# Inflammatory Cytokine Networks in Gastrointestinal Tract Graft Versus Host Disease

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $608,125

## Abstract

Graft versus host disease (GVHD) is the major complication associated with allogeneic hematopoietic stem cell
transplantation (HSCT). During the acute phase of this disease, a restricted set of organs is affected of which the
gastrointestinal (GI) tract is the most clinically significant. Proinflammatory cytokines play a critical role in the
pathophysiology of intestinal GVHD, in part, by activating donor innate and T cell populations which
subsequently induce tissue damage. We previously demonstrated that CD4+ T cell production of granulocyte-
macrophage colony stimulating factor (GM-CSF) plays a critical inflammatory role in the pathophysiology of GI
GVHD. More recently, we have identified two CD4+ GM-CSF+ T cell populations within the GVHD colon
microenvironment that possess distinct transcriptional profiles, employ non-overlapping gene regulatory units,
emerge with divergent temporal kinetics, have differential responsiveness to IL-7, and are distinguishable by the
presence or absence of IFN-γ co-expression, suggesting that they may have different pathogenic roles in
mediating GVHD in the GI tract. In addition, our preliminary studies have uncovered a previously unappreciated
interleukin 34 (IL-34)-mediated regulatory pathway that inhibits the emergence of CD4+ GM-CSF+ T cells in
the GI tract, indicating the existence of a potential therapeutically targetable cytokine to reduce GM-CSF-
mediated inflammation in this tissue site. The overall goal of this proposal is therefore to delineate mechanistic
pathways by which CD4+ GM-CSF+ T cells promote pathological damage in the GI tract and define how these
populations are regulated by IL-34. Our overall hypothesis is that there exist discrete CD4+ GM-
CSF+ T cell populations that have distinct functional roles in mediating pathological damage
in the GI tract and that are regulated by the host production of IL-34. Studies in Specific Aim 1 will
define the pathogenicity of CD4+ GM-CSF+ T cell populations during GVHD. To address this question, we will
employ a recently created GM-CSF fate reporter mouse model that faithfully identifies viable GM-CSF-
expressing CD4+ T cells in GVHD target organs. Experiments in Specific Aim 2 will identify key transcription
factors and define the role of IL-7 in the development of CD4+ GM-CSF+ T cells. We will employ genetically
modified murine models that will ascertain the extent to which specific transcription factors are required for the
development and pathogenicity of CD4+ GM-CSF+ T cells and determine the dependency of these cells on IL-7
receptor signaling. Studies in Specific Aim 3 will characterize how IL-34 regulates GM-CSF-responsive innate
immune cell populations in the GI tract during GVHD and affects the emergence of CD4+ GM-CSF+ T cells.
Experiments will identify mechanistic pathways by which IL-34 regulates GVHD and determine whether these
pathways can be therapeutically targeted to reduce disease severity. The overall objective of this proposal is to...

## Key facts

- **NIH application ID:** 10801241
- **Project number:** 2R01HL126166-13
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** William R. Drobyski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $608,125
- **Award type:** 2
- **Project period:** 2015-08-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801241

## Citation

> US National Institutes of Health, RePORTER application 10801241, Inflammatory Cytokine Networks in Gastrointestinal Tract Graft Versus Host Disease (2R01HL126166-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10801241. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*