VARIATION IN THE LEVEL OF XENOANTIGEN EXPRESSION IN PORCINE ORGANS

Hyperacute rejection of vascularized porcine to primate xenografts is initiated by the binding of xenoreactive natural antibodies to donor e ndothelium. We tested the hypothesis that the level of xenoantigen exp ression varies in the population of potential porcine donors and may d etermine the amount of binding of xenoreactive natural antibodies to a porcine organ perfused by xenogeneic blood. Two hundred ninety pigs w ere studied using an inhibition ELISA that quantitated the xenoantigen level on porcine platelets. Based on this assay, the levels of xenoan tigen expression in the population adhered to a normal distribution. K idneys from pigs found to express high antigen levels and kidneys from pigs found to express low antigen levels were perfused with baboon bl ood using an extracorporeal circuit. In multiple experiments, a signif icant difference was observed in the amount of xenoreactive natural an tibody adsorbed by high antigen versus low antigen organs. Normalizing for the weight of the perfused organs and for levels of natural antib ody in individual baboons, high antigen organs adsorbed 3.6+/-1.3 U of xenoreactive natural antibody/g and low antigen organs adsorbed -0.8/-1.0 U of xenoreactive natural antibody/g (P<0.002). Immunopathology of tissues from the perfused organs demonstrated more deposition of Ig M and C4 in high than in low xenoantigen organs. The quantitative rela tionship between binding of xenoreactive natural antibodies to platele ts and to whole organs suggests that platelets are a valid representat ion of endothelial cell antigen expression in vivo. Despite the probab le importance of Gal(alpha(1-3)Gal as an epitope recognized by xenorea ctive natural antibodies, differences in the binding to platelets or t o organs of the GS-I-B-4 lectin that recognizes that sugar had no corr elation with the differences in binding of IgM to these tissues. Varia tion in expression of xenoantigen may be exploited to selectively bree d donors for xenotransplantation that are less susceptible to attack b y xenoreactive natural antibodies.