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

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $1,941,328

## Abstract

OVERALL – ABSTRACT
Orthotopic liver transplantation (OLT) is the accepted treatment in patients with end-stage liver failure and those
with tumors of hepatic origin. However, the organ shortage has prompted the use of extended criteria donors,
which are particularly susceptible to ischemia-reperfusion injury (IRI). The overarching hypothesis of this P01
renewal is that IRI in OLT results from impaired regulation between donor liver-specific and host-derived innate
immunity. The project and core objectives, functioning in a highly synergistic manner, are to 1/ identify new target
molecules for improving donor liver quality (organ rejuvenation); 2/ provide novel therapeutic means against
acute IR-stress while promoting inflammation resolution (homeostatic reparation); and 3/ prevent sustained/
chronic inflammation to mitigate alloimmunity and improve outcomes (tolerance induction).
Project 1 focuses on a newly discovered CEACAM1 (CC1) negative checkpoint regulation of IR-triggered innate
immune activation/sterile inflammation in the mechanism of donor liver rejuvenation. Aim 1 and 2 will delineate
mechanisms by which enforced CC1 alternative splicing in the donor liver (S-isoform), or the recipient-derived
neutrophils (L-isoform) exert anti-inflammatory/cytoprotective functions in mouse IRI-OLT (synergy: Project 2/3).
Aim 3 will elucidate whether/how modulation of hepatic CC1 might improve the function of discarded human
livers (deemed untransplantable) when subjected to normothermic machine preservation (synergy: Project 3).
Project 2 defines mechanisms by which reprogramming of IR-stressed mouse liver-infiltrating macrophages and
resident heterogeneic KCs orchestrate the restoration of hepatic tissue homeostasis. In synergy with Project 1/3,
Aim 1 will determine the functional mechanisms by which embryonic vs. monocyte-derived KCs promote liver
IR-inflammation resolution. Aim 2 will define MerTK-mediated pro-resolution effector pathways in the liver-
resident KCs. Aim 3 will dissect the roles of KCs in OLT settings and whether/how liver inflammation resolution
and its kinetics impact the activation of alloimmunity and putative acquisition of transplant tolerance.
Project 3 dissects the innate immune DAMPs and associated cofactors/PRRs driving myeloid cell plasticity in
human IRI-OLT patients. In synergy with Project 1/2, Aim 1 will determine the TLR7/NOD2 and TLR9 ligands
and signaling pathways mediating differential polarization of regulatory vs. inflammatory macrophages and
crosstalk with T cells. Aim 2 will assess the therapeutic potential of PRR inhibition/preconditioning to mitigate
myeloid cell activation and OLT-IRI. Aim 3 will elucidate the impact of DAMP/PRR endotypes on the generation
of alloimmunity and graft outcome, and potential transplantation tolerance acquisition.
The Projects will be supported by an Administrative Core (Core A), Mouse/Human Liver Surgery Core (Core B),
and Computational/Biostatistics Core (Core C). This P01 unif...

## Key facts

- **NIH application ID:** 10328209
- **Project number:** 2P01AI120944-06
- **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:** 2022
- **Award amount:** $1,941,328
- **Award type:** 2
- **Project period:** 2017-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328209

## Citation

> US National Institutes of Health, RePORTER application 10328209, Innate-Adaptive Immunoregulation in Liver Transplant Ischemia/Reperfusion Injury (2P01AI120944-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10328209. Licensed CC0.

---

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