# Inflammatory Cytokine Networks in Gastrointestinal Tract Graft Versus Host Disease

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2021 · $504,154

## Abstract

PROJECT SUMMARY
Graft versus host disease (GVHD) is the major complication associated with allogeneic
hematopoietic stem cell transplantation (HSCT). Damage to the gastrointestinal (GI) tract from
acute GVHD is a particularly serious event leading to significant morbidity and mortality.
Proinflammatory cytokines play a critical role in the pathophysiology of intestinal GVHD, in part,
by activating donor T cell populations which subsequently induce tissue damage. In preliminary
studies, we have identified GM-CSF as a pivotal cytokine which plays an important role in the
pathophysiology of acute GVHD in the GI tract. The goal of this proposal is to define the
mechanistic pathways by which GM-CSF affects the innate and adaptive arms of the immune
system to induce inflammation in this tissue site during GVHD. Our overall hypothesis is
that GM-CSF induces a proinflammatory environment in the GI tract, and that this
effect is attributable to the recruitment of pathogenic myeloid cell populations and
the augmentation of alloreactive donor T cell responses. Studies in Specific Aim 1 will
characterize the innate cell populations that are responsive to GM-CSF signaling and define the
functional role of specific GM-CSF-responsive cells in mediating damage in the GI tract during
acute GVHD. To address this question, we will employ novel Csf2rbfl/fl mice in which the high
affinity beta chain of the GM-CSF receptor has flanking lox p sites, which will allow for myeloid
cell-specific deletion when bred with appropriate lineage-specific Cre animals. Experiments in
Specific Aim 2 will define mechanistic pathways by which GM-CSF affects T cell-mediated
inflammatory and regulatory functions in the immune system, and thereby modulates the severity
of GVHD in the GI tract. Specifically, we will determine whether GM-CSF elicits IL-23 production
by donor-derived APCs in the GI tract, examine whether CD4+ T cell-derived GM-CSF promotes
indirect alloantigen presentation by donor-derived APCs in the colon, and define the role of GM-
CSF in the reconstitution of the regulatory T cell compartment during GVHD. Studies in Specific
Aim 3 will determine whether CD4+ GM-CSF+ T cells represent a stable T cell lineage that is
regulated by interleukin 7 (IL-7) signaling. To address this question, we will construct a novel
GM-CSF fate reporter mouse that will allow us to fate map immune cell populations that produce
GM-CSF and define their response to IL-7. The overall objective of this proposal is to develop
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
recipients and improve outcomes in patients with blood cancers.

## Key facts

- **NIH application ID:** 10159292
- **Project number:** 5R01HL126166-11
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** William R. Drobyski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $504,154
- **Award type:** 5
- **Project period:** 2015-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159292

## Citation

> US National Institutes of Health, RePORTER application 10159292, Inflammatory Cytokine Networks in Gastrointestinal Tract Graft Versus Host Disease (5R01HL126166-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10159292. Licensed CC0.

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