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Expression of the human α:1,2‐fucosyltransferase in transgenic pigs modifies the cell surface carbohydrate phenotype and confers resistance to human serum‐mediated cytolysis
Author(s) -
Costa Cristina,
Zhao Lisa,
Burton Willis V.,
Bondioli Kenneth R,
Williams Barry L.,
Hoagland Thomas A.,
Ditullio Paul A.,
Ebert Karl M.,
Fodor William L.
Publication year - 1999
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.13.13.1762
Subject(s) - biology , epitope , fucosyltransferase , xenotransplantation , transgene , antibody , microbiology and biotechnology , transplantation , cytolysis , antigen , immunology , in vitro , biochemistry , enzyme , cytotoxicity , gene , medicine , surgery
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 α1,2‐fucosyltransferase (H‐transferase, HT). H‐transferase expression modifies the cell surface carbohydrate phenotype of the xe‐nogeneic cell, resulting in the expression of the universal donor O antigen and a concomitant reduction in the expression of the antigenic Galα1,3‐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 Galα1,3‐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 α1,2‐fucosyltrans‐ferase in transgenic pigs modifies the cell surface carbohydrate phenotype and confers resistance to human serum‐mediated cytolysis. FASEB J . 13, 1762–1773 (1999)