# The Role of Donor T Cell-Derived GM-CSF in the Pathogenesis of Gastrointestinal Acute GVHD

> **NIH NIH F30** · MEDICAL COLLEGE OF WISCONSIN · 2021 · $46,222

## Abstract

PROJECT SUMMARY
Graft-versus-host disease (GVHD) is the most serious complication of allogeneic hematopoietic stem cell
transplantation (HSCT) and occurs in approximately 50% of all HSCT recipients despite routine immune
prophylaxis. GVHD is mediated by mature alloreactive donor-derived T cells, which are present in the graft at
the time of transplant and ultimately cause tissue damage. During the acute phase of GVHD, which typically
occurs in the first 100 days post-transplantation, inflammation is restricted to a limited number of target organs,
specifically the skin, liver, and gastrointestinal (GI) tract. Damage to the GI tract from GVHD is a particularly
serious event leading to significant morbidity and mortality. Proinflammatory cytokines play a critical role in
the pathophysiology of intestinal GVHD by activating both the innate and adaptive arms of the immune system.
While T cells are the proximate drivers of GVHD, disease induction and amplification rely on this crosstalk
between innate and adaptive immune cells. However, the cellular and cytokine networks which mediate this
interplay are incompletely understood. Preliminary studies using well-characterized murine models of GVHD
have identified GM-CSF as a cytokine which is produced at high levels by donor-derived CD4+ T cells in the GI
tract during GVHD. Moreover, disruption of GM-CSF signaling in CD4+ T cells significantly prolongs survival in
murine recipients undergoing GVHD and reduces inflammatory damage to the colon, indicating that this
cytokine plays an important role in GVHD biology. Based on these studies, the overall hypothesis of this
proposal is that GM-CSF promotes inflammation in the GI tract via the downstream activation
of innate immune populations that potentiate T cell alloreactivity. Studies in Specific Aim 1 will
determine the GM-CSF responsive myeloid cell populations that mediate inflammation in the GI tract during
GVHD. This aim will employ novel genetic and antibody-based approaches to identify the relevant GM-CSF-
dependent innate immune populations and will determine how these cellular mediators are able to directly
contribute to the proinflammatory milieu. Studies in Specific Aim 2 will define the mechanistic pathways by
which GM-CSF modulates T cell alloreactivity in GVHD. These experiments will examine how GM-CSF affects
the production of interleukin-23 by donor-derived antigen presenting cells (APCs), a cytokine that has previously
been shown to be crucial for the induction of gastrointestinal inflammation during GVHD, determine how GM-
CSF signaling in APCs affects indirect alloantigen presentation in the GI tract, and characterize how GM-CSF
modulates reconstitution of the regulatory T cell compartment. The overall objective of this proposal is to
provide new insights into the pathophysiology and regulation of GVHD within the GI tract that will foster the
development of clinically relevant strategies to mitigate this complication in allogeneic HSCT reci...

## Key facts

- **NIH application ID:** 10226919
- **Project number:** 5F30HL143870-04
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Clinton T Piper
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,222
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226919

## Citation

> US National Institutes of Health, RePORTER application 10226919, The Role of Donor T Cell-Derived GM-CSF in the Pathogenesis of Gastrointestinal Acute GVHD (5F30HL143870-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10226919. Licensed CC0.

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