Functional outcome of discordant xenoislet grafts from a large animal donor after recipient defibrinogenation with ancrod

Abstract

E ARLY posttransplant intraand perigraft fibrinogen and fibrin deposition is a hallmark of the hyperacute rejection observed after transplantation of discordant xenogeneic solid organs into unmodified recipients.‘,’ We previously showed that discordant free tissue grafts (xenoislets) do not undergo hyperacute rejection, but rather accelerated graft failure.3 However, by immunohistology, fibrinogen deposits are also a prominent feature in early biopsies of intraportal xenoislet grafts.’ Fibrinogen and fibrin deposition may not have the same immediate consequences for discordant free tissue xenografts (which initially do not rely on a directed blood flow through a vascular system) vs solid-organ xenografts (which are lost hyperacutely from intravascular coagulation and subsequent strangulation of their blood supply). But fibrin deposition and clot formation are associated with platelet thrombi, tissue ischemia, polymorphonuclear leukocyte (neutrophil) chemotaxis, and phagocytosis.‘,2,4 Neutrophils are known to secrete cytokines (eg, interleukin l-p), which can impair endocrine p-cell function.‘-’ Thus, fibrin may also have a deleterious effect, through a variety of mechanisms, on discordant free tissue grafts (xenoislets), and may facilitate their previously reported accelerated graft failure (observed even under maximal immunosuppression).’ We hypothesized that preventing fibrin deposition may improve the outcome of discordant xenoislet grafts. The purpose of this study was to investigate the effect of ancrod, a defibrinogenating enzyme derived from the venom of the Malaysian pit viper (Agkistrodon rhodostoma),“,” on nonvascularized free tissue xenograft endocrine function in the well-established, strongly discordant dog-to-Lewis rat model. 10.1 1