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INFLAMMATION AND IMMUNOPHARMACOLOGY

Effect of E6060 [4-{5-[7-Fluoro-4-(trifluoromethyl)benzo[b]furan-2-yl]-1H-2-pyrrolyl}benzoic Acid], a Novel Subtype-Selective Retinoid, on Lupus-Like Nephritis in Female (NZBxNZW)F1 Mice

Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba Science City, Ibaraki, Japan (T.Y., A.I., K.S., N.T., M.N.); RIKEN Research Center for Allergy and Immunology, Suehiro-cho, Tsurumi, Yokohama, Kanagawa, Japan (K.-i.S.); Precursory Research for Embryonic Science and Technology, Japan Science and Technology, Kawaguchi, Saitama, Japan (K.-i.S.); and Eisai Research Institute, Eisai Co., Ltd., Wilmington, Massachusetts (S.K.)

Disease amelioration by retinoids in various nephritic models has been reported from either immunological or pathophysiologic viewpoints. It has also been reported that retinoids exert immunosuppressive effects in a retinoic acid receptor (RAR)--dependent manner. In particular, synthetic retinoid agonists with selectivity to RAR- have been reported to have a remarkable disease-ameliorating effect in some immune disease models via their potent immunosuppressive activities; however, there has been no report in which the effect of RAR--selective agonists in the nephritic models was examined. In this report, we investigated the effect of a newly synthesized RAR--selective retinoid agonist, E6060 [4-{5-[7-fluoro-4-(trifluoromethyl)benzo[b]furan-2-yl]-1H-2-pyrrolyl}benzoic acid], on the disease progression in a murine lupus nephritis model. Female (NZBxNZW)F1 mice were prophylactically treated with E6060 from 5 months of age, and their nephritic (proteinuria, blood urea nitrogen) and immunological parameters (serum anti-DNA autoantibodies and total serum immunoglobulins) were monitored with age up to 10 months old. E6060 at 0.03 and 0.1 mg/kg (once daily, p.o.) significantly improved survival rate and prevented the development of proteinuria in (NZBxNZW)F1 mice. Anti-DNA autoantibodies and total serum IgG were also significantly reduced in the E6060-treated mice. Among IgG isotypes, IgG2a was substantially reduced by E6060 treatment, indicating reduced T helper 1 responses in E6060-treated mice. In accordance with this possibility, elevation of serum interleukin-12 (p40) in old female (NZBxNZW)F1 mice was significantly inhibited by E6060 treatment. Our data suggest that the RAR--selective retinoid E6060 is a promising candidate of new remedy for lupus nephritis in systemic lupus erythematosus patients.

Address correspondence to: Dr. Toshihiko Yamauchi, Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba Science City, Ibaraki, 300-2635, Japan. E-mail: t-yamauchi{at}hhc.eisai.co.jp