# Mechanisms of GM-CSF effect in CNS autoimmune demyelination

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $390,000

## Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pro-inflammatory
cytokine essential for the development and progression of experimental autoimmune
encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Although GM-CSF is
mainly produced by pathogenic Th17 and Th1 cells, GM-CSF receptor (GM-CSFR) is not
expressed on T and B cells, but is expressed on antigen-presenting cells (APCs). Among them,
Ly6ChiCCR2+ monocytes are essential for the pathogenic role of GM-CSF in EAE. Further, GM-
CSF signaling in peripheral, but not CNS cells, plays a vital role in the development of acute
EAE. However, whether lack of GM-CSF signaling results in development of immunoregulatory
APCs has not been studied, and the role of GM-CSF signaling in CNS cells in EAE chronicity,
for which microglia activation plays a major role, remains unknown.
 Our preliminary results for the first time show enhanced production of immunoregulatory
molecules in APCs, and increased IL-10 and Foxp3 expression in CD4+ T cells of mice lacking
GM-CSF. Similarly, neutralizing GM-CSF in human monocyte culture results in an increase of
IL-27 and TGF-β production. Based on these observations, we hypothesize that GM-CSF
induces proinflammatory monocytes, whereas its blockade results in the induction of
immunoregulatory APCs and suppression of EAE. We will test this hypothesis in the following
specific aims: 1) To determine the impact of GM-CSF on phenotype of APCs and T cells in
EAE. We will test the hypothesis that blockade of GM-CSF signaling in monocytes leads to the
development of immunoregulatory APCs that promote development of Tr1/Treg cells, resulting
in suppression of EAE. 2) To investigate the effect of GM-CSF on the phenotype of
microglia/macrophages in chronic phase of EAE. We will test our hypothesis that GM-CSF
promotes activation and pro-inflammatory M1 phenotype of macrophages/microglia in chronic
phase of EAE, which contributes to disease chronicity. 3) To determine the effects of blocking
GM-CSF on phenotype and function of human monocytes. We will test the hypothesis that
GM-CSF promotes development of a proinflammatory phenotype of human monocytes. These
studies should fill the gap in our knowledge on mechanisms of proinflammatory action of GM-
CSF and its relevant cellular targets in EAE/MS, with potential therapeutic effect in certain
autoimmune diseases.

## Key facts

- **NIH application ID:** 9830005
- **Project number:** 5R01AI124386-13
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** A.M. Rostami
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2016-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830005

## Citation

> US National Institutes of Health, RePORTER application 9830005, Mechanisms of GM-CSF effect in CNS autoimmune demyelination (5R01AI124386-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9830005. Licensed CC0.

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