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The immunological responses to xenotransplantation of various tissue types. A. Xenografts of free tissues such as pancreatic islets or isolated cells such as bone marrow cells are subject to early failure due to primary non-function, failure to neovascularize, or molecular incompatibilities and subsequent cell-mediated rejection. B. A porcine organ transplanted into a human would be subject to one or more of the immunological reactions shown here. Transplantation into an untreated recipient would give rise to hyperacute rejection. If hyperacute rejection is avoided, for example, by the inhibition of complement, the graft is subjected to acute vascular rejection. If anti-donor antibodies are depleted from the recipient, the graft may undergo accommodation, a condition in which acute vascular rejection does not occur despite the presence of anti-donor antibodies in the circulation of the recipient. If acute vascular rejection is avoided, the graft will undergo cell-mediated rejection or chronic rejection.
Possible ways in which Galαl-3Gal expression could be decreased by genetic engineering. Synthesis of Galα1-3Gal is catalyzed by α1,3-galactosyltransferase (GT); the biosynthetic pathway is shown by dashed arrows. This enzyme adds galactose residues at the termini of oligosaccharide chains. Four possible approaches to preventing the synthesis of the sugar are shown by normal arrows. First, the expression of antisense RNA or a ribozyme might disrupt the structure or function of the GT mRNA. Second, introduction of a gene for an inhibitory ligand for GT, such as an appropriate Fv (an antibody-like molecule) or an aptamer (a small oligonucleotide inhibitor), might inhibit the function of the enzyme. Third, overexpression of another glycosyl transferase, such as H transferase, which adds fucose residues, might compete for the subterminal residues on oligosaccharide chains. This has been achieved in rats by the overexpression of a human H transferase, resulting in the addition of fucose rather than Galα1-3Ga1 to oligosaccharide side chains ( 101 ). Fourth, expression of a glycosidase, such as a-galactosidase, might lead to cleavage of the antigenic saccharide chains. Reprinted by permission from Nature 392(Suppl.):l 1-17, 1998, Macmillan Magazines Ltd.
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