Regulation of Natural Killer Cell-Mediated Swine Endothelial Cell Lysis through Genetic Remodeling of a Glycoantigen

The effect of remodeling of a glycoantigen such as the a-Gal epitope, Galαl, 3Galβl, 4GlcNAc-R, by the introduction of glycosyltransferase genes on natural killer (NK) cell-mediated direct cytotoxicity was investigated using human peripheral blood mononuclear cells (PBMC) or an NK-like cell line, YT...

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Published in:Journal of biochemistry (Tokyo) 1999-12, Vol.126 (6), p.1067-1079
Main Authors: Miyagawa, Shuji, Nakai, Rie, Yamada, Mako, Tanemura, Masahiro, Ikeda, Yoshitaka, Taniguchi, Naoyuki, Shirakura, Ryota
Format: Article
Language:English
Subjects:
a-Gal epitope
alpha-Galactosidase - metabolism
Animals
Endothelium - immunology
Flow Cytometry
glycosyltransferase
Glycosyltransferases - genetics
Glycosyltransferases - immunology
Humans
Killer Cells, Natural - immunology
Lectins - immunology
Mice
natural killer cell
Plant Lectins
remodeling of glycoanti-gen
Swine
swine endothelial cell
Transfection
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Summary:The effect of remodeling of a glycoantigen such as the a-Gal epitope, Galαl, 3Galβl, 4GlcNAc-R, by the introduction of glycosyltransferase genes on natural killer (NK) cell-mediated direct cytotoxicity was investigated using human peripheral blood mononuclear cells (PBMC) or an NK-like cell line, YT cells, as an effector, and swine endothelial cells (SEC) as a target. Several SEC transfectants were established by transfection with the genes for βl, 4-N-acetylgluco8aminyltransferase III, a2, 3-sialyltransferase and al, 2-fucosyl-transferase. These transfections led to dramatic reductions in both direct and indirect NK cell-mediated cytotoxicity, by 72–94% in the case of PBMC and 27–72% in that of YT cells, in addition to an effective reduction in xenoantigenicity, which is substantially caused by the a-Gal epitope, to human natural antibodies. The NK cell-mediated direct cytotoxicity was remarkably blocked by an anti-a-Gal epitope monoclonal antibody or GSI lectin which preferentially binds to the epitope. Furthermore, treatment of the parental cells with a-galactosidase resulted in a significant reduction in cytotoxicity. These results suggest that the a-Gal epitope is involved not only in hyperacute rejection and acute vascular rejection, but also in NK cell-mediated direct cytotoxicity. Thus, the genetic remodeling of the a-Gal epitope and probably other glycoantigens as well can be expected to represent a new approach for overcoming not only indirect but also direct immunity to xenografts.
ISSN:0021-924X
DOI:10.1093/oxfordjournals.jbchem.a022551