The therapeutic effect of TNFR1-selective antagonistic mutant TNF-alpha in murine hepatitis models.
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.
Shibata
Hiroko
H
Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
Yoshioka
Yasuo
Y
Ohkawa
Akiko
A
Abe
Yasuhiro
Y
Nomura
Tetsuya
T
Mukai
Yohei
Y
Nakagawa
Shinsaku
S
Taniai
Madoka
M
Ohta
Tsunetaka
T
Mayumi
Tadanori
T
Kamada
Haruhiko
H
Tsunoda
Shin-ichi
S
Tsutsumi
Yasuo
Y
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*
D016207:Cytokines; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D002251:Carbon Tetrachloride; D000410:Alanine Transaminase