Aim 2.2. Hypothesis: TIM-3 – CECACAM1 signaling enhances hepatocyte autophagy program.
 Integration with PPG: By providing novel insights into TIM-3 – CEACAM1 checkpoint regulation at the
innate – adaptive immune interface in IR-stressed iso-OLT, Project I naturally informs/precedes studies
assessing how host rejection regulates innate immune activation/IRI sequel in allo-OLT (Project II). Direct
application of approaches blunting inflammation while promoting hepatoprotection in mouse OLT models will
accelerate assessments of immune phenotypes in human liver transplants (Project III).

## Key facts

- **NIH application ID:** 9975698
- **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:** $382,305
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975698

## Citation

> US National Institutes of Health, RePORTER application 9975698, Innate-Adaptive Immune Interface in  Liver Ischemia-Reperfusion Injury (5P01AI120944-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9975698. Licensed CC0.

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