Prevention of acute and chronic allograft rejection by a novel retinoic acid receptor-alpha-selective agonist.
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.
Seino
Ken-ichiro
K
RIKEN Research Center for Allergy and Immunology, Yokohama-City, Kanagawa 230-0045, Japan. seinok@rcai.riken.jp
Yamauchi
Toshihiko
T
Shikata
Kohdoh
K
Kobayashi
Seiichi
S
Nagai
Mitsuo
M
Taniguchi
Masaru
M
Fukao
Katashi
K
D000208:Acute Disease; D000818:Animals; D001162:Arteriosclerosis Obliterans / Q000188:drug therapy; D002908:Chronic Disease; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D016207:Cytokines / Q000276:immunology; D005663:Furans / Q000627:therapeutic use*; D006082:Graft Enhancement, Immunologic; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D011758:Pyrroles / Q000627:therapeutic use*; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000494:pharmacology; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
C108573:CdkI-p30 protein, Cricetulus griseus; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D016207:Cytokines; D005663:Furans; D008869:Microtubule-Associated Proteins; D011758:Pyrroles; C000607071:RARA protein, human; C000607072:Rara protein, mouse; C000607073:Rara protein, rat; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; C406083:ER 38925