title: A reversible S-adenosyl-L-homocysteine hydrolase inhibitor ameliorates experimental autoimmune encephalomyelitis by inhibiting T cell activation.
abstract: 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.
authors.affiliation: 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.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Fu
authors.forename: Yi-Na
authors.initials: YN
authors.lastname: Zhu
authors.forename: Jia
authors.initials: J
authors.lastname: Ni
authors.forename: Xiang-Gen
authors.initials: XG
authors.lastname: Zhong
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Yu-Dan
authors.initials: YD
authors.lastname: Re
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Shi
authors.forename: Jin
authors.initials: J
authors.lastname: Wan
authors.forename: Yi-Fu
authors.initials: YF
authors.lastname: Yang
authors.forename: Chong
authors.initials: C
authors.lastname: Yuan
authors.forename: Fa-Jun
authors.initials: FJ
authors.lastname: Nan
authors.forename: Brian R
authors.initials: BR
authors.lastname: Lawson
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Zuo
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors*; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D002087:Butyrates / Q000627:therapeutic use*; D017252:CD3 Complex / Q000276:immunology; D002453:Cell Cycle / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D002087:Butyrates; D017252:CD3 Complex; D016207:Cytokines; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C509291:methyl 4-(adenin-9-yl)-2-hydroxybutanoate; C445081:myelin oligodendrocyte glycoprotein (35-55); D043383:Adenosylhomocysteinase; D000225:Adenine