# Project 4-Early Liver Transplantation for Severe Alcoholic Hepatitis: Animal Studies

> **NIH NIH P50** · JOHNS HOPKINS UNIVERSITY · 2024 · $437,511

## Abstract

Promising clinical outcomes in early liver transplantation (ELT) for severe alcoholic hepatitis raise new questions:
Does chronic and active alcohol use impact allograft rejection after ELT? Is a living donor or reduced sized liver
suitable for ELT? How early is too early to have an ELT? Is there a biologic basis why the majority of SAH
patients (>75%) without pre-transplant abstinence have no alcohol relapse 2-3 years after ELT? These questions
can be approached in animal models of liver transplantation. In the last funding period, we established a rat liver
transplantation model in which a DA or Lewis rat liver is transplanted into Lewis recipients fed with alcohol vs a
control diet for 8 weeks. We found chronic alcohol exposure not only reduced the recipient survival times
significantly, but also reduced the efficacy of immunosuppressive therapy. Both chronic alcohol exposure and
immunosuppressive therapy inhibited liver regeneration following reduced sized (50%) liver transplantation;
Searching for an underlying mechanism, we found evidence of dramatically increased neutrophilic infiltration in
liver allografts of alcohol fed recipients early following transplantation and chronic alcohol exposure produced
excessive priming of the neutrophil respiratory burst in circulating leukocytes suggesting priming of the neutrophil
respiratory burst by alcohol exposure may play an important role in liver allograft rejection/oxidative injury and
regeneration. A striking finding is that a new stem cell mobilizing therapy (MRG-001) not only improved survival
of alcohol fed recipients (100%) following allogeneic liver transplantation, but also promoted liver allograft
regeneration. Based on these findings, we hypothesize that chronic and active alcohol abuse impacts innate
immunity especially neutrophils, and infiltration of alcohol dysregulated neutrophils promotes liver allograft
rejection/damage following transplantation. Further, current immunosuppressive therapy is ineffective in
preventing neutrophil infiltration and inhibits liver regeneration following reduced sized graft transplantation. We
propose that short-term abstinence or a new bone marrow stem cell/immunoregulatory cell mobilizing therapy
(MRG-001) may eliminate alcohol dysregulated neutrophils/innate immunity and promote allograft acceptance
and regeneration in alcohol fed recipients. In addition, transplantation of a genetically different liver may alter
alcohol use behavior. The following aims test these hypotheses. Our proposed studies involve: 1) evaluating the
impact of alcohol dysregulated neutrophils on allograft rejection and oxidative damage and to determine if short-
term abstinence or MRG-001 pretreatment eliminates alcohol dysregulated neutrophils following LT, 2)
developing a strategy for living donor ELT to promote regeneration and tolerance of small liver allografts, and 3)
determining if transplantation of a genetically different liver to alcohol-preferring (P) rats alters al...

## Key facts

- **NIH application ID:** 10741447
- **Project number:** 2P50AA027054-06
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** ZHAOLI SUN
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $437,511
- **Award type:** 2
- **Project period:** 2019-02-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10741447

## Citation

> US National Institutes of Health, RePORTER application 10741447, Project 4-Early Liver Transplantation for Severe Alcoholic Hepatitis: Animal Studies (2P50AA027054-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10741447. Licensed CC0.

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