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

• Published in: International immunology 2004-03, Vol.16 (5), p.665-673
• Main Author: Seino, K.-i.
• Format: Article
• Language: English
• ISSN: 1460-2377; 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxh066

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 [Right arrow] 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.