title: Oral administration of 1,4-aryl-2-mercaptoimidazole inhibits T-cell proliferation and reduces clinical severity in the murine experimental autoimmune encephalomyelitis model.
abstract: T cells play a pivotal role in the initiation and progression of multiple sclerosis. We have found that 1,4-aryl-2-mercaptoimidazole (KRM-III) inhibited T-cell antigen receptor- and phorbol myristate acetate/ionomycin-induced activation of nuclear factor of activated T cells (NFAT) and T-cell proliferation with an IC(50) of 5 microM. The KRM-III-mediated inhibitory effect was specific for NFAT activation but not for nuclear factor kappaB. Oral administration of 90 mg/kg KRM-III resulted in complete abrogation of anti-CD3 antibody-induced T-cell activation and a 45.8% reduction in footpad swelling in bovine serum albumin-induced delayed-type hypersensitivity. In the murine experimental autoimmune encephalomyelitis (EAE) model, oral administration of KRM-III significantly attenuated the severity of disease when given before or after disease onset. Draining lymph node cells from KRM-III-treated mice showed markedly reduced proliferation in response to myelin oligodendrocyte glycoprotein peptide. Histological analysis indicated that KRM-III reduced the infiltration of inflammatory cells to the white matter of spinal lumbar cords. These results demonstrate that KRM-III efficiently inhibits T-cell activation and inflammatory responses and lessens EAE clinical signs, which suggest KRM-III as a potential lead compound for the treatment of T-cell-driven autoimmune diseases.
authors.affiliation: Molecular Immunology Division, Mogam Biotechnology Research Institute, Yongin, Korea.
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Jung
authors.forename: Minkyu
authors.initials: M
authors.lastname: Hur
authors.forename: Young Lim
authors.initials: YL
authors.lastname: Kim
authors.forename: Ge Hyeong
authors.initials: GH
authors.lastname: Lee
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Kim
authors.forename: Ikyon
authors.initials: I
authors.lastname: Kim
authors.forename: Minwoo
authors.initials: M
authors.lastname: Lee
authors.forename: Ho-Kyun
authors.initials: HK
authors.lastname: Han
authors.forename: Mi-Soon
authors.initials: MS
authors.lastname: Kim
authors.forename: Sejin
authors.initials: S
authors.lastname: Hwang
authors.forename: Sungjoo
authors.initials: S
authors.lastname: Kim
authors.forename: A Mi
authors.initials: AM
authors.lastname: Woo
authors.forename: Yeup
authors.initials: Y
authors.lastname: Yoon
authors.forename: Heon Jin
authors.initials: HJ
authors.lastname: Park
authors.forename: Jonghwa
authors.initials: J
authors.lastname: Won
mesh_terms: D000284:Administration, Oral; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000276:immunology; D019169:Jurkat Cells; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009103:Multiple Sclerosis / Q000276:immunology / Q000517:prevention & control; D050778:NFATC Transcription Factors / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D013871:Thiones / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: C545737:1,4-diphenyl-2-mercaptoimidazole; D007093:Imidazoles; D007155:Immunologic Factors; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D013871:Thiones