Transplantation of immediately vascularized organs between species that are phylogenetically widely separated, referred to as discordant species combinations, results in hyperacute rejection. The basis of hyperacute rejection likely involves (i) natural antibodies of the recipient that bind to donor vascular endothelium, (ii) complement that is activated consequent to natural antibody binding or via the alternative pathway, and (iii) activation of endothelial cells of the donor organ resulting in intravascular thrombosis. The picture of hyperacute rejection includes what are the commonly accepted consequences of endothelial activation: extravasation of cells into the extravascular space, edema, deposition of granulocytes and platelets on the endothelium and thrombosis. Hyperacute rejection can occur in as little as 15 minutes but is usually completed within 2 hours, depending in some measure on the discordant species combination studied. Past studies have attempted, for the most part, to interfere with one or the other of the three areas related to hyperacute rejection as outlined above. It is our hypothesis that to avert hyperacute rejection it will be necessary to interfere with several of the pathogenetic features of the rejection process. Especially important, to our mind, is the careful evaluation of interventions that may prevent endothelial cell activation or interfere in the consequences thereof. We believe, however, that such interventions must be attempted in animals in which natural antibody action and complement action have been compromised to the extent possible. Such experiments are proposed herein. We shall transplant guinea pig hearts to rats (n very rare instances, we shall use newborn micropig hearts as the donor organ). We plan to deplete natural antibodies and attempt to maintain very low levels of such antibodies primarily through the use of immunosuppressive agents directed at the B cells producing the natural antibodies. We shall use cobra venom factor to abrogate complement action of both the alternative and classical pathways. It is on a background of depleted natural antibodies and compromised complement that we shall test various interventions dealing with endothelial cell activation or the aftermath of activation. After the evaluation of various treatment protocols individually, we plan to combine therapeutic strategies based largely on the immunopathology of the rejecting hearts, from which studies we hope to learn which strategies are truly complementary in attempts to avert hyperacute rejection.