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

Abstract

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:

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.

KEY 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 AND IMPLICATIONS:

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: Qiong Luo, Yang Sun, Fang-Yuan Gong, Wen Liu, Wei Zheng, Yan Shen, Zi-Chun Hua, Qiang Xu
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 171 Issue 7 Pg. 1706-21 (Apr 2014) ISSN: 1476-5381 [Electronic] England
• PMID: 24372081 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The British Pharmacological Society.

Chemical References

• Anti-Inflammatory Agents
• Biomarkers
• Cmkor1 protein, mouse
• Cytokines
• Enzyme Inhibitors
• Myelin-Oligodendrocyte Glycoprotein
• NSC-87877
• Peptide Fragments
• Quinolines
• Receptors, CXCR
• myelin oligodendrocyte glycoprotein (35-55)
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• Ptpn11 protein, mouse

Topics

• Adoptive Transfer
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Biomarkers (blood)
• CD8-Positive T-Lymphocytes (drug effects, enzymology, immunology, transplantation)
• Cells, Cultured
• Chemotaxis, Leukocyte (drug effects)
• Cytokines (blood)
• Encephalomyelitis, Autoimmune, Experimental (chemically induced, enzymology, immunology, prevention & control)
• Enzyme Inhibitors (pharmacology)
• Female
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myelin-Oligodendrocyte Glycoprotein
• Peptide Fragments
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (antagonists & inhibitors, genetics, metabolism)
• Quinolines (pharmacology)
• Receptors, CXCR (drug effects, metabolism)
• Spinal Cord (drug effects, enzymology, immunology)
• Time Factors