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International Immunology Advance Access originally published online on March 29, 2004
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International Immunology, Vol. 16, No. 5, pp. 665-673, May 2004
© 2004 Japanese Society for Immunology

FEATURED ARTICLE OF THE MONTH

Prevention of acute and chronic allograft rejection by a novel retinoic acid receptor-{alpha}-selective agonist

Ken-ichiro Seino1,2,3, Toshihiko Yamauchi4, Kohdoh Shikata4, Seiichi Kobayashi5, Mitsuo Nagai4, Masaru Taniguchi1,6 and Katashi Fukao3

1 RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan 2 PRESTO, JST, Kawaguchi, Saitama 332-0012, Japan 3 Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8575, Japan 4 Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki 300-2635, Japan 5 Eisai Research Institute, Eisai Co., Ltd, 100 Research Drive, Wilmington, MA 01887, USA 6 Department of Molecular Immunology, Chiba University, Chiba 260-8670, Japan

Correspondence to: K.-i. Seino, Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi, Yokohama-City, Kanagawa 230-0045, Japan. E-mail: seinok{at}rcai.riken.jp
Transmitting editor: K. Okumura

To investigate the involvement of retinoic acid receptor (RAR)-{alpha} in allograft rejection, we investigated the effect of a novel selective agonist to the receptor, ER-38925, in a mouse cardiac allograft model. Prophylactic treatment with ER-38925 inhibited the acute rejection of the mouse cardiac allograft (BALB/c -> C3H/HeN) at 0.3 and 3 mg/kg, and its effect was enhanced in combination with tacrolimus. In this model, ER-38925 remarkably inhibited cytotoxic T lymphocyte induction and alloantigen-stimulated production of cytokines, i.e. IL-2, IL-12 and IFN-{gamma}. In the chronic rejection model, combined treatment with tacrolimus and ER-38925 reduced the grade and incidence of arteriosclerosis in the cardiac allografts significantly more potently than tacrolimus monotherapy. ER-38925 inhibited the proliferation of rat aortic smooth muscle cells stimulated in vitro, presumably through the induction of a cyclin-dependent kinase inhibitor, p27kip-1. Those results provide a rationale for using RAR-{alpha} agonists as immunosuppressants in human organ transplantation.

Keywords: arteriosclerosis, cell differentiation, retinoid, Th1/Th2, transplantation


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