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

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, p27(kip-1). Those results provide a rationale for using RAR-alpha agonists as immunosuppressants in human organ transplantation.

journal_name

Int Immunol

journal_title

International immunology

authors

Seino K,Yamauchi T,Shikata K,Kobayashi S,Nagai M,Taniguchi M,Fukao K

doi

10.1093/intimm/dxh066

subject

Has Abstract

pub_date

2004-05-01 00:00:00

pages

665-73

issue

5

eissn

0953-8178

issn

1460-2377

pii

dxh066

journal_volume

16

pub_type

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