# Cellular and molecular mechanisms of target tissue resistance for mitigating GVHD severity

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $477,565

## Abstract

ABSTRACT:
Allogeneic hematopoietic stem cell transplantation is potentially curative therapy for many
malignant diseases whose applicability has been impeded by the development of its most
serious complication, graft-versus-host disease (GVHD). GVHD results from the damage
caused to the host epithelial cell targets by the many immune cells and inflammatory cytokines.
While significant progress is being made in understanding the complex role of various immune
cells in causing GVHD, little is known about the role played by the target tissues themselves in
regulating the severity of disease. Specifically, induction of host intestinal epithelial cell (IEC)
apoptosis by the alloreactive donor T cells and inflammatory cytokines causes gastrointestinal
(GI) GVHD; however host IEC intrinsic resistance mechanisms to allo-immune T-cell mediated
damage, the epigenetic mechanisms that are critical for these resistance mechanisms and its
regulation by the tissue resident microflora generated metabolites has never been explored. IEC
homeostasis and resistance depends on complex interactions between the metabolic energy
substrates (such as short chain fatty acids and amino acid metabolites) and the regulation of
transcription and epigenetic chromatin modifications such as histone acetylation. We have
demonstrated that epigenetic regulation by systemic administration of histone deacetylase
inhibitors (HDACi) regulates experimental GVHD and successfully translated this concept into a
proof of principle human trial for prevention of clinical GVHD. Preliminary data generated
demonstrate significant alterations in substrates that are derived from microbial metabolites
such as essential short chain fatty acids (SCFA) and amino acids metabolites, specifically in
butyrate and tryptophan metabolite indole-3-acetaldehyde (I-3-A) levels, in the GI tract (IECs)
after allogeneic BMT. Preliminary data also show that (a) butyrate, a known HDACi, enhances
histone acetylation, modulates IECs resistance to damage and regulates GVHD (b) expression
of aryl hydrocarbon receptor (AhR) (a sensor of tryptophan metabolite indole-3-acetaldehyde)
mitigates GVHD severity. But the pathways of sensing and the mechanisms underlying the
butyrate and tryptophan metabolite indole-3-acetaldehyde -mediated effects in GVHD remain
unknown. Therefore, in this proposal, we will build on these exciting and novel preliminary
observations and bring together the diverse fields of microbiota, metabolomics, tissue
bioenergetics and epigenetics, to explore the interplay between microbial metabolites and their
effects on epigenomic alterations of the IECs in reducing GI GVHD. Specifically, we will test
the central premise that regulation of target tissue (IEC) resistance by the endogenous intestinal
microbial metabolites butyrate and tryptophan metabolite indole-3-acetaldehyde, alter the
acetylation dependent epigenome of IECs and negatively regulates GI GVHD.

## Key facts

- **NIH application ID:** 9978726
- **Project number:** 5R01CA203542-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** PAVAN REDDY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $477,565
- **Award type:** 5
- **Project period:** 2016-08-25 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978726

## Citation

> US National Institutes of Health, RePORTER application 9978726, Cellular and molecular mechanisms of target tissue resistance for mitigating GVHD severity (5R01CA203542-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9978726. Licensed CC0.

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