Immunosuppression by human gangliosides: II. Carbohydrate structure and inhibition of human NK activity

• Published in: Cellular immunology Vol. 139; no. 1; pp. 18 - 29
• Main Authors: Grayson, Guy, Ladisch, Stephan
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 1992; Elsevier
• Subjects: Biological and medical sciences; Brain Chemistry; Carbohydrate Sequence; Cytotoxicity, Immunologic - drug effects; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gangliosides - chemistry; Gangliosides - pharmacology; Humans; Immunity, Cellular - drug effects; Immunity, Innate - drug effects; Immunobiology; In Vitro Techniques; Killer Cells, Natural - immunology; Modulation of the immune response (stimulation, suppression); Molecular Sequence Data; Structure-Activity Relationship; Natural killer cell; Human; Immunosuppression; Ganglioside; Structure activity relation; Molecular structure; Cytotoxicity; Carbohydrate; In vitro; Brain (vertebrata)
• ISSN: 0008-8749; 1090-2163
• DOI: 10.1016/0008-8749(92)90096-8

Gangliosides shed by tumors enhance tumor formation, possibly by suppressing host antitumor immune function, and gangliosides purified from animal tissues and cultured cells inhibit human cellular immune function in vitro. Determination of immunosuppressive activity of highly purified gangliosides, to uncover structure-activity relationships, is therefore important. Here we have studied a series of gangliosides obtained from human tissue and determined their effects on human natural killer (NK) activity. Total gangliosides from human brain tissue were moderately inhibitory; 100 nmol/ml reduced NK activity of human nonadherent PBMC by 43%. The influence of carbohydrate structure upon inhibitory activity was determined by study of eight highly (HPLC) purified individual gangliosides. Of these, we unexpectedly found that the two minor brain gangliosides with the simplest carbohydrate structures, G M2 and G M3 , were very active inhibitors (75 and 47%, respectively, at 50 nmol/ml). In contrast, the structurally more complex major species, G M1 , G D1a , G D1b , G T1b , and two other minor gangliosides, G D2 and G D3, were inactive. Reduced effector-target binding in a single-cell binding assay by G M2 but not G M3 suggests different mechanisms of inhibition by these two active gangliosides. Since G M2 and G M3 are present in high concentrations in, and are shed by, several common human tumors (e.g., neuroblastoma, melanoma, and glioma), their ability to inhibit NK cytotoxicity supports the hypothesis of a role of shed tumor gangliosides in the enhancement of tumor formation.