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

Tumor necrosis factor-a (TNF-a) 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-a (R1antTNF) and shown that R1antTNF efficiently inhibits TNF-a/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 sub(4)) or concanavalin A (ConA). In a CCl sub(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-a antibody therapy. Our results suggest that R1antTNF may be a clinically useful TNF-a antagonist in hepatitis.