The relationship of eicosanoids and complement components to hyperacute xenogeneic rejection and its modification by the PAF-antagonist WEB 2086BS

Abstract

Experimental and clinical observations suggest that the xenograft rejection is based on two mechanisms. In animal species without natural antibodies, a mechanism similar to that in the allogeneic situation is responsible for the rejection. On the other hand, in species combinations where preformed natural antibodies (PNAB) directed against xenogeneic antigens are present, a hyper-acute rejection is typical. The principle features of this hyperacute xenogeneic renal rejection (HXAR) are a rapid increase of arterial resistance, cessation of the organ’s microcirculation within minutes, extravasation of blood and hematuria and cessation of urine production. Up to now, no reliable method to suppress this HXAR has been developed. Therefore, the major interest still lies either in the elimination of preformed antibodies or in blocking the major response of humoral mediators of which platelet-activating factor (PAF, PAF-acether) is supposed to be one. Recently, it was shown that PAF-acether does participate in transplant rejection. The first association with hyperacute rejection was suggested by Camussi et al. (1). In this reaction, PAF is regarded as a potent mediator of inflammatory reactions because of its broad range of biological activities. Commonly, the i.v. injection of PAF into different animal species is followed by hypotension, pulmonary hypertension, bronchoconstriction and increase of vascular permeability as systemic effects. The cellular sources of PAF are polymorphonuclear leukocytes (PMN), mast cells, platelets and endothelial cells. PAF is released from these cells when stimulated but also induces its own activation. Neutrophils and eosinophils participate in endothelial cell injury, e.g. by secreting proteases which destroy the basal membrane and activate the complement cascade. The close relationship between PAF synthesis and endothelial cell-dependent neutrophil adherence as well as the fact that PAF directly stimulates PMN activation and adhesion suggest that PAF may directly participate in transplant rejection (2, 3). The first evidence for PAF involvement in renal immune injury comes from the observation that PAF is released during hyperacute allograft rejection in kidneys. The participation of platelets and leukocytes in xenograft rejection provides the basis for the rationale of our trial to use PAF-antagonists in organ xenotransplantation.