Miller David C, Whittington Karen B, Brand David D, Hasty Karen A, Rosloniec Edward F
Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
Arthritis Res Ther. 2016 Jan 12;18:8. doi: 10.1186/s13075-015-0909-6.
Fingolimod (FTY720) is an immunomodulating drug that inhibits sphingosine-1-phosphate binding and blocks T-cell egress from lymph nodes. We analyzed the effect of FTY720 on the autoimmune T- and B-cell response in autoimmune arthritis and studied the mechanisms by which it alters the function of T cells.
Human leukocyte antigen (HLA)-DR1 humanized mice were immunized with type II collagen (CII) and treated with FTY720 three times per week for 3 weeks. Arthritis was evaluated and autoimmune T- and B-cell responses were measured using proliferation assays, enzyme-linked immunosorbent assays, HLA-DR tetramers, and flow cytometry. The functional capacity of regulatory T (Treg) cells from FTY720-treated mice was measured using an in vitro suppression assay, and the role of Treg cells in inhibiting arthritis in FTY720-treated mice was evaluated using mice treated with anti-CD25 to deplete Treg cells.
Treatment with FTY720 delayed the onset of arthritis and significantly reduced disease incidence. FTY720 did not prevent the generation of a CII-specific autoimmune T-cell response in vivo. However, as the treatment continued, these T cells became unresponsive to restimulation with antigen in vitro, and this anergic state was reversed by addition of interleukin 2. Measurements of CD4(+)CD25(+)Foxp3(+) cells in the lymph nodes revealed that the ratio of Treg to helper T (Th) cells increased twofold in the FTY720-treated mice, and in vitro assays indicated that the regulatory function of these cells was enhanced. That FTY720 stimulation of Treg cells played a major role in arthritis inhibition was demonstrated by a loss of disease inhibition and restitution of the T-cell proliferative function after in vivo depletion of the Treg cells.
While FTY720 affects the recirculation of lymphocytes, its ability to inhibit the development of autoimmune arthritis involves several mechanisms, including the enhancement of Treg cell function by increasing the Treg/Th ratio and increased regulatory function on a per-cell basis. FTY720 did not inhibit the development of the autoimmune T-cell response, but disease inhibition appeared to be mediated by Treg cell-mediated suppression of the CII-specific T cells. These data suggest that specific targeting of Treg cells with FTY720 may be a novel therapy for autoimmunity.
芬戈莫德（FTY720）是一种免疫调节药物，可抑制1-磷酸鞘氨醇结合并阻止T细胞从淋巴结逸出。我们分析了FTY720对自身免疫性关节炎中自身免疫性T细胞和B细胞反应的影响，并研究了其改变T细胞功能的机制。
用II型胶原（CII）免疫人白细胞抗原（HLA）-DR1人源化小鼠，并每周用FTY720治疗3次，持续3周。使用增殖试验、酶联免疫吸附试验、HLA-DR四聚体和流式细胞术评估关节炎，并测量自身免疫性T细胞和B细胞反应。使用体外抑制试验测量FTY720处理小鼠的调节性T（Treg）细胞的功能能力，并使用抗CD25处理以耗尽Treg细胞的小鼠评估Treg细胞在抑制FTY720处理小鼠关节炎中的作用。
FTY720治疗延迟了关节炎的发作并显著降低了疾病发病率。FTY720并未阻止体内CII特异性自身免疫性T细胞反应的产生。然而，随着治疗的持续，这些T细胞在体外对抗原再刺激变得无反应，并且通过添加白细胞介素2可逆转这种无反应状态。对淋巴结中CD4(+)CD25(+)Foxp3(+)细胞的测量显示，FTY720处理小鼠中Treg与辅助性T（Th）细胞的比例增加了两倍，体外试验表明这些细胞的调节功能增强。体内耗尽Treg细胞后疾病抑制丧失和T细胞增殖功能恢复，证明了FTY720刺激Treg细胞在关节炎抑制中起主要作用。
虽然FTY720影响淋巴细胞的再循环，但其抑制自身免疫性关节炎发展的能力涉及多种机制，包括通过增加Treg/Th比例增强Treg细胞功能以及在单个细胞基础上增强调节功能。FTY720并未抑制自身免疫性T细胞反应的发展，但疾病抑制似乎是由Treg细胞介导的对CII特异性T细胞的抑制介导的。这些数据表明，用FTY720特异性靶向Treg细胞可能是一种治疗自身免疫性疾病的新方法。
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