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Blocking initial infiltration of pioneer CD 8 + T ‐cells into the CNS via inhibition of SHP ‐2 ameliorates experimental autoimmune encephalomyelitis in mice
Author(s) -
Luo Qiong,
Sun Yang,
Gong FangYuan,
Liu Wen,
Zheng Wei,
Shen Yan,
Hua ZiChun,
Xu Qiang
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12565
Subject(s) - experimental autoimmune encephalomyelitis , myelin oligodendrocyte glycoprotein , adoptive cell transfer , t cell , chemistry , protein tyrosine phosphatase , encephalomyelitis , chemokine , microbiology and biotechnology , immunology , biology , receptor , immune system , multiple sclerosis , biochemistry
Background and Purpose In 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 Approach C 57 BL /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 Results NSC‐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 CXCR 7 on CD 8 + T ‐cells. Adoptive transfer of T ‐cells from 2 D 2‐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 Implications NSC ‐87877 almost completely abolished the development of EAE by blocking the initial infiltration of pioneer CD 8 + 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.