Journal
JOURNAL OF IMMUNOLOGY
Volume 198, Issue 8, Pages 3069-3080Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1601532
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Funding
- National Institutes of Health/National Institute of Allergy and Infectious Diseases [R03-AI105029, R21-AI115117]
- Autoimmune Center of Excellence [UM1-AI110557]
- National Institutes of Health/National Institute of Allergy and Infectious Diseases Autoimmune Center of Excellence [UM1-AI110557]
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01-NS080821]
- University of Michigan Department of Neurology
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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-gamma 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.
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