Binding of human preformed natural antibodies (PNAb) to xenogeneic antigenic determinants on porcine endothelial cells (EC) leads to hyperacute rejection, a phenomenon that characterizes the recognition of transplanted vascularized organs. A major epitope recognized on EC by human PNAb is the Gal α 1,3 Gal disaccharide, the expression of which is due to the presence of an α1,3 galactosyltransferase. Recognition and rejection of non-vascularized tissues and cells, and in particular porcine islets of Langerhans, occurs via mechanisms that have not been fully elucidated. Porcine islets of Langerhans are bound by human PNAb, yet they do not express the α 1,3 galactosyltransferase, suggesting that additional xenogeneic epitopes exist. The only component of the islets that expresses high levels of the αGal epitope is the EC component, as demonstrated by double fluorescence imaging with the isolectin B4 from G. Simplicifolia (that specifically binds the αGal epitope) and anti-Factor VIII antibodies. We have started to characterize such epitopes by affinity chromatography of porcine islet cell lysates on solid phase-bound human Ig's. Elution of the Ig-bound material was followed by gel electrophoresis, transfer on membranes and blotting with the isolectin B4 from G. Simplicifolia, to confirm the lack of reactivity of the eluted bands with the Gal α 1,3 Gal-specific lectin. Further characterization of the islet-specific xenoantigens is under way.