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Dimethyl fumarate suppresses granulocyte macrophage colony-stimulating factor-producing Th1 cells in CNS
Farinaz Safavi1, Rodolfo Thome1, Zichen Li1
1From the Department of Neurology (F.S., R.T., Z.L., G.-X.Z., A.R.), Thomas Jefferson University, Philadelphia, PA. Dr. Safavi is now at National Institute of Health, NINDS, Bethesda, MD.
Objective:
To study the immunomodulatory effect of dimethyl fumarate (DF) on granulocyte macrophage colony-stimulating factor (GM-CSF) production in CD4+ T cells in experimental autoimmune encephalomyelitis (EAE) and human peripheral blood mononuclear cells (PBMCs).
Methods:
We collected splenocytes and CD4+ T cells from C57BL/6 wild-type and interferon (IFN)-γ-deficient mice. For human PBMCs, venous blood was collected from healthy donors, and PBMCs were collected using the Percoll gradient method. Cells were cultured with anti-CD3/28 in the presence/absence of DF for 3 to 5 days. Cells were stained and analyzed by flow cytometry. Cytokines were measured by ELISA in cell supernatants. For in vivo experiments, EAE was induced by myelin oligodendrocyte glycoprotein35-55 and mice were treated with oral DF or vehicle daily.
Results:
DF acts directly on CD4+ T cells and suppresses GM-CSF-producing Th1 not Th17 or single GM-CSF+ T cells in EAE. In addition, GM-CSF suppression depends on the IFN-γ pathway. We also show that DF specifically suppresses Th1 and GM-CSF-producing Th1 cells in PBMCs from healthy donors.
Conclusions:
We suggest that DF exclusively suppresses GM-CSF-producing Th1 cells in both animal and human CD4+ T cells through an IFN-γ-dependent pathway. These findings indicate that DF has a better therapeutic effect on patients with Th1-dominant immunophenotype. However, future longitudinal study to validate this finding in MS is needed.
Insights
Dimethyl fumarate (DF) specifically suppresses granulocyte macrophage colony-stimulating factor (GM-CSF)-producing Th1 cells in CD4+ T cells. This effect is dependent on interferon-gamma (IFN-γ) and observed in both experimental autoimmune encephalomyelitis (EAE) and human cells.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- Dimethyl fumarate (DF) is an immunomodulatory drug used in treating autoimmune diseases.
- Granulocyte macrophage colony-stimulating factor (GM-CSF) is a pro-inflammatory cytokine implicated in autoimmune pathogenesis.
- CD4+ T cells play a central role in adaptive immunity and are key players in autoimmune responses.
Purpose of the Study:
- To investigate the effect of DF on GM-CSF production in CD4+ T cells.
- To determine if DF's immunomodulatory effects are specific to certain T cell subsets.
- To explore the role of the interferon-gamma (IFN-γ) pathway in DF's mechanism of action.
Main Methods:
- CD4+ T cells and splenocytes were isolated from C57BL/6 wild-type and IFN-γ-deficient mice.
- Peripheral blood mononuclear cells (PBMCs) were obtained from healthy human donors.
- Cells were stimulated and treated with DF, followed by flow cytometry analysis and ELISA for cytokine measurement. In vivo experiments involved inducing experimental autoimmune encephalomyelitis (EAE) and treating mice with DF.
Main Results:
- DF directly suppresses GM-CSF production in Th1 cells within CD4+ T cells in EAE models, but not Th17 or single GM-CSF+ T cells.
- GM-CSF suppression by DF is dependent on the IFN-γ pathway.
- DF also specifically suppresses Th1 and GM-CSF-producing Th1 cells in human PBMCs.
Conclusions:
- DF selectively inhibits GM-CSF-producing Th1 cells in both murine and human CD4+ T cells via an IFN-γ-dependent mechanism.
- DF may be particularly effective in patients with a Th1-dominant autoimmune profile.
- Further longitudinal studies are warranted to confirm these findings in multiple sclerosis (MS) patients.
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