TRANSGENIC EXPRESSION OF HUMAN ALPHA-1,2-FUCOSYL-TRANSFERASE (H-TRANSFERASE) PROLONGS MOUSE HEART SURVIVAL IN AN EX-VIVO MODEL OF XENOGRAFTREJECTION

Background. The expression of human alpha 1,2-fucosyltransferase (H-tr ansferase, HT) has been proposed as an alternative strategy to alpha 1 ,3-galactosyltransferase (GT) gene knockout, which is not currently fe asible in pigs, to reduce the galactose-alpha 1,3-galactose (Gal) epit ope expression, HT expression has recently been shown in transgenic mi ce and pigs to significantly reduce Gal expression on a variety of cel ls; however, its ability to do so on endothelial cells and its effecti veness at prolonging xenograft survival are yet to be determined. Meth ods. HT-transgenic, Gal knockout (Gal KO) mice, and mice containing bo th genetic modifications (HT-transgenic/Gal KO) were tested for II-sub stance and Gal expression on splenocytes and endothelial cells by flow cytometric analysis. In addition, the hearts of these mice were perfu sed ex vivo with 6% human plasma, and the effect on cardiac function w as determined, Results and Conclusion. H-substance expression was dete cted on both splenocytes and endothelial cells of HT-transgenic mice, The level of II-substance expression was not affected by the presence or absence of GT in the cells, consistent with HT being dominant over GT, The ability of HT expression to reduce Gal expression was highly v ariable depending on the cell type, Gal expression on splenocytes was almost completely eliminated, whereas on endothelial cells, substantia l Gal remained despite a 70% reduction, When perfused ex vivo with hum an plasma, hearts from HT-transgenic, Gal KO, and HT-transgenic/Gal KO mice demonstrated a similar prolongation in survival, compared with w ild-type controls, Therefore, as far as hyperacute rejection is concer ned, HT expression may be as effective as Gal KO in protecting against xenoantibody and complement mediated injury, However, the effect of r esidual Gal on non-hyperacute rejection responses remains to be determ ined.