# TIM-3 Negative Costimulation Signaling at the Innate-Adaptive Immune interface in Liver Transplant Ischemia-Reperfusion Injury

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $346,500

## Abstract

   
DESCRIPTION (provided by applicant): 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, an exogenous Ag-independent, innate immune-dominated sterile inflammation response, requires activated CD4+ T cells to facilitate tissue damage. T cell Immunoglobulin Mucin (TIM)-3 receptor has been recognized as a central regulator of T cell activation in a number of auto- / allo-immunity pathologies and organ transplantation. We reported that disruption of TIM-3 - Gal-9 pathway exacerbated hepatocellular injury in mouse livers subjected to warm IR. Then, we found that recipient CD4+TIM-3+ cells conferred resistance against liver IRI, suggesting a discrete host T cell subset should be spared while applying T cell-targeted therapy in transplant recipients. This proposal explores the function of TIM-3 signaling pathway in the mechanism of hepatic IRI in a clinically relevant mouse model of extended cold storage followed by orthotopic liver transplantation (OLT). First, we found that stressed hepatocytes express Gal-9 and HMGB1, i.e., known TIM-3 ligands. Second, we discovered robust expression of TIM-3 on activated liver endothelial cells (LEC). These preliminary data have led us to a central hypothesis that negative regulation between hepatocellular-derived Gal-9/HMGB1 and TIM-3 expressed on host circulating CD4+ T cells/graft LEC is essential to control tissue injury, and impose cytoprotective phenotype in IR-stressed OLT. Two interlocked specific aims will test this hypothesis:  Aim 1: Define molecular mechanisms by which hepatocyte Gal-9 - CD4+ T cell TIM-3 negative regulation confers OLT resistance against IR stress. Aim 1.1. Hypothesis: Gal-9 - TIM-3 signaling triggers anti-oxidant response in which amplified Nrf2 activity represses macrophage NFB/inflammation responses. Aim 1.2. Hypothesis: Gal-9 - TIM-3 signaling enhances hepatocyte autophagy via Keap1/Nrf2 redox network.  Aim 2: Define molecular mechanisms by which hepatocellular HMGB1 - endothelial TIM-3 negative regulation alleviates IRI in OLT. Aim 2.1. Hypothesis: HMGB1 conditioning prior to IR insult triggers activation of liver endothelial TIM-3 to repress macrophage trafficking and sequestration in OLT. Aim 2.2. Hypothesis: Hepatocellular HMGB1 - endothelial TIM-3 signaling promotes LEC protective phenotype.  These studies will discern novel mechanisms at the innate-adaptive immune interface, which control organ damage/promote homeostasis in IR-stressed OLT; and should contribute to the development of new therapies to increase donor organ pool and improve clinical outcomes.

## Key facts

- **NIH application ID:** 9836842
- **Project number:** 5R01DK107533-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Jerzy W Kupiec-Weglinski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $346,500
- **Award type:** 5
- **Project period:** 2016-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836842

## Citation

> US National Institutes of Health, RePORTER application 9836842, TIM-3 Negative Costimulation Signaling at the Innate-Adaptive Immune interface in Liver Transplant Ischemia-Reperfusion Injury (5R01DK107533-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9836842. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*