# Mechanistic Inflammatory Pathways in Graft Versus Host Disease

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $695,482

## Abstract

PROJECT SUMMARY
Graft versus host disease (GVHD) is the major complication associated with allogeneic
hematopoietic stem cell transplantation (HSCT). Pathological damage to the skin,
gastrointestinal tract, and liver are hallmarks of this disease; however, GVHD can also induce
inflammation in the central nervous system (CNS) as well as cognitive and behavioral alterations
in patients. We previously observed that host interleukin 6 (IL-6) production and the associated
expansion of CNS resident macrophages (microglia) appear to have critical roles in the induction
of neuroinflammation, but that blockade of IL-6 signaling does not completely mitigate disease
severity. In preliminary studies, we have now identified endocannabinoid signaling through the
type 2 cannabinoid receptor (CB2R) and the kynurenine metabolic pathway as novel IL-6-
independent mechanisms by which inflammation is propagated in the brain. The overall goal of
this proposal is to validate and characterize these two putative mechanistic pathways by which
GVHD induces inflammation in the brain and ascertain how they modulate systemic
manifestations of this disease. Our overall hypothesis is that inflammation during
GVHD is attributable to CNS resident macrophages which induce inflammation
and behavioral dysfunction through both the endocannabinoid signaling and
kynurenine metabolic pathways. Studies in Specific Aim 1 will define the effect of CB2R
signaling blockade on CNS and systemic manifestations of GVHD. We will employ
pharmacological and genetic approaches that directly antagonize CB2R receptor signaling or
inhibit the synthesis of 2-AG, the natural endocannabinoid ligand of the CB2R, to address this
question. Experiments in Specific Aim 2 will determine whether expression of the CB2R on CNS
resident macrophages is critical for mediating GVHD-induced inflammation. We will utilize novel
CB2Rfl/fl mice which have flanking lox p sites which will allow for cell-specific deletion when bred
with appropriate lineage-specific Cre animals. Studies in Specific Aim 3 will define the role of
the kynurenine pathway in the pathophysiology of CNS and systemic inflammation that occur
during GVHD. We will determine whether CNS resident macrophages are the dominant source
of neurotoxic kynurenine metabolites, and define whether inhibition of this pathway using both
genetic and pharmacological approaches prevents inflammation in the brain and periphery. The
overall goal is to define relevant biochemical and immunological pathways that are responsible
for GVHD-associated neuroinflammation in order to foster the development of clinically relevant
strategies to mitigate this complication in allogeneic HSCT patients with blood cancers.

## Key facts

- **NIH application ID:** 10070849
- **Project number:** 1R01HL154579-01
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** William R. Drobyski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $695,482
- **Award type:** 1
- **Project period:** 2020-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070849

## Citation

> US National Institutes of Health, RePORTER application 10070849, Mechanistic Inflammatory Pathways in Graft Versus Host Disease (1R01HL154579-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10070849. Licensed CC0.

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