Blocking initial infiltration of pioneer CD8+ T-cells into the CNS via inhibition of SHP-2 ameliorates experimental autoimmune encephalomyelitis in mice
Blocking initial infiltration of pioneer CD8+ T-cells into the CNS via inhibition of SHP-2 ameliorates experimental autoimmune encephalomyelitis in mice
复制标题
通过抑制 SHP-2 阻断先锋 CD8( ) T 细胞最初浸润至中枢神经系统可改善小鼠实验性自身免疫性脑脊髓炎
DOI：
10.1111/bph.12565
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发表时间：
2014-04-01
影响因子：
7.3
通讯作者：
Xu, Qiang
中科院分区：
文献类型：
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作者：
Luo, Qiong;Sun, Yang;Xu, Qiang
背景和目的与外周 T 细胞启动相反，针对 T 细胞转运至 CNS 起始步骤的治疗策略尚未得到广泛研究。在本研究中，我们检测了 NSC-87877（一种有效的含有 Src 同源性 2 的蛋白酪氨酸磷酸酶 2 (SHP-2) 抑制剂）对实验性自身免疫性脑脊髓炎 (EAE) 的作用，并阐明了其独特的作用机制。实验方法用髓磷脂少突胶质细胞糖蛋白 (35-55) 免疫 C57BL/6 小鼠，并监测其临床严重程度中枢神经系统疾病和组织病理学特征。通过酶联免疫吸附测定血清中细胞因子的水平。通过定量 PCR 测定 NSC-87877 对 CNS 趋化因子和细胞因子表达的影响。 主要结果 NSC-87877 治疗的小鼠产生了传统的 T(H)1 和 T(H)17 反应，但对 EAE 的诱导具有高度抵抗力。 NSC-87877 减少 CNS 中淋巴细胞的积累，并增加 CD8+ T 细胞上趋化因子受体 CXCR7 的功能表达。来自 2D2 转基因小鼠的 T 细胞的过继转移恢复了 NSC-87877 治疗小鼠的 EAE 易感性，表明 NSC-87877 仅针对先锋 T 细胞的初始迁移。此外，用 NSC-87877 治疗的 T 细胞条件化 SHP-2 缺陷小鼠不再对 EAE 产生耐药性，这表明 SHP-2 的抑制有助于 NSC-87877 改善 EAE。 结论和意义 NSC-87877 通过阻止先锋 CD8(+) T 细胞最初浸润到未发炎的 CNS 中，几乎完全消除了 EAE 的发展。这些结果揭示了 SHP-2 在调节 EAE 发病机制中的关键作用，并表明 NSC-87877 是治疗复发缓解型多发性硬化症的潜在候选药物。
Background and PurposeIn contrast to T-cell priming in the periphery, therapeutic strategies targeting the initiation step of T-cell trafficking into the CNS have not been extensively investigated. In this study, we examined the effect of NSC-87877, a potent Src homology 2-containing protein tyrosine phosphatase 2 (SHP-2) inhibitor, on experimental autoimmune encephalomyelitis (EAE) and elucidated its unique mechanism of action.Experimental ApproachC57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein(35-55) and monitored for clinical severity of disease and histopathological features in the CNS. Levels of cytokines in serum were measured by elisa. Effects of NSC-87877 on expressions of chemokines and cytokines in the CNS were determined by quantitative PCR.Key ResultsNSC-87877-treated mice developed conventional T(H)1 and T(H)17 responses, but were highly resistant to the induction of EAE. NSC-87877 decreased the accumulation of lymphocytes in the CNS and increased the functional expression of chemokine receptor CXCR7 on CD8(+) T-cells. Adoptive transfer of T-cells from 2D2-transgenic mice restored EAE susceptibility in NSC-87877-treated mice, indicating that NSC-87877 only targets the initial migration of pioneer T-cells. Furthermore, T-cell-conditioned SHP-2-deficient mice treated with NSC-87877 were no longer resistant to EAE, suggesting that inhibition of SHP-2 contributes to the amelioration of EAE by NSC-87877.Conclusions and ImplicationsNSC-87877 almost completely abolished the development of EAE by blocking the initial infiltration of pioneer CD8(+) T-cells into the uninflamed CNS. These results reveal a critical role for SHP-2 in regulating EAE pathogenesis and indicate that NSC-87877 is a potential candidate for the treatment of relapsing-remitting multiple sclerosis.