Dimethyl fumarate treatment alters circulating T helper cell subsets in multiple sclerosis

Abstract

Objective:To evaluate the effect of dimethyl fumarate (DMF; Tecfidera, Biogen, Weston, MA) on CD4+ and CD8+ T cell subsets in patients with multiple sclerosis (MS).Methods:Peripheral lymphocyte subsets, including CD4+ and CD8+ memory cells and T helper (TH) cells TH1, TH2, TH17, and peripheral regulatory T cell (pTreg) subpopulations were analyzed before and 6 months after onset of DMF treatment.Results:CD4+ and CD8+ memory T cells were preferentially decreased compared to naive CD4+ and CD8+ T cell populations. Within the CD4+ memory T cell population, frequencies of TH1 cells were decreased, whereas those of TH2 cells were increased and those of TH17 cells remained unaltered. Accordingly, we observed decreased production of interferon γ, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor α, and interleukin (IL)-22 by CD4+ T cells under DMF treatment, whereas the frequency of IL-4- and IL-17A-producing CD4+ T cells remained unchanged. With regard to regulatory T cells, proportions of pTreg increased following DMF treatment.Conclusion:Our data demonstrate that DMF treatment of patients with MS affects predominantly memory T cells accompanied by a shift in TH cell populations, resulting in a shift toward anti-inflammatory responses. These findings indicate that monitoring of memory subsets might enhance vigilance of impaired antiviral immunity and that patients with TH1-driven disease might preferentially benefit from DMF treatment.Classification of Evidence:This study provides Class IV evidence that DMF might preferentially reduce CD4+ and CD8+ memory T cells in MS.

Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity

“…They may also explain important observations of DMF therapy in patients. DMF differentially impacts distinct lymphocyte subsets, producing lymphopenia that selectively depletes highly glycolytic effector T cells while sparing oxidative naïve T cells and Treg cells (28, 29). Our findings suggest that the inhibition of aerobic glycolysis underlies these selective effects.…”

Multiple Sclerosis Therapies in Pediatric Patients: Challenges and Opportunities

“…Although not fully understood, dimethyl fumarate may reduce cytokine production and lymphocyte count, resulting in a decrease in immune cells migratory activity through the BBB (59). Its active metabolite is monomethyl fumarate and the most common adverse effects include itching and redness, nausea and vomiting, abdominal pain and diarrhea, lymphopenia, PML, vision problems, and hypersensitivity reactions (60).…”

Immunomonitoring Lymphocyte Subpopulations in Multiple Sclerosis Patients

“…A decrease of central and effector memory T-cells with a concomitant expansion of naïve T-cells in peripheral blood of patients under treatment with DMF have been reported. Moreover, a shift in T helper (Th) subpopulations (a decrease in Th1 and Th17, and an increase in Th2 and regulatory T-cells) has been reported (55)(56)(57)(58). Regarding B-cell subpopulations, an increase of a subset of B-cells with regulatory capacity has been described (59).…”