Journal
MULTIPLE SCLEROSIS JOURNAL
Volume 24, Issue 6, Pages 728-738Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1177/1352458517707069
Keywords
Dimethyl fumarate; multiple sclerosis; immunology; disease-modifying therapy
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Funding
- pilot grant from the National MS Society [PP-1412-02199]
- NIH training grant [UL1 TR000448]
- Sylvia Lawry Fellowship from the National MS Society
- National MS Society [FG-2010A1/2]
- Manny & Rosalyn Rosenthal-Dr. John L. Trotter MS Center Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation
- Harry Weaver Neuroscience Scholar award of the National MS Society [JF 2144A2/1]
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR001863, UL1TR000448, UL1TR002345] Funding Source: NIH RePORTER
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Background: Dimethyl fumarate (DMF) is used to treat relapsing multiple sclerosis and causes lymphopenia in a subpopulation of treated individuals. Much remains to be learned about how the drug affects B- and T-lymphocytes. Objectives: To characterize changes in B- and T-cell phenotype and function induced by DMF and to investigate whether low absolute lymphocyte count (ALC) is associated with unique functional changes. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from DMF-treated patients, untreated patients, and healthy controls. A subset of DMF-treated patients was lymphopenic (ALC<800). Multiparametric flow cytometry was used to evaluate cellular phenotypes. Functional response to non-specific and viral peptide stimulation was assessed. Results: DMF reduced circulating memory B-cells regardless of ALC. Follicular T-helper cells (CD4(+) CXCR5(+)) and mucosal invariant T-cells (CD8(+) CD161(+)) were also reduced. DMF reduced T-cell production of pro-inflammatory cytokines in response to polyclonal (PMA/ionomycin) and viral peptide stimulation, regardless of ALC. No differences in activation-induced cell death or circulating progenitors were observed between lymphopenic and non-lymphopenic DMF-treated patients. Conclusion: These data implicate DMF-induced changes in lymphocytes as an important component of the drug's efficacy and expand our understanding of the functional significance of DMF-induced lymphopenia.
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