Immunosuppressive Activity of Chemically Synthesized Gangliosides

Abstract

New chemical synthetic methods have permitted the synthesis of a spectrum of glycosphingolipid molecular species, some of which are not naturally occurring. Here we have studied a number of chemically synthesized gangliosides for immunosuppressive activity, using a human in vitro specific antigen (tetanus toxoid)-induced assay of the cellular immune response. Chemically synthesized GM3 and GM4 had the same high degree of immunosuppressive activity as did natural GM3 and GM4 gangliosides, verifying that inhibition is intrinsic to the ganglioside molecules and not caused by other molecules sometimes found in natural preparations (e.g., proteins). Studies of modified molecular species of GM3 and GM4, also prepared by chemical synthesis, have shown the influence of certain structural details upon the immunosuppressive activity of gangliosides: (i) the inverse relationship between fatty acyl chain length and immunosuppressive activity is extended to even shorter chain lengths, with the synthetic gangliosides d18:1-C2:0-GM3 and d18:1-C14:0-GM3 being more immunosuppressive than d18:1-C18:0-GM3 and d18:1-C24:0-GM3; (ii) hydroxylation of the fatty acyl group decreases immunosuppressive activity; (iii) substitution of an S-glycosidic bond for an O-glycosidic bond in the sialic acid ketosidic linkage in GM4 does not alter its activity; and (iv) modifications of the sialic acid group variably influence immunosuppressive activity, since KDN-GM3 and -GM4 ganglioside analogues, which contain a 3-deoxy-D-glycero-D-galacto-2-nonulopyranosonic acid in place of N-acetylneuraminic acid, retain activity, while other modifications such as 8-epi-GM3, and to a lesser extent 9-deoxy-GM3, reduce immunosuppressive activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Cellular Gangliosides Promote Growth Factor-induced Proliferation of Fibroblasts

“…Growth factors were directly added to the culture medium by diluting the stock solutions before use. Synthetic G M3 (d18:1-C18:0), which we previously studied in assays of lymphoproliferation (19,20), was kindly provided by Dr. Akira Hasegawa of Gifu University (Gifu, Japan). G D1a (bovine brain), G M3 and G D3 (bovine buttermilk), and PPPP were purchased from Matreya (Pleasant Gap, PA).…”

“…proteins) in the ganglioside preparation, we tested a synthetic (chemically synthesized) ganglioside, G M3 (d18:1-C18:0), which we had previously shown to be equivalent to natural G M3 in its immunological properties (20). As shown in Fig.…”

Influence of dietary gangliosides on neonatal brain development

“…Potential implications of these fatty acid variations with respect to immunosuppression have been reported. 13 In brain tissue gangliosides (human and rat) the ceramide-linked fatty acid composition also changes with age (in utero and post birth) as does the sphingosine component, with increasing proportions of C-20 sphingosine and decreasing proportions of C-18 sphingosine. 14 Any possible link between the variation in the ceramides of milk over lactation and the variation in brain gangliosides ceramides within the corresponding time period is unexplored, but human milk gangliosides are dominated by C16:0, C18:0, and C18:1 12 early on in lactation, with variation increasing as lactation progresses; the human brain gangliosides are also dominated by those three fatty acids plus C20:0 early in life.…”

A strategy for constructing C-sialosides based on Ireland-Claisen rearrangement and its application for synthesis of CF2-linked ganglioside GM4 analog

“…Because the C-linked ganglioside analog should act as a sialidase-resistant ganglioside, it was expected that this analog would inhibit human sialidase [24]. Since Ladisch et al reported that natural and chemically synthesized GM3 and GM4 inhibited the tetanus toxoid-induced proliferation of human lymphocytes [25], we also examined the activity of C-linked ganglioside analog on lymphoproliferation. …”