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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

A Reversible S-Adenosyl-L-Homocysteine Hydrolase Inhibitor Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibiting T Cell Activation

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China (Y.-F.F., Y.-N.Z., J.N., X.-G.Z., W.T., Y.-D.R., L.-P.S., J.W., Y.-F.Y., F.-J.N., J.-P.Z.); Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China (J.-P.Z.); and Diazyme Laboratories Division General Atomics, San Diego, California (C.Y., B.R.L.)

The reversible S-adenosyl-L-homocysteine hydrolase inhibitor DZ2002 [methyl 4-(adenin-9-yl)-2-hydroxybutanoate] suppresses antigen-induced-specific immune responses, particularly type 1 helper T cell (Th1)-type responses. Experimental autoimmune encephalomyelitis (EAE) is thought to be a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of human multiple sclerosis (MS). In this study, we examined the effects of DZ2002 on active EAE induced by myelin oligodendrocyte glycoprotein (MOG) 35-55 in female C57BL/6 mice. Administration of DZ2002 (50 mg/kg/day i.p.) significantly reduced the incidence and severity of EAE, which was associated with the inhibition of MOG35-55-specific T cell proliferation and Th1-type cytokine production. In vitro studies also demonstrated that DZ2002 inhibited anti-CD3/28-induced naive T cell activation concomitant with the down-regulation of cyclin-dependent kinase (CDK) 4, CDK6, cyclin D3, and the up-regulation or protection of the CDK inhibitor p27. These findings highlight the fact that DZ2002 likely prevents EAE by suppressing T cell activation and suggest its utility in the treatment of MS and other Th1-mediated inflammatory diseases.

Address correspondence to: Dr. Jian-Ping Zuo, Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, People's Republic of China. E-mail: jpzuo{at}mail.shcnc.ac.cn

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