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

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $377,500

## Abstract

PROJECT 3 - SUMMARY/ABSTRACT
Ischemia and reperfusion injury (IRI), the inevitable consequence of the transplant process, is a key limitation to
human liver transplantation. The cellular damage incurred by IRI can lead to primary non-function necessitating
re-transplantation. Liver IRI also predisposes the recipient to both acute and chronic rejection and graft loss, as
well as, decreasing the pool of transplantable organs. Key observations in murine models indicate that liver IRI
is mediated by both the innate and adaptive immune systems. Little is known whether similar mechanisms are
at play in human liver transplantation. Our central hypothesis is that identifying the DAMPs and their associated
PRRs driving myeloid cell plasticity during human OLT-IRI will permit us to develop therapeutic interventions to
improve OLT outcomes. Aim 1, we will determine the TLR9 and TLR7/NOD2 ligands mediating differential
polarization of inflammatory vs. regulatory macrophages and crosstalk with T cells. We will characterize the cell-
free DNA/TLR9 ligands mitochondrial DNA, neutrophil extracellular traps, and HMGB1/RAGE in pre/post
reperfusion blood to establish their contributions to human OLT-IRI, ability to polarize macrophages and develop
alloreactive T cells. We will also determine the tolerogenic effect of TLR7 and NOD2 ligands for their regulatory
potential to mitigate TLR4 and/or TLR9 polarization and suppression of alloimmunity. Characterization of
longitudinal changes in myeloid and T cell phenotypes of recipient blood and donor allograft biopsies obtained
pre- and post-reperfusion will identify new targetable interactions along the endotype-specific pathways
TLR4/TLR9 and TLR7/NOD2 in situ. Aim 2 will determine the therapeutic potential of PRR preconditioning to
mitigate myeloid activation and OLT-IRI. We will assess the therapeutic potential of TLR4/9 antagonists to
mitigate IR mediated-injury, macrophage inflammatory polarization and T cell alloreactivity in vitro using blood
from human OLT recipients, and in vivo in rodent models of IRI. In situ assessment of the spatial immune profile
of donor vs. recipient myeloid cells in control vs. tolerized organs will explore the IRI-mediated immune cell and
parenchymal changes contributing to a regulatory vs inflammatory state in the graft. Aim 3 will determine the
impact of DAMP/PRR endotypes on generation of alloimmunity and graft outcome. We will assess the
DAMP/PRR endotypes that direct the generation and breadth of alloreactive T cells and donor specific
antibodies. Data will be integrated with clinical metadata, blood and graft immunophenotypes, IRI and transplant
outcomes to determine DAMP/PRR endotypes responsible for susceptibility to IRI and worse outcomes.

## Key facts

- **NIH application ID:** 10906004
- **Project number:** 5P01AI120944-08
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** ELAINE F REED
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $377,500
- **Award type:** 5
- **Project period:** 2017-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906004

## Citation

> US National Institutes of Health, RePORTER application 10906004, Innate-Adaptive Immunoregulation in Liver Transplant Ischemia/Reperfusion Injury (5P01AI120944-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10906004. Licensed CC0.

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