title: Dimethyl Fumarate Selectively Reduces Memory T Cells and Shifts the Balance between Th1/Th17 and Th2 in Multiple Sclerosis Patients.
abstract: Dimethyl fumarate (DMF; trade name Tecfidera) is an oral formulation of the fumaric acid ester that is Food and Drug Administration approved for treatment of relapsing-remitting multiple sclerosis. To better understand the therapeutic effects of Tecfidera and its rare side effect of progressive multifocal leukoencephalopathy, we conducted cross-sectional and longitudinal studies by immunophenotyping cells from peripheral blood (particularly T lymphocytes) derived from untreated and 4-6 and 18-26 mo Tecfidera-treated stable relapsing-remitting multiple sclerosis patients using multiparametric flow cytometry. The absolute numbers of CD4 and CD8 T cells were significantly decreased and the CD4/CD8 ratio was increased with DMF treatment. The proportions of both effector memory T cells and central memory T cells were reduced, whereas naive T cells increased in treated patients. T cell activation was reduced with DMF treatment, especially among effector memory T cells and effector memory RA T cells. Th subsets Th1 (CXCR3+), Th17 (CCR6+), and particularly those expressing both CXCR3 and CD161 were reduced most significantly, whereas the anti-inflammatory Th2 subset (CCR3+) was increased after DMF treatment. A corresponding increase in IL-4 and decrease in IFN-γ and IL-17-expressing CD4+T cells were observed in DMF-treated patients. DMF in vitro treatment also led to increased T cell apoptosis and decreased activation, proliferation, reactive oxygen species, and CCR7 expression. Our results suggest that DMF acts on specific memory and effector T cell subsets by limiting their survival, proliferation, activation, and cytokine production. Monitoring these subsets could help to evaluate the efficacy and safety of DMF treatment.
authors.affiliation: Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Guangmei
authors.identifier: 0000-0001-7840-3035
authors.initials: G
authors.lastname: Mao
authors.affiliation: Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Dowling
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109; and.|Graduate Program in Immunology, Program in Biomedical Sciences, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Lundy
authors.affiliation: Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109; maodraay@umich.edu.|Graduate Program in Immunology, Program in Biomedical Sciences, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Yang
authors.initials: Y
authors.lastname: Mao-Draayer
mesh_terms: D000328:Adult; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003430:Cross-Sectional Studies; D000069462:Dimethyl Fumarate / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects* / Q000276:immunology; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008137:Longitudinal Studies; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D000069462:Dimethyl Fumarate