Antibody-dependent cytotoxicity mediated by natural killer cells is enhanced by castanospermine-induced alterations of IgG glycosylation.
Inhibitors of glycosylation and carbohydrate processing were used to probe the functional consequences of specific, differential alterations in glycosylation of monoclonal IgG secreted by hybridoma clones. Neither the absence of glycosylation nor the presence of atypical oligosaccharides significantly influenced binding of the monoclonal antibody to the cell surface antigen recognized. However, lymphocyte-mediated antibody-dependent cytotoxicity was enhanced significantly, as compared to native (unmodified) IgG-sensitized target cells, when target cells were sensitized with IgG bearing the atypical oligosaccharides induced metabolically by castanospermine, N-methyldeoxynojirimycin, deoxymannojirimycin or monesin, but not by swainsonine. The enhanced cytotoxicity was mediated by natural killer cells but not by monocytes or interferon-activated polymorphonuclear leukocytes. By contrast, antibody-dependent cytotoxicity mediated by activated polymorphonuclear leukocytes against target cells sensitized with the IgG glycosylation phenotypes induced by swainsonine and tunicamycin, but not by castanospermine, was decreased in comparison to cytotoxicity against target cells sensitized with native IgG. The enhanced lymphocyte-mediated cytotoxicity was Fc receptor-dependent. A panel of monoclonal antibodies directed against different human tumor target cells was used to demonstrate that the castanospermine-induced IgG phenotype generally enhanced antibody-dependent tumoricidal activity mediated by natural killer cells. However, differences in lymphocyte response to an alteration in IgG glycosylation were observed.
Rothman
R J
RJ
Wistar Institute of Anatomy and Biology, Philadelphia, PA 19104.
Perussia
B
B
Herlyn
D
D
Warren
L
L
D000470:Alkaloids / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000937:Antigen-Antibody Reactions / Q000187:drug effects; D005959:Glucosidases / Q000037:antagonists & inhibitors; D006020:Glycopeptides / Q000032:analysis; D006031:Glycosylation; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D007212:Indolizines; D007694:Killer Cells, Natural / Q000276:immunology*; D014407:Tumor Cells, Cultured / Q000276:immunology; D054836:Indolizidines
D000470:Alkaloids; D005959:Glucosidases; D006020:Glycopeptides; D007074:Immunoglobulin G; D007212:Indolizines; C037806:castanospermine; D054836:Indolizidines