xenoreactive natural antibodies (XNAs). Hyperacute rejection This rapid and violent type of rejection occurs within minutes to hours from the time of the transplant. It is mediated by the binding of XNAs (xenoreactive natural antibodies) to the donor endothelium, causing activation of the human complement system, which results in endothelial damage, inflammation, thrombosis and necrosis of the transplant. XNAs are first produced and begin circulating in the blood in neonates, after colonization of the bowel by bacteria with galactose moieties on their cell walls. Most of these antibodies are the IgM class, but also include IgG, and IgA. The epitope XNAs target is an α-linked galactose moiety, galactose-alpha-1,3-galactose (also called the α-Gal epitope), produced by the enzyme alpha-galactosyltransferase. Most non-primates contain this enzyme thus, this epitope is present on the organ epithelium and is perceived as a foreign antigen by primates, which lack the galactosyl transferase enzyme. In pig to primate xenotransplantation, XNAs recognize porcine glycoproteins of the integrin family. The binding of XNAs initiate complement activation through the classical complement pathway. Complement activation causes a cascade of events leading to: destruction of endothelial cells, platelet degranulation, inflammation, coagulation, fibrin deposition, and hemorrhage. The result is thrombosis and necrosis of the xenograft. Overcoming hyperacute rejection Since hyperacute rejection presents such a barrier to the success of xenografts, several strategies to overcome it are under investigation: Interruption of the complement cascade The recipient's complement cascade can be inhibited through the use of cobra venom factor (which depletes C3), soluble complement receptor type 1, anti-C5 antibodies, or C1 inhibitor (C1-INH). Disadvantages of this approach include the toxicity of cobra venom factor, and most importantly these treatments would deprive the individual of a functional complement system. Transgenic organs (Genetically engineered pigs) 1,3 galactosyl transferase gene knockouts – These pigs do not contain the gene that codes for the enzyme responsible for expression of the immunogeneic gal-α-1,3Gal moiety (the α-Gal epitope). Increased expression of H-transferase (α 1,2 fucosyltransferase), an enzyme that competes with galactosyl transferase. Experiments have shown this reduces α-Gal expression by 70%. Expression of human complement regulators (CD55, CD46, and CD59) to inhibit the complement cascade. Plasmaphoresis, on humans to remove 1,3 galactosyltransferase, reduces the risk of activation of effector cells such as CTL (CD8 T cells), complement pathway activation and delayed type hypersensitivity (DTH). Acute vascular rejection Also known as delayed xenoactive rejection, this type of rejection occurs in discordant xenografts