title: The therapeutic effect of TNFR1-selective antagonistic mutant TNF-alpha in murine hepatitis models.
abstract: Tumor necrosis factor-alpha (TNF-alpha) is critically involved in a wide variety of inflammatory pathologies, such as hepatitis, via the TNF receptor-1 (TNFR1). To develop TNFR1-targeted anti-inflammatory drugs, we have already succeeded in creating a TNFR1-selective antagonistic mutant TNF-alpha (R1antTNF) and shown that R1antTNF efficiently inhibits TNF-alpha/TNFR1-mediated biological activity in vitro. In this study, we examined the therapeutic effect of R1antTNF in acute hepatitis using two independent experimental models, induced by carbon tetrachloride (CCl(4)) or concanavalin A (ConA). In a CCl(4)-induced model, treatment with R1antTNF significantly inhibited elevation in the serum level of ALT (alanine aminotransferase), a marker for liver damage. In a ConA-induced T-cell-mediated hepatitis model, R1antTNF also inhibited the production of serum immune activated markers such as IL-2 and IL-6. These R1antTNF-mediated therapeutic effects were as good as or better than those obtained using conventional anti-TNF-alpha antibody therapy. Our results suggest that R1antTNF may be a clinically useful TNF-alpha antagonist in hepatitis.
authors.affiliation: Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shibata
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yoshioka
authors.forename: Akiko
authors.initials: A
authors.lastname: Ohkawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Abe
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nomura
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mukai
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Madoka
authors.initials: M
authors.lastname: Taniai
authors.forename: Tsunetaka
authors.initials: T
authors.lastname: Ohta
authors.forename: Tadanori
authors.initials: T
authors.lastname: Mayumi
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Kamada
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tsunoda
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Tsutsumi
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology; D002460:Cell Line; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D006520:Hepatitis, Animal / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D016207:Cytokines; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D002251:Carbon Tetrachloride; D000410:Alanine Transaminase