title: Blocking initial infiltration of pioneer CD8(+) T-cells into the CNS via inhibition of SHP-2 ameliorates experimental autoimmune encephalomyelitis in mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  C57BL/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.
  
  
  RESULTS
  NSC-87877-treated mice developed conventional TH 1 and TH 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
  NSC-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.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Luo
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Fang-Yuan
authors.initials: FY
authors.lastname: Gong
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.forename: Zi-Chun
authors.initials: ZC
authors.lastname: Hua
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000637:transplantation; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D016207:Cytokines / Q000097:blood; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D054387:Receptors, CXCR / Q000187:drug effects / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; C501897:Cmkor1 protein, mouse; D016207:Cytokines; D004791:Enzyme Inhibitors; D063308:Myelin-Oligodendrocyte Glycoprotein; C512715:NSC-87877; D010446:Peptide Fragments; D011804:Quinolines; D054387:Receptors, CXCR; C445081:myelin oligodendrocyte glycoprotein (35-55); D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse
keywords: CXCR7; EAE; SHP-2; multiple sclerosis; pioneer CD8+ T-cells