Dimethyl fumarate suppresses granulocyte macrophage colony-stimulating factor–producing Th1 cells in CNS neuroinflammation

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 glycoprotein(35–55) 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.