Blocking initial infiltration of pioneer CD8+T‐cells into the CNS via inhibition of SHP‐2 ameliorates experimental autoimmune encephalomyelitis in mice

Qiong Luo; Yi Sun; Fang‐Yuan Gong; Wen Liu; Wei Zheng; Yan Shen; Zi‐Chun Hua; Qiang Xu

doi:10.1111/bph.12565

journal article Mar 18, 2014

Blocking initial infiltration of pioneer CD8+T‐cells into the CNS via inhibition of SHP‐2 ameliorates experimental autoimmune encephalomyelitis in mice

Qiong Luo

Yi Sun

Fang‐Yuan Gong Wen Liu

Wei Zheng

Yan Shen

Zi‐Chun Hua Qiang Xu

British Journal of Pharmacology Vol. 171 No. 7 pp. 1706-1721 · Wiley

View at Publisher Save 10.1111/bph.12565

Abstract

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 glycoprotein35–55 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 TH1 and TH17 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.

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Published: Mar 18, 2014
Vol/Issue: 171(7)
Pages: 1706-1721
License: View

Authors

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Qiong Luo