Dimethyl Fumarate Selectively Reduces Memory T Cells and Shifts the Balance between Th1/Th17 and Th2 in Multiple Sclerosis Patients

Abstract

Dimethyl fumarate (DMF; trade name Tecfidera™) is an oral formulation of the fumaric acid ester that is FDA approved for treatment of relapsing-remitting multiple sclerosis (RRMS). To better understand the therapeutic effects of Tecfidera and its rare side-effect of progressive multifocal leukoencephalopathy (PML), we conducted cross-sectional and longitudinal studies by immunophenotyping cells from peripheral blood (particularly T lymphocytes) derived from untreated, 4-6 month and 18-26 month Tecfidera-treated stable RRMS patients using multi-parametric flow cytometry. The absolute numbers of CD4 and CD8 T cells were significantly decreased and the CD4/CD8 ratio was increased with DMF treatment. The proportion of both effector memory (Tem) and central memory T cells (Tcm) were reduced while naïve T cells (Tn) increased in treated patients. T cell activation was reduced with DMF treatment especially among Tem and effector memory RA (Temra) T cells. T helper subsets Th1 (CXCR3+), Th17 (CCR6+), and particularly those expressing both CXCR3 and CD161 were reduced most significantly, while the anti-inflammatory Th2 subset (CCR3+) was increased after DMF treatment. A corresponding increase in IL-4, and decrease in IFNγ and IL-17-expressing CD4+ T cells was observed in DMF-treated patients. DMF in vitro treatment also led to increased T cell apoptosis and decreased activation, proliferation, reactive oxygen species, and CCR7 expression. Our results suggest that DMF acts on specific memory and effector T cell subsets by limiting their survival, proliferation, activation, and cytokine production. Monitoring these subsets could help to evaluate the efficacy and safety of DMF treatment.

STAT5B: A Differential Regulator of the Life and Death of CD4+ Effector Memory T Cells

“…S1). The mother of the patient had several immune-related disorders including multiple sclerosis (MS), arthritis, and recurrent infections, and was receiving 17 different medications at the time of blood sampling, including dimethyl fumarate (DMF), which has been shown to selectively decrease memory T cell populations in MS patients (39). For these reasons and the lack of access, we did not further investigate the mother.…”

Chemical and genetic control of IFN γ‐induced MHCII expression

“…Here, we identified several genetic factors and compounds that interfere with IFNc-induced MHCII expression (Fig 6). CXCR3 is a receptor for CXCL9 and CXCL10 [83]. Dimethyl fumarate (DMF) has recently been FDA approved for the treatment of relapsing-remitting MS, but its exact mechanism of action is still under debate [74,75].…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…Recent findings indicated that DMF reduced the number of CD4 + , CD8 + , Th1, and Th17 cells, whereas the CD4 + /CD8 + ratio and the Th2 subset were increased in the blood of these patients. Interestingly, the inhibitory effects of DMF/MMF on T cell activation were confined mainly to memory T cells (Wu et al, 2017). These immunomodulatory activities of DMF or MMF are important for the protection of oligodendrocytes against ROS-induced cytotoxicity (Scannevin et al, 2012).…”