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International Immunology Advance Access published online on March 29, 2004
International Immunology, doi:10.1093/intimm/dxh066
© 2004 by The Japanese Society for Immunology
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Received July 28, 2003
Accepted February 4, 2004

Article

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

Ken-ichiro Seino 1*, Toshihiko Yamauchi 2, Kohdoh Shikata 2, Seiichi Kobayashi 3, Mitsuo Nagai 2, Masaru Taniguchi 4, Katashi Fukao 5

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

* To whom correspondence should be addressed. E-mail: seinok{at}rcai.riken.jp.


  Abstract

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


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