# Project 2: REG3A Regulation of GI GVHD

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $441,044

## Abstract

PROJECT 2 SUMMARY/ABSTRACT
Acute graft versus host disease (GVHD) is the major cause of non-relapse mortality (NRM) following
allogeneic bone marrow transplantation (BMT). The GI tract is the GVHD target organ that is most
difficult to treat. Studies from this P01 grant have identified and validated Regenerative 3 alpha
(REG3ΓA) as a plasma biomarker specific for the GVHD of the GI tract. REG3ΓA (and its mouse
homologue Reg3γγ) are antimicrobial peptides produced by intestinal epithelial cells that protect the
barrier function and integrity of the intestinal mucosa. Our long term objective is to develop novel
strategies to reduce the morbidity and mortality of GVHD. Our central hypothesis is that REG3ΓA
functions as a master regulator of GI GVHD. We have formulated our hypothesis based on our own
published data that show that the destruction of Paneth cells by GVHD correlates with NRM.
Unpublished data show that GVHD suppresses production of Reg3γγ in mice, and that mice deficient in
Reg3γγ suffer more severe GVHD than normal mice. Further preliminary data show that administration
of IL-22 which induces Reg3γγ, restores endogenous Reg3γγ and reduces GI GVHD. But in the
absence of Reg3γγ, IL-22 loses its ability to protect mice from GVHD. Thus REG3ΓA/Reg3γγ appears
to be a master (negative) regulator of GVHD. Once the role of Reg3γγ in the pathophysiology of GI
GVHD is better understood, these mechanistic insights will lay the foundation for innovative approaches
to prevent and treat GVHD through modulation of the epimmunome.
We will test our central hypothesis and achieve the objective of this project by pursing the following two
specific aims:
1. To define the mechanisms by which Reg3γ reduces GVHD. We will examine effects of Reg3γ on
both intestinal epithelium and hematopoietic cells that drive T cell responses. In collaboration with
Project 1 we will examine the role of butyrate in modulating Reg3γ in its prevention of GVHD. We will
also evaluate the effects of Reg3γ on GVL effects.
2. To determine if Enterococcus drives GVHD. Using the gnotobiotic expertise in revised Core 2,
have demonstrated that germ free (GF) mice do not develop severe GVHD after allogeneic BMT. Given
the predominance of enterococcus in both severe GVHD in both humans and experimental models is
both necessary and sufficient to cause GVHD using customized human microbial laboratories to
customize GF mice. We will use advanced metagonomic sequencing techniques to correlate shifts in
the microbiota with evolving GVHD status.
3. To determine the effects of the antibiotic treatment and therapeutic probiotics on GVHD
severity. Early systemic antibiotic treatment is associated with more severe GVHD in humans and
mice. Experiments in Core 2 have now shown that systemic antibiotics dramatically decrease Reg3γ in
mice. This SA we will test the hypothesis that the increased severity of GVHD after antibiotic treatment
is mediated by a loss of Reg3γ. The second subaim will test probio...

## Key facts

- **NIH application ID:** 10006010
- **Project number:** 5P01CA039542-32
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** JAMES L. M. FERRARA
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $441,044
- **Award type:** 5
- **Project period:** 1997-09-10 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006010

## Citation

> US National Institutes of Health, RePORTER application 10006010, Project 2: REG3A Regulation of GI GVHD (5P01CA039542-32). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10006010. Licensed CC0.

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