Platelet-activating factor and hyperacute rejection. The effect of a platelet-activating factor antagonist, SRI 63-441, on rejection of xenografts and allografts in sensitized hosts.

The hyperacute form of organ graft rejection was originally recognized in patients who had received kidneys from ABO-blood-group incompatible donors (1). The reaction is mediated by the presence of preformed antibody against donor renal graft ABO antigens and is associated with endothelial damage secondary to deposition of antibody and complement (2) and vascular thrombosis (3). Hyperacute rejection (HAR)* can also be seen in patients who have been stimulated to produce antidonor antibodies to specific HLA antigens (4), either because of the rejection of an HLA incompatible graft, multiple blood transfusions, or, secondarily, because of multiple pregnancies. Experimental studies of the mechanism of HAR have shown that the primary target for the reaction is the capillary endothelium of the graft (5, 6). Within 1 min after transplantation, widespread blockage of the microvascular system by platelet and neutrophil aggregates and fibrin occurs. The reaction depends upon the activation of complement (7), and results in vasoconstriction and a disseminated intravascular coagulation in the microvasculature. The occlusion of the microvasculature of the graft results in an ischemic necrosis of the transplanted organ that shares many of the features of an experimentally induced generalized Shwartzman reaction (4). Severe injury to vascular endothelium is associated with the release of a variety of biologically active mediators of coagulation and inflammation, stimulation of platelet aggregation, and modulation of inflammatory cell interaction with the endothelium. Platelet-activating factor (PAF) is one of the more recently recognized biological mediators, and it represents a class of potent lipid autocoids that have been reported to be important in the pathogenesis of acute inflammation (8), endotoxin shock (9), and anaphylaxis (10). PAF exhibits a broad spectrum of activities, including aggregation and activation of platelets and neutrophils, increased vascular permeability, smooth muscle contraction, and the release of vasoactive amines (8, 11). More recently, PAF has been implicated as a key biological mediator in the pathogenesis of antibody and complement-mediated hyperacute organ rejection (12). When kidney grafts were transplanted to sensitized rabbits, PAF was identified in the blood draining the transplanted kidney. PAF was detected in the blood effluent within 2–10 min after revascularization and was not found in syngeneic controls or unsensitized recipients. Injection of a synthetic, purified PAF into the renal artery induced lesions in the kidney that were identical to those seen in the Shwartzman reaction. Similar results were obtained in vitro when perfusion of isolated rabbit hearts with transplantation alloantibodies was associated with a complement-dependent release of PAF (13). The potential that PAF may play an important role in the early initiation of the lesions of HAR has led us to examine the influence of specific inhibitors of PAF on hyperacute rejection. A variety of specific PAF receptor antagonists have been synthesized and have been reported to block PAF binding to its high-affinity receptor. These compounds are capable of inhibiting and/or reversing PAF-induced hypotension (14), neutropenia (15), bronchospasm (16), endotoxin shock (9), and anaphylaxis (10). Our initial studies indicated that a single bolus of one of these PAF receptor antagonists (SRI 63-441) at a dose of 15 mg/kg was capable of significantly prolonging hyperacute rejection by sensitized LEW rats of ACI strain cardiac allografts (17). This treatment inhibited but did not prevent HAR, and, at somewhat higher doses, there was evidence of a toxic effect on the recipients. The inclusion of either CsA or prostaglandin E2 (PGE2) did not consistently improve the graft survival times. The effect of SRI 63-441 was also tested for its ability to prevent discordant cat-to-rabbit (17) and pig-to-dog (18) xenograft reactions, and our results demonstrated significant prolongation of graft survival, particularly when the SRI 63-441 was used in combination with immunosuppressants or prostaglandins. The current report evaluates in more detail the effect of SRI 63-441, either alone or in combination with additional pharmacologic agents, on the rejection of rat cardiac allografts in presensitized recipients, and on cardiac survival in a series of concordant and discordant xenografts in rats. The SRI 63-441 compound is a specific PAF receptor antagonist manufactured by the Sandoz Company (East Hanover, NJ). It represents one of a family of agents that can be synthesized to meet various therapeutic requirements, including intravenous or oral administration. Our results indicate that the use of these compounds may be effective in inhibiting humoral effector arms of the inflammatory reaction of hyperacute rejection and that the effective control of this reaction may be possible when these compounds are combined with other therapeutic agents directed at the cellular components of the rejection process.