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1,2-fucosyltransferase in transgenic pigs modifies the cell surface carbohydrate phenotype and confers resistance to human serum-mediated cytolysis
* Department of Molecular Sciences, Alexion Pharmaceuticals Inc, New Haven, Connecticut 06511, USA;
U.S. Surgical Corporation, North Haven, Connecticut 06473, USA;
Department of Animal Sciences, University of Connecticut, Storrs, Connecticut 06269, USA; and
§ TranXenoGen, Shrewsbury, Massachusetts 01545, USA
1Correspondence: Department of Molecular Sciences, Alexion Pharmaceuticals Inc., 25 Science Park, New Haven, CT 06511, USA. E-mail: fodorw{at}alxn.com
Hyperacute rejection (HAR) is the first critical immunological hurdle
that must be addressed in order to develop xenogeneic organs for human
transplantation. In the area of cell-based xenotransplant therapies,
natural antibodies (XNA) and complement have also been considered
barriers to successful engraftment. Transgenic expression of human
complement inhibitors in donor cells and organs has significantly
prolonged the survival of xenografts. However, expression of complement
inhibitors without eliminating xenogeneic natural antibody (XNA)
reactivity may provide insufficient protection for clinical
application. An approach designed to prevent XNA reactivity during HAR
is the expression of human 
1,2-fucosyltransferase (H-transferase,
HT). H-transferase expression modifies the cell surface carbohydrate
phenotype of the xenogeneic cell, resulting in the expression of the
universal donor O antigen and a concomitant reduction in the expression
of the antigenic Gal1,3-Gal epitope. We have engineered various
transgenic pig lines that express HT in different cells and tissues,
including the vascular endothelium. We demonstrate that in two
different HT transgenic lines containing two different HT promoter
constructs, expression can be differentially regulated in a
constitutive and cytokine-inducible manner. The transgenic expression
of HT results in a significant reduction in the expression of the
Gal1,3-Gal epitope, reduced XNA reactivity, and an increased
resistance to human serum-mediated cytolysis. Transgenic pigs that
express H-transferase promise to become key components for the
development of xenogeneic cells and organs for human
transplantation.—Costa, C., Zhao, L., Burton, W. V., Bondioli,
K. R., Williams, B. L., Hoagland, T. A., DiTullio,
P. A., Ebert, K. M., Fodor, W. L. Expression of the
human 1,2-fucosyltransferase in transgenic pigs modifies the cell
surface carbohydrate phenotype and confers resistance to human
serum-mediated cytolysis.
Key Words: 1 • 2 • H-transferase • hyperacute rejection • delayed xenograft rejection • xenotransplantation
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