The CII-specific autoimmune T-cell response develops in the presence of FTY720 but is regulated by enhanced Treg cells that inhibit the development of autoimmune arthritis.
The CII-specific autoimmune T-cell response develops in the presence of FTY720 but is regulated by enhanced Treg cells that inhibit the development of autoimmune arthritis.
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DOI：
10.1186/s13075-015-0909-6
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发表时间：
2016-01-12
影响因子：
4.9
通讯作者：
Rosloniec EF
中科院分区：
文献类型：
--
作者：
Miller DC;Whittington KB;Brand DD;Hasty KA;Rosloniec EF
Fingolimod（FTY 720）是一种免疫调节药物，可抑制鞘氨醇-1-磷酸结合并阻断T细胞从淋巴结中排出。我们分析了FTY 720对自身免疫性关节炎中自身免疫T细胞和B细胞应答的影响，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）-DR 1人源化小鼠，并用FTY 720每周处理三次，持续3周。关节炎进行了评估和自身免疫T细胞和B细胞反应进行了测量，使用增殖试验，酶联免疫吸附试验，HLA-DR四聚体，流式细胞术。使用体外抑制测定来测量来自FTY 720处理的小鼠的调节性T（Treg）细胞的功能能力，并且使用用抗CD 25处理以耗尽Treg细胞的小鼠来评估Treg细胞在FTY 720处理的小鼠中抑制关节炎的作用。FTY 720治疗延迟了关节炎的发作，并显著降低了疾病的发病率。FTY 720不能阻止体内CII特异性自身免疫T细胞应答的产生。然而，随着治疗的继续，这些T细胞在体外对抗原的再刺激变得无反应，并且这种无反应性状态通过加入白细胞介素2而逆转。对淋巴结中CD 4 + CD 25 + Foxp 3+细胞的测量显示，在FTY 720处理的小鼠中Treg与辅助性T（Th）细胞的比率增加了两倍，并且体外测定表明这些细胞的调节功能增强。体内耗尽Treg细胞后，疾病抑制作用丧失和T细胞增殖功能恢复，证明FTY 720对Treg细胞的刺激在关节炎抑制中发挥了重要作用。虽然FTY 720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几种机制，包括通过增加Treg/Th比率来增强Treg细胞功能和增加每个细胞的调节功能。FTY 720不抑制自身免疫性T细胞应答的发展，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FTY 720特异性靶向Treg细胞可能是用于自身免疫的新疗法。本文的在线版本（doi：10.1186/s13075-015-0909-6）包含补充材料，可供授权用户使用。
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. The online version of this article (doi:10.1186/s13075-015-0909-6) contains supplementary material, which is available to authorized users.