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Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes
Department of Clinical Neurosciences, Section of Neurology, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Neurosciences, Section of Neurology, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Neurosciences, Section of Neurology, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Neurosciences, Section of Neurology, Karolinska Institutet, Stockholm, Sweden.
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2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, no 1, p. 1-13, article id 3081Article in journal (Refereed) Published
Abstract [en]

Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019. Vol. 10, no 1, p. 1-13, article id 3081
Keywords [en]
placebo-controlled phase-3, TH17 cell-differentiation, regulatory T-cells, oxidative stress, hydrogen-peroxide, redox regulation, NRF2 pathway, oral BG-12, arthritis, suppression
National Category
Hematology
Research subject
Bioinformatics
Identifiers
URN: urn:nbn:se:his:diva-17478DOI: 10.1038/s41467-019-11139-3ISI: 000475295300003PubMedID: 31300673Scopus ID: 2-s2.0-85068978610OAI: oai:DiVA.org:his-17478DiVA, id: diva2:1338916
Available from: 2019-07-25 Created: 2019-07-25 Last updated: 2019-11-08Bibliographically approved

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Badam, Tejaswi

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