Dimethyl fumarate induces changes in B- and T-lymphocyte function independent of the effects on absolute lymphocyte count

Mult Scler. 2018 May;24(6):728-738. doi: 10.1177/1352458517707069. Epub 2017 May 8.

Abstract

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.

Keywords: Dimethyl fumarate; disease-modifying therapy; immunology; multiple sclerosis.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • B-Lymphocytes / drug effects*
  • Cross-Sectional Studies
  • Dimethyl Fumarate / therapeutic use*
  • Female
  • Humans
  • Immunosuppressive Agents / therapeutic use*
  • Lymphocyte Count
  • Lymphopenia / chemically induced
  • Male
  • Middle Aged
  • Multiple Sclerosis, Relapsing-Remitting / drug therapy*
  • Multiple Sclerosis, Relapsing-Remitting / immunology
  • T-Lymphocytes / drug effects*

Substances

  • Immunosuppressive Agents
  • Dimethyl Fumarate