Inhibition of transplant vasculopathy in a rat aortic allograft model after infusion of anti-inflammatory viral serpin

Background-Transplant vasculopathy remains a difficult therapeutic problem, resulting in the majority of late cardiac graft losses. This chronic vascu lar disease is thought to be triggered by alloantigen-dependent and alloant igen-independent inflammatory factors. Despite improved I-year survival, th e incidence of transplant vasculopathy has not improved with current immuno suppressive protocols. Highly effective strategies have evolved in the larg e DNA viruses that shield infecting viruses from host inflammatory response s. Serp-1 is a secreted myxoma virus anti-inflammatory serine proteinase in hibitor. Serp-1 inhibits plasminogen activators in a manner similar to plas minogen activator inhibitor (PAI-I), a vascular protein that plays a pivota l regulatory role in vascular wound healing. In this study, we tested the a bility of purified Serp-1 protein to ameliorate posttransplant vasculopathy after rat aortic allograft surgery. Methods and Results-Serp-1 protein or controls were infused into 98 rats im mediately after segmental aortic allograft transplantation. After either la te (28 days, 64 rats) or early (12 to 48 hours, 24 rats) follow-up, transpl anted aortic segments were harvested for morphological and immunohistochemi cal analysis. Significant reductions in intimal plaque growth (P<0.002) and mononuclear cell invasion (P<0.033) were detected after Serp-1 infusion at nanogram doses. Serp-1 reduced early macrophage (P<0.0016) and nonspecific lymphocyte (P<0.0179) invasion into medial and adventitial layers and inhi bited associated depletion of medial smooth muscle cells (P<0.0006). Conclusions-Infusion of a viral anti-inflammatory serpin, Serp-1, significa ntly reduces early inflammatory responses and later luminal occlusion in a rat aortic allograft model.