Document Type

Article

Publication Date

7-1-2020

Comments

This article is the final version published in Neurology Neuroimmuniology & Neuroinflammation, Volume 7, Issue 4, May 2020, e729. The final published version can be found at http://doi.org/10.1212/NXI.0000000000000729. Copyright Safavi et al.

Abstract

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.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

32371548

Language

English

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