Dimethyl fumarate induces a persistent change in the composition of the innate and adaptive immune system in multiple sclerosis patients

Abstract

The effects of dimethyl fumarate (DMF) on the immune system in multiple sclerosis (MS) are not completely elucidated. In this study, an extensive immunophenotypic analysis of innate and adaptive immune cells of DMF-treated MS patients was performed. Peripheral blood immune cell phenotypes were determined using flow cytometry in a follow-up study of 12 MS patients before, after 3 and 12 months of DMF treatment and a cross-sectional study of 25 untreated and 64 DMF-treated MS patients. Direct effects of DMF on B cells were analyzed in vitro. After 12 months of DMF treatment, percentages of monocytes, natural killer cells, naive T and B cells and transitional B cells increased. Percentages of (effector) memory T cells, (non) class-switched memory B cells and double negative B cells decreased together with CD4+ T cells expressing interferon-γ (IFN-γ), granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-17 (IL-17). DMF treatment was fully effective as of 6 months and directly induced apoptosis and decreased expression of costimulatory CD40, antigen presentation molecule MHCII and B cell activating factor receptor (BAFFR) on B cells. DMF induced a persistent change of the immune system of MS patients, directly induced apoptosis and reduced expression of functional markers on B cells.

Optimal response to dimethyl fumarate is mediated by a reduction of Th1‐like Th17 cells after 3 months of treatment

“…It was not addressed whether this increase was due to an increase of transitional B cells or to a suppression of their differentiation to naïve mature B cells. This finding is in accordance with previous studies also showing an increase of transitional B cells following 12 months of treatment, although our work is the first reporting this effect after only 3 months of DMF therapy.…”

“…On the other hand, we also observed a selective decrease on circulating memory B cells (both switched and preswitched), in parallel with an increase of naïve B lymphocytes, in accordance with previous publications . B cells can produce pro‐inflammatory cytokines, and treatments depleting the B‐cell compartment such as rituximab (anti‐CD20 monoclonal antibody) have demonstrated beneficial effects on MS patients.…”

“…As described, DMF reduced the absolute number of circulating lymphocytes, affecting more extensively CD8 + cytotoxic T cells and therefore increasing the CD4 + /CD8 + T‐cell ratio . Further analyses evidenced the characteristic phenotypic alterations produced by DMF treatment on CD4 + and CD8 + T‐cell subpopulations, a selective reduction of central and effector memory T cells, and an expansion of naïve T cells.…”

Targeting immunometabolism as an anti-inflammatory strategy

“…17 Finally, DMF treatment causes a decrease in the number of CD19 + B-lymphocytes in MS patients, coupled to a drop in GM-CSF, IL-6 and TNFα. 7,18,19 Despite extensive research on the beneficial immunomodulatory effects of DMF and its hydrolyzed counterpart mono methyl fumarate (MMF), the exact mechanism of action for DMF has yet to be determined. DMF promotes expression of antioxidant genes by stabilizing the ubiquitously and constitutively expressed transcription factor Nuclear Factor (erythroid-derived 2) like 2 (Nrf2 or NFE2L2).…”

NRF2 as a Therapeutic Target in Neurodegenerative Diseases

“…The exact mechanism by which DMF exerts its beneficial effects has not been fully described, although multiple mechanisms including shifting toward anti-inflammatory immune balance, inhibition of T cell activation, induction of B and T cell apoptosis, inhibition of proinflammatory cytokines, and reduction of memory T cells have all been suggested as contributing factors (Treumer et al, 2003;Longbrake et al, 2016;Schulze-Topphoff et al, 2016;Smith et al, 2017;Montes Diaz et al, 2018a). There have been many clinical and basic science studies of DMF in MS. An excellent and thorough review of the history and mechanism of DMF as an MS therapy was recently published by Montes Diaz et al (2018b).…”