# Ischemia-Reperfusion Injury in Human  Liver Transplantation: Reciprocal  Regulation of Innate/Adaptive Immune  Responses

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $379,884

## Abstract

PROJECT III - SUMMARY/ABSTRACT
Orthotropic human liver transplantation is the primary therapy for end-stage liver disease and acute liver failure.
However, ischemia and reperfusion injury (IRI), the inevitable consequence of the transplant process, is a key
limitation. The cellular damage incurred by IRI occurs in about 20% of cases and 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. Seminal 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
continuum of innate and adaptive immune phenotypes during human liver transplant IRI will permit us to select,
monitor and refine the practice of therapeutic interventions and hence improve liver transplant outcomes. Under
Aim 1 we will determine the role of DAMP/Pattern Recognition Receptor (PRR) signaling in the activation of
innate and adaptive immune responses in human OLT IRI. We hypothesize that IRI-stressed hepatocytes
release the endogenous DAMPs that trigger TLR and other PRR signaling on innate myeloid cells, which then
induce adaptive immunity via T cell activation. We will investigate whether effluents from IRI+ allografts trigger
innate myeloid cell activation through TLR/PRR signaling. Furthermore, we will define the role of DAMPs within
the IRI effluent in triggering myeloid cell activation and see if DAMPs alter T cell activation and polarization.
Under Aim 2 we will delineate the pathological signature of human liver transplant IRI. We hypothesize that IRI
leads to activation of hepatocytes and resident Kupffer cells and LSECs, and recruitment/activation of myeloid
cells and circulating T cells in human liver allografts, and this pathological cascade will perpetuate damage to
the graft. To prove this concept, we will establish a “transcriptome” profile for IRI biopsies to better understand
mechanisms of injury and characterize the acute and long-term pro-inflammatory profile of IRI and elucidate
interactions between innate and adaptive immune cells in situ. Under Aim 3 we will determine the crosstalk
between alloimmunity and IRI. We postulate memory T cells enhance inflammation and tissue injury in human
liver transplant through antigen-dependent and antigen-independent mechanisms. We will therefore determine
if allospecific T memory cells augment human liver IRI and also determine if IRI potentiates alloreactivity. Detailed
insights into the interactions of the innate and adaptive immune system in human liver transplantation IRI will
generate novel concepts to better understand the mechanistic underpinnings and to develop novel therapeutics
to treat this major clinical problem.

## Key facts

- **NIH application ID:** 10232247
- **Project number:** 5P01AI120944-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** ELAINE F REED
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $379,884
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232247

## Citation

> US National Institutes of Health, RePORTER application 10232247, Ischemia-Reperfusion Injury in Human  Liver Transplantation: Reciprocal  Regulation of Innate/Adaptive Immune  Responses (5P01AI120944-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10232247. Licensed CC0.

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