Luessi Felix, Kraus Stefan, Trinschek Bettina, Lerch Steffen, Ploen Robert, Paterka Magdalena, Roberg Torsten, Poisa-Beiro Laura, Klotz Luisa, Wiendl Heinz, Bopp Tobias, Jonuleit Helmut, Jolivel Valérie, Zipp Frauke, Witsch Esther
Department of Neurology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany
Department of Neurology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany.
Mult Scler. 2015 Dec;21(14):1811-22. doi: 10.1177/1352458515574895. Epub 2015 Mar 2.
We aimed to clarify whether fingolimod has direct effects on antigen-presenting cells in multiple sclerosis patients.
Frequency and phenotype of directly ex vivo dendritic cells and monocytes were analyzed in 43 individuals, including fingolimod-treated and untreated multiple sclerosis patients as well as healthy subjects. These cells were further stimulated with lipopolysaccharide to determine functional effects of fingolimod treatment.
Absolute numbers of CD1c+ dendritic cells and monocytes were not significantly reduced in fingolimod-treated patients indicating that fingolimod did not block the migration of antigen-presenting cells to peripheral blood. CD86 was upregulated on CD1c+ dendritic cells and thus their activation was not impaired under fingolimod treatment. Quantitative analyses of gene transcription in cells and protein content in supernatants from ex vivo CD1c+ dendritic cells and monocytes, however, showed lower secretion of TNFα, IL1-β and IL-6 upon lipopolysaccharide-stimulation. These results could be matched with CD4+MOG-specific transgenic T cells exhibiting reduced levels of TNFα and IFN-γ but not IL-4 upon stimulation with murine dendritic cells loaded with MOG, when treated with fingolimod.
Our data indicate that fingolimod - apart from trapping lymphocytes in lymph nodes - exerts its disease-modulating activity by rebalancing the immune tolerance networks by modulation of antigen-presenting cells.
我们旨在阐明芬戈莫德是否对多发性硬化症患者的抗原呈递细胞有直接作用。
分析了43名个体直接离体的树突状细胞和单核细胞的频率及表型，其中包括接受芬戈莫德治疗和未接受治疗的多发性硬化症患者以及健康受试者。用脂多糖进一步刺激这些细胞，以确定芬戈莫德治疗的功能效果。
接受芬戈莫德治疗的患者中，CD1c⁺树突状细胞和单核细胞的绝对数量没有显著减少，这表明芬戈莫德并未阻断抗原呈递细胞向外周血的迁移。CD1c⁺树突状细胞上的CD86上调，因此在芬戈莫德治疗下其激活并未受损。然而，对离体CD1c⁺树突状细胞和单核细胞的细胞基因转录及上清液中蛋白质含量的定量分析显示，脂多糖刺激后TNFα、IL1-β和IL-6的分泌较低。当用芬戈莫德处理时，这些结果与用负载髓鞘少突胶质细胞糖蛋白（MOG）的鼠树突状细胞刺激后，CD4⁺MOG特异性转基因T细胞表现出TNFα和IFN-γ水平降低但IL-4水平未降低的情况相符。
我们的数据表明，芬戈莫德除了将淋巴细胞滞留在淋巴结中外，还通过调节抗原呈递细胞来重新平衡免疫耐受网络，从而发挥其疾病调节活性。
