Department of Neurology, University Hospitals Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
Neurology. 2010 Aug 3;75(5):403-10. doi: 10.1212/WNL.0b013e3181ebdd64. Epub 2010 Jun 30.
FTY720 is a sphingosine 1-phosphate (S1P) receptor modulator that showed efficacy in phase II and III clinical trials in patients with multiple sclerosis (MS). FTY720 inhibits lymphocyte egress from secondary lymphoid organs into the peripheral circulation, thereby reducing the number of circulating naïve and central memory T cells, but not effector memory T cells in blood. Little is known to which of these memory T-cell subsets interleukin 17 (IL-17)-producing T cells (Th17 cells) belong, which are considered to be key mediators of inflammation in MS, and how they are affected by treatment with FTY720. In this study, we determined the phenotype and frequency of Th17 cells in blood of untreated, FTY720-treated, and interferon-beta (IFNbeta)-treated patients with MS and healthy donors.
In a prospective observational study, circulating T cells were phenotypically characterized and Th17 cells enumerated in T-cell subsets ex vivo. Production of IL-17 upon activation and expression of the Th17-specific transcription factor RORC2 was assessed in vitro.
Th17 cells were found primarily within central memory T cells in all study populations. FTY720 treatment reduced blood central memory T cells, including RORC2+ and IL-17-producing T cells, by >90%. FTY720 did not per se affect IL-17 production when added to activated T cells in vitro.
Phenotypic Th17 cells are defined by a central memory T-cell phenotype. FTY720 reduces these Th17 cells in blood. This is presumably because central memory T cells are retained by FTY720 in secondary lymphoid organs.
FTY720 是一种鞘氨醇 1-磷酸（S1P）受体调节剂，在多发性硬化症（MS）患者的 II 期和 III 期临床试验中显示出疗效。FTY720 抑制淋巴细胞从次级淋巴器官迁出到外周循环，从而减少循环中的幼稚和中央记忆 T 细胞数量，但不影响血液中的效应记忆 T 细胞。目前尚不清楚这些记忆 T 细胞亚群中的哪一种是白细胞介素 17（IL-17）产生的 T 细胞（Th17 细胞），它们被认为是 MS 炎症的关键介质，以及它们如何受到 FTY720 治疗的影响。在这项研究中，我们确定了未经治疗、FTY720 治疗和干扰素-β（IFNbeta）治疗的 MS 患者和健康供体血液中 Th17 细胞的表型和频率。
在一项前瞻性观察性研究中，我们对循环 T 细胞进行表型特征分析，并在体外对 Th17 细胞进行计数。在体外评估激活后 IL-17 的产生和 Th17 特异性转录因子 RORC2 的表达。
在所有研究人群中，Th17 细胞主要存在于中央记忆 T 细胞中。FTY720 治疗使血液中的中央记忆 T 细胞（包括 RORC2+和产生 IL-17 的 T 细胞）减少超过 90%。FTY720 本身不会影响体外激活的 T 细胞中 IL-17 的产生。
表型 Th17 细胞的特征是中央记忆 T 细胞表型。FTY720 减少了血液中的这些 Th17 细胞。这大概是因为中央记忆 T 细胞被 FTY720 保留在次级淋巴器官中。
