Progression of type 1 diabetes from the prediabetic stage is controlled by interferon-α signaling
Progression of type 1 diabetes from the prediabetic stage is controlled by interferon-α signaling
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DOI：
10.1073/pnas.1700878114
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发表时间：
2017-04-04
影响因子：
11.1
通讯作者：
Oldstone, Michael B. A.
中科院分区：
文献类型：
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作者：
Marro, Brett S.;Ware, Brian C.;Oldstone, Michael B. A.
在小鼠 Rip-LCMV T1D 模型中，使用抗体或选择性 S1PR1 激动剂 CYM-5442 阻断 IFN-α 而不是 IFN-β 信号传导可预防 1 型糖尿病 (T1D)。首先，用抗体或 CYM-5442 治疗限制了自身免疫“抗自身”T 细胞迁移到胰岛周围的外部边界，并阻止它们进入胰岛，因此它们无法定位以接合、杀死并从而去除产生胰岛素的 β 细胞。其次，CYM-5442 通过上调负性免疫调节受体基因 Pdcd1、Lag3、Ctla4、Tigit 和 Btla 来诱导抗自身 T 细胞衰竭，从而限制其杀伤能力。通过这种方式，胰岛素的产生得以保留，葡萄糖调节得以维持，并描述了 S1PR1 免疫调节的机制。
Blockade of IFN-alpha but not IFN-beta signaling using either an antibody or a selective S1PR1 agonist, CYM-5442, prevented type 1 diabetes (T1D) in the mouse Rip-LCMV T1D model. First, treatment with antibody or CYM-5442 limited the migration of autoimmune "anti-self" T cells to the external boundaries around the islets and prevented their entry into the islets so they could not be positioned to engage, kill, and thus remove insulin-producing beta cells. Second, CYM-5442 induced an exhaustion signature in antiself T cells by up-regulating the negative immune regulator receptor genes Pdcd1, Lag3, Ctla4, Tigit, and Btla, thereby limiting their killing ability. By such means, insulin production was preserved and glucose regulation maintained, and a mechanism for S1PR1 immunomodulation described.