Drug Discov Ther. 2008;2(1):35-44.
Immunosuppressive effect of ER-38925, a retinoic acid receptor subtype α-selective agonist, in mouse models of human graft-vs-host disease.
Hida T, Shikata K, Tokuhara N, Ishibashi A, Nagai M, Yamauchi T, Kobayashi S
Graft-vs-host disease (GVHD) is a devastating disorder that determines the prognosis of patients who receive a bone marrow transplant. GVHD is caused by donor cells responding to host disparate MHC alleles. In this report, we demonstrate that ER-38925, a newly discovered retinoid agonist with selectivity to retinoic acid receptor subtype α (RAR-α), is a potent immunosuppressive agent in mouse models of human GVHD. In a mouse model of lethal acute GVHD (aGVHD), ER-38925 prolonged the lifespan of the recipient mice in a dose-dependent manner. Its effect at 1 mg/kg was almost comparable to that of cyclosporin A at 30 mg/kg. ER-38925 profoundly prevented the development of antiallogeneic cytotoxic T lymphocyte (CTL) response in the mouse model of aGVHD at 0.1 and 0.3 mg/kg. It strongly inhibited in vitro proliferation of alloantigenstimulated donor T lymphocytes, and RAR-α seemed to play an exclusive role in this effect since inhibition by all-trans retinoic acid, which can activate all subtypes of RAR, was completely reversed by an RAR-α selective antagonist. Moreover, it significantly inhibited the elevation of serum IL-12 and IFN-γ and LPS-induced serum TNF-α elevation, all of which are known to be crucial disease-exacerbating factors in this model and human GVHD, in the mouse model of aGVHD. These results suggest that ER-38925 prevents the development of aGVHD through substantial inhibition of anti-allogeneic responses of donor T lymphocytes. In addition, in vivo administration of ER-38925 also blocked serum anti-DNA autoantibody production in a mouse model of human chronic GVHD. This is the first report to clearly show the remarkable immunosuppressive effects of an RAR-α selective agonist in mouse models of human GVHD. These findings may allow an RAR-α selective agonist like ER-38925 to serve as a novel therapy to prevent both acute and chronic types of human GVHD.