The therapeutic effect of TNFR1-selective antagonistic mutant TNF-alpha in murine hepatitis models

Cytokine. 2008 Nov;44(2):229-33. doi: 10.1016/j.cyto.2008.07.003. Epub 2008 Sep 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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