SEROTONIN RECEPTOR ANTAGONIST INDUCES INDEFINITE SURVIVAL OF FULLY-ALLOGENEIC CARDIAC GRAFTS.

Abstract

P1118 Aims: Sarpogrelate hydrochloride, a serotonin receptor antagonist, is used clinically as an antithrombotic agent for peripheral arterial disease. It has also been reported that sarpogrelate hydrochloride possesses a potential to inhibit O2- production by neutrophils in vitro models. We investigated whether sarpogrelate hydrochloride could induce unresponsiveness to fully-mismatched cardiac graft in mice. Methods: CBA (H2k) mice underwent heterotopic cardiac transplantation on day 0 from C57BL/10 (H2b) donors using microsurgical technique. The CBA recipients were left untreated or treated with 10mg/kg of sarpogrelate hydrochloride from day 0 through day 7. To examine the mechanisms, adoptve transfer study was performed. Hundred days after heterotopic cardiac transplantation, 50x106 splenocytes of the treated recipients with functioning graft were adoptively transferred into naive CBA mice (secondary recipients), and then C57BL/10 hearts were transplanted into the secondary recipients on the same day. Histological examination of the allografts and mixed leukocyte culture analysis were also performed. Results: Naive CBA mouse rejected C57BL/10 cardiac grafts acutely (median survival time [MST], 8 days). The treatment with sarpogrelate hydrochloride induced indefinite graft survival (MST, >100 days). Histological examinations of grafts at 30 days after transplantation did not show any signs of acute rejection in the recipients treated with sarpogrelate hydrochloride. In the adoptive transfer study, majority of the grafts in the secondary recipients enjoyed remarkably prolonged survival (MST, >40 days), suggesting that regulatory cells were generated. In vitro, sarpogrelate hydrochloride suppressed cellular proliferation in mixed leukocyte reaction. Conclusion: The treatment with sarpogrelate hydrochloride induced indefinite survival of cardiac grafts and generated regulatory cells. Sarpogrelate hydrochloride can be not only an antithrombotic agent but also a strong immunomodulating agent.