# Blockade of IL-23 for the Prevention of Graft Versus Host Disease

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2021 · $558,195

## Abstract

PROJECT SUMMARY
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 T cell populations which subsequently induce tissue damage.
In pre-clinical murine studies, we have identified interleukin 23 (IL-23) as a key inflammatory
cytokine that mediates pathological damage in the GI tract during GVHD. The overall goal of this
proposal is therefore to define the mechanistic pathways by which IL-23 induces inflammation in
the GI tract, and to directly translate these findings into the clinic to examine whether blockade
of this pathway reduces the severity of GVHD in human allogeneic HSCT recipients. Our overall
hypothesis is that IL-23 produced by donor antigen presenting cells (APCs)
induces a proinflammatory environment in the GI tract and that this pathway is a
clinically viable target for the prevention of GVHD in humans. Experiments in
Specific Aim 1 will define the cellular mechanism(s) by which IL-23 promotes inflammation in the
GI tract during GVHD in murine transplant recipients. To address this question, we will identify
the relevant donor APC populations that produce IL-23 and are functionally important for the
induction of inflammation in the colon, examine whether donor APC-derived IL-23 promotes
indirect alloantigen presentation which is a critical pathway for the propagation of GVHD in the
GI tract, and define whether IL-23 production adversely impacts the regulatory arm of the
immune system by deleteriously affecting CD4+ and CD8+ regulatory T cell reconstitution.
Studies in Specific Aim 2 will consist of a phase 2 clinical trial to determine whether
administration of the IL-23p19-specific antibody, tildrakizumab, attenuates the severity of GVHD
in human allogeneic HSCT recipients with underlying hematological malignancies. In addition,
we will perform correlative studies to define the effect of this therapeutic approach on immune
reconstitution and determine whether tildrakizumab is able to mitigate systemic inflammatory
cytokine production that occurs during GVHD. We will also serially examine the microbiome to
delineate whether administration of tildrakizumab preserves microbial diversity that is otherwise
adversely affected during this disease. The overall goal of these studies is to define the
mechanisms by which IL-23 facilitates GVHD in the GI tract and to determine whether blockade
of this pathway constitutes a clinically viable strategy for the prevention of GVHD in humans.

## Key facts

- **NIH application ID:** 10209084
- **Project number:** 1R01HL153192-01A1
- **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:** $558,195
- **Award type:** 1
- **Project period:** 2021-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10209084

## Citation

> US National Institutes of Health, RePORTER application 10209084, Blockade of IL-23 for the Prevention of Graft Versus Host Disease (1R01HL153192-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10209084. Licensed CC0.

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