Wu Qi, Wang Qin, Mao Guangmei, Dowling Catherine A, Lundy Steven K, Mao-Draayer Yang
Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109.
Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109; and.
J Immunol. 2017 Apr 15;198(8):3069-3080. doi: 10.4049/jimmunol.1601532. Epub 2017 Mar 3.
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.
富马酸二甲酯（DMF；商品名泰法米司）是一种富马酸酯的口服制剂，已获美国食品药品监督管理局批准用于治疗复发缓解型多发性硬化症。为了更好地了解泰法米司的治疗效果及其罕见的进行性多灶性白质脑病副作用，我们通过多参数流式细胞术对未经治疗以及接受泰法米司治疗4 - 6个月和18 - 26个月的稳定复发缓解型多发性硬化症患者外周血中的细胞（特别是T淋巴细胞）进行免疫表型分析，开展了横断面和纵向研究。使用DMF治疗后，CD4和CD8 T细胞的绝对数量显著减少，CD4/CD8比值增加。效应记忆T细胞和中枢记忆T细胞的比例均降低，而在接受治疗的患者中幼稚T细胞增加。DMF治疗可降低T细胞活化，尤其是在效应记忆T细胞和效应记忆RA T细胞中。Th亚群Th1（CXCR3）、Th17（CCR6），特别是同时表达CXCR3和CD161的亚群减少最为显著，而抗炎性Th2亚群（CCR3）在DMF治疗后增加。在接受DMF治疗的患者中，观察到IL - 4相应增加，表达IFN - γ和IL - 17的CD4 T细胞减少。DMF体外治疗还导致T细胞凋亡增加，活化、增殖、活性氧生成及CCR7表达减少。我们的结果表明，DMF通过限制特定记忆和效应T细胞亚群的存活、增殖、活化及细胞因子产生来发挥作用。监测这些亚群有助于评估DMF治疗的疗效和安全性。
