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: Hiroko Shibata, Yasuo Yoshioka, Akiko Ohkawa, Yasuhiro Abe, Tetsuya Nomura, Yohei Mukai, Shinsaku Nakagawa, Madoka Taniai, Tsunetaka Ohta, Tadanori Mayumi, Haruhiko Kamada, Shin-ichi Tsunoda, Yasuo Tsutsumi
• Journal: Cytokine (Cytokine) Vol. 44 Issue 2 Pg. 229-33 (Nov 2008) ISSN: 1096-0023 [Electronic] England
• PMID: 18815054 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Receptors, Tumor Necrosis Factor, Type I
• Tumor Necrosis Factor-alpha
• Concanavalin A
• Carbon Tetrachloride
• Alanine Transaminase

Topics

• Alanine Transaminase (blood)
• Animals
• Carbon Tetrachloride (pharmacology)
• Cell Line
• Concanavalin A (pharmacology)
• Cytokines (blood)
• Disease Models, Animal
• Female
• Hepatitis, Animal (blood, chemically induced, drug therapy, immunology)
• Humans
• Mice
• Mice, Inbred BALB C
• Receptors, Tumor Necrosis Factor, Type I (antagonists & inhibitors, metabolism)
• Tumor Necrosis Factor-alpha (metabolism, therapeutic use)