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

Abstract

Aim Dimethyl fumarate (DMF) is one of the most promising therapies for relapsing‐remitting multiple sclerosis (RRMS) patients since it has shown immunomodulatory and neuroprotective effects. However, a percentage of RRMS patients do not exhibit an optimal response to DMF. The objective of this study was to identify early biomarkers of treatment response by analyzing changes in peripheral leukocyte subpopulations directly in whole blood samples. Methods A longitudinal and prospective study analyzing peripheral blood leukocyte subpopulations in 22 RRMS patients before initiating DMF treatment (baseline) and at 1, 3, 6, and 12 months of follow‐up was performed. Differences between no evidence of disease activity (NEDA) and ongoing disease activity (ODA) patients were analyzed. Results The beneficial effect of DMF was associated with a specific depletion of memory CD4+ and CD8+ T lymphocytes and B cells. Importantly, only NEDA patients showed (a) a shift from a pro‐ to an antiinflammatory profile, with an increase of Th2 cells and a decrease of Th1‐like Th17 lymphocytes; and (b) an increase of regulatory CD56bright NK cells. Conclusion The optimal response to DMF is mediated by a shift to antiinflammatory and immunoregulatory profile, which puts forward Th1‐like Th17 lymphocytes as a potential early biomarker of treatment response.

Immunological effects of dimethyl fumarate treatment in blood and CSF of patients with primary progressive MS

“…The effects of DMF treatment on peripheral lymphocytes in patients with RRMS have previously been investigated thoroughly (Ghadiri et al, 2017;Gross et al, 2016;Høglund et al, 2018;Holm Hansen et al, 2019a;Li et al, 2017;Mansilla et al, 2019;Mehta et al, 2019;Spencer et al, 2015;Traub et al, 2019;Wu et al, 2017). Our study indicates that many effects of DMF on peripheral blood cell subsets are comparable between patients with RRMS and PPMS.…”

“…However, both CD4 + and CD8 + T cells expressing CXCR3 and CCR6 (Th1-like Th17 cells) were downregulated upon treatment with DMF. Reductions in this subset have been suggested to mediate beneficial effects of DMF treatment (Mansilla et al, 2019).…”

“…In addition, patients diagnosed with RRMS treated with DMF show reduced concentrations of CSF NFL and depletion of several immune cell subsets linked to disease activity (Gold et al, 2012;Høglund et al, 2018;Kappos et al, 2008;Sejbaek et al, 2019). Immunological effects of DMF treatment include depletion of B and T cells (especially Th1-like Th17 CD4 + T cells and CD8 + T cells) and an increase in monocyte frequencies in blood (Carlström et al, 2019;Fleischer et al, 2018;Mansilla et al, 2019;Wu et al, 2017). Although the precise pharmacodynamics of DMF have not been fully elucidated, interference with aerobic glycolytic metabolic pathways seems essential for the reduction in effector lymphocyte subsets that may contribute to the drug's disease-modifying effects in RRMS (Kornberg et al, 2018).…”

Immunosurveillance of CCR6+ T-cells predicts treatment response to dimethyl-fumarate: implications for personalized treatment strategies in multiple sclerosis

“…There have also been several published reports revealing reductions in CCR6+ T-cells in DMF-treated MS patients 1,27,47 , but the relation to treatment response was not evaluated. Regarding treatment response biomarkers for DMF specifically, two studies have used CD8+ T-cell 48 or IL-17+CD8+ T-cell percentage 49 and one study used Th1-like Th17 cell frequency 40 . Of note IL17+ CD8 T-cells highly express CCR6 5,50 , which make this population detected in our study (CCR6+CD8+).…”

“…It is important to make a distinction here between prognostic indicators, which are baseline metrics that can stratify disease severity, and biomarkers of treatment response, which are metrics that can assess response of patients to specific treatments and are the focus of this study 28 . Various methods have been used in the past to predict future disease activity and treatment response 29–36 , from immunophenotyping of peripheral blood 37–40 and CSF 41 to cytokine and serologic profiling 42,43 , pharmacogenomics 44 , MRI metrics 45 and RNA sequencing 38,46 . There have also been several published reports revealing reductions in CCR6+ T-cells in DMF-treated MS patients 1,27,47 , but the relation to treatment response was not evaluated.…”