# Role of the retinoic acid pathway during graft-versus-host disease

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $385,155

## Abstract

Graft-versus-host disease (GVHD) remains the most significant obstacle to the broader application of
allogeneic hematopoietic stem cell transplantation (HSCT), a life-saving treatment for many malignant and
nonmalignant diseases. It is mediated primarily by donor T cells that cause multi-organ damage, including the
skin, liver, and gastrointestinal tract in HSCT recipients. Of these target organs, the gastrointestinal tract is of
particular clinical and immunological significance. Indeed, severe intestinal damage is largely responsible for
the GVHD-associated deaths in patients and experimental animals. However, the cellular and molecular
mechanisms underlying the inflammatory responses in the GI tract during GVHD remain unclear. Our long-
term goal is to develop clinically based strategies to prevent or mitigate intestinal damage during GVHD,
thereby improving the outcomes of allogeneic HSCT. We recently identify retinoic acid (RA), the active
metabolite of vitamin A, as a key molecule in facilitating the development of intestinal GVHD. Specifically,
administration of exogenous RA exacerbates gut damage in recipient mice and significantly increases GVHD-
associated mortality. Importantly, donor T cells from the retinoic acid receptor (RAR)-α deficient mice show
markedly diminished ability to cause lethal GVHD and, more specifically, intestinal damage. These novel
findings identify an organ-specific role of RA in GVHD and provide evidence that the RA pathway is critically
involved in the pathogenesis of intestinal GVHD. The objective of this proposal is to address clinically relevant
questions with respect to how the RA pathway controls intestinal GVHD development and whether
manipulating this pathway can reduce disease severity. We hypothesize that the RA pathway is critical for host
and donor dendritic cells to initiate and perpetuate intestinal GVHD and this pathway can be manipulated for
therapeutic purposes. We will combine genetic, nutritional, and pharmacological approaches to examine the
hypotheses. In Aim 1, we will determine how RA production and RAR signaling are altered after allogeneic
HSCT. We will then examine how these changes affect the function of host and donor dendritic cells to cause
intestinal GVHD. Aim 2 will determine if manipulating the RA pathway is a novel approach to prevent and/or
treat intestinal GVHD. We will examine if pharmacological blockade of the RA pathway using novel small
molecule inhibitors can prevent intestinal GVHD. We will also explore if RA-programmed regulatory T cells can
be used to treat established intestinal GVHD. Finally, we will determine whether the critical graft-versus-
leukemia effect is preserved using these approaches. We expect that insights gained from these studies will
contribute to a better understanding of the fundamental role of the RA pathway in the pathophysiology of
intestinal GVHD and provide preclinical data to develop novel strategies to prevent or treat this devastating
compl...

## Key facts

- **NIH application ID:** 9841341
- **Project number:** 5R01AI125334-04
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Xiao Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,155
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841341

## Citation

> US National Institutes of Health, RePORTER application 9841341, Role of the retinoic acid pathway during graft-versus-host disease (5R01AI125334-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9841341. Licensed CC0.

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