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PubMed1995

Approaches to augmenting the immunogenicity of melanoma gangliosides: from whole melanoma cells to ganglioside-KLH conjugate vaccines.

Gangliosides are neuraminic acid containing glycosphingolipids that are anchored into the lipid bilayer of the plasma membrane by their lipophilic ceramide moiety. They are overexpressed on tissues of neuroectodermal origin, particularly in tumors such as melanomas, sarcomas, neuroblastomas and astrocytomas. With the ganglioside-KLH plus immunological adjuvant QS-21 conjugate vaccine, GM2 and GD2 have been shown to be consistently immunogenic, inducing cytotoxic IgM antibodies in most patients. The immunogenicity of other gangliosides also expressed on melanoma cells such as 9-0-acetyl GD3 and GD3 lactone is currently being tested with this conjugate vaccine approach. From the initiation of our adjuvant vaccine trials in 1975 to the present, the immunogenicity of ganglioside vaccines has increased significantly as vaccine development has progressed. For instance, GM2 antibody responses increased from low titer IgM antibodies induced in occasional patients after whole cell vaccines, to moderate titer IgM antibodies in 86% of patients after GM2/BCG vaccines, to higher titer IgM antibodies in 100% of patients treated with the GM2-KLH plus QS-21 vaccine. These antibodies are capable of mediating complement mediated cytotoxicity of GM2 expressing melanoma cells in the majority of patients and such antibodies, whether naturally produced or vaccine induced, have been associated with a significantly improved disease-free and overall survival. An initial double-blind randomized trial in AJCC Stage III melanoma patients comparing GM2/BCG with BCG alone, demonstrated a 14% improvement in disease-free interval at 4 years and an 11% improvement in overall survival, though neither result achieved statistical significance. Based on these encouraging clinical results and the clearly improved immunogenicity of the GM2-KLH plus QS-21 vaccine compared to the previous GM2/BCG vaccine, the following two large clinical trials are anticipated to begin in 1995-1996. The GM2-KLH plus QS-21 vaccine will be tested in the intergroup setting by ECOG in 450 patients with AJCC Stage II or III melanoma who are free of disease after surgery. Also to be tested in a multicenter trial is a GM2-KLH plus GD2-KLH plus QS-21 vaccine in patients with high risk AJCC Stage II-IV sarcoma after surgical excision of all known disease.

Adjuvants, Immunologic↗
PubMedDate not supplied

High levels of GM1-ganglioside beta-galactosidase in the salivary glands and GM1-like-ganglioside storage in parotids of deficient mice.

We have previously demonstrated high levels of GM1-ganglioside beta-galactosidase (beta-gal) in the salivary glands of Swiss-Webster mice (Nowroozi et al., J Craniofac Genet Dev Biol 18:51, 1998), and suggested that this activity reflects an important role for the lysosome in catabolism of salivary glycoconjugates. Here, we characterized and compared activities of lysosomal glycosidases among the salivary glands, spleen, and muscle of C57BL/6 mice, beta-gal hexosaminidase, and beta-glucuronidase activities are high in all three glands relative to muscle. Enzyme activities in the sublingual gland were substantially higher than in the submandibular and parotid glands. Spleen displays levels of activity that are comparable or higher (for beta-glucuronidase) than those in the salivary glands, whereas muscle displays substantially lower levels of these lysosomal glycosidases. In order to investigate the role of beta-gal in the salivary glands, we further characterized the salivary phenotype of knock-out mice deficient in this enzyme, mimicking human GM1-gangliosidosis. In contrast with the relative levels of beta-gal specific-activity among the salivary glands, only the parotid developed severe, generalized, degenerative histopathological changes in beta-gal-deficient knock-out mice. GM1-like-ganglioside, typically found at high levels only in the nerve tissue, where its exact function is still not clear, was demonstrated in storage vacuoles of the parotid glands of the deficient mice by binding of cholera toxin subunit B. Thus, beta-gal activity observed in the parotid gland most likely reflects its role in GM1-ganglioside catabolism, and this ganglioside, never previously reported in the salivary glands, may have a role in parotid exocrine secretory functions. beta-gal may also serve in secretory glycoprotein catabolism in other salivary glands, but this function may be non-essential for these glands.

Animals↗
PubMed1992

[Gangliosides and antibodies to gangliosides in blood serum].

The concentration and composition of gangliosides from normal and pathological blood serum of animals and man are reviewed. Data concerning the elevation of the ganglioside content in the serum under malignization are summarized. The appearance of ganglioside-specific antibodies in some pathological states is described. The possible influence of changes in the serum ganglioside content and composition on immunity is discussed.

Animals↗
PubMed1992

Human meconium gangliosides. Characterization of a novel I-type ganglioside with the NeuAc alpha 2-6Gal structure.

Three monosialogangliosides containing the NeuAc alpha 2-6Gal structure have been detected in human meconium by immunological analysis using a monoclonal antibody, MSG-15, and purified by repeated silica beads column chromatography. One was previously shown to be NeuAc alpha 2-6Gal beta 1-4GlcNAc beta 1-3Gal beta 1-4Glc beta 1-1Cer. The remaining two were characterized by proton NMR, fast atom bombardment mass spectrometry, methylation analysis by gas chromatography-mass spectrometry, and immunological studies, and their structures were concluded to be as follows. [formula: see text] The second ganglioside has the same structure that was isolated from bovine buttermilk (Takamizawa, K., Iwamori, M., Mutai, M., and Nagai, Y. (1986) J. Biol. Chem. 261, 5625-5630), and this is the first description of the occurrence of the ganglioside with the branched structure with two N-acetyllactosamines linked to lactosylceramide via beta 1-6 and beta 1-3 in human linked to lactosylceramide via beta 1-6 and beta 1-3 in human tissues. The third ganglioside is a novel ganglioside with blood group I-type and a NeuAc alpha 2-6Gal structure.

Amino Sugars↗
PubMed1991

A specific type of ganglioside as a modulator of insulin-dependent cell growth and insulin receptor tyrosine kinase activity. Possible association of ganglioside-induced inhibition of insulin receptor function and monocytic differentiation induction in HL-60 cells.

Insulin-dependent cell growth has been correlated with insulin receptor function, particularly receptor-associated kinase activity, in in vitro studies. The insulin-dependent phosphorylation of the 95-kDa receptor subunit was clearly inhibited, in a concentration-dependent manner, by the presence of unbranched neolacto series gangliosides having a NeuAc2----3Gal terminus, particularly 2----3-sialosylparagloboside (2----3SPG; IV3NeuAc-nLc4), but not by other gangliosides with a NeuAc2----6Gal terminus or by branched neolacto series gangliosides (e.g. G10). Such inhibition of phosphorylation was minimal with ganglio series gangliosides and negligible with sphingosine, neutral glycolipids, or sulfatide. 2----3SPG did not affect insulin binding to the insulin receptor. Insulin-dependent cell growth and its inhibition by 2----3SPG were observed in three human cell lines so far tested: lymphoid cell line IM9, promyelocytic leukemia cell line HL-60, and erythroleukemia cell line K562. Since IM9 cells contain a much higher quantity of insulin receptor than do HL-60 or K562 cells, insulin-dependent receptor phosphorylation and its inhibition by 2----3SPG in intact cells were clearly observed with IM9 cells. Receptor phosphorylation in intact cells was inhibited when cells were preincubated in the presence of 2----3SPG. Insulin-dependent growth of HL-60 and K562 cells was also inhibited by prolonged culture (96-144 h) with exogenous 2----3SPG. Subsequent to the inhibition of insulin-dependent HL-60 cell growth, a remarkable phenotypic transformation was observed, i.e. changes in morphology, enzymes, and cell-surface markers to those characteristic of monocytes. The level of 2----3SPG in HL-60 cells increased when cells were cultured with 1 alpha,25-dihydroxyvitamin D3 to the same degree seen in cells cultured with 5 microM 2----3SPG. Both these treatments led to inhibition of insulin-dependent cell growth, followed by induction of monocytic differentiation. Thus, the cellular level of 2----3SPG may modulate insulin-dependent cell growth and define the lineage specificity of differentiation through modulation of receptor-associated kinase activity.

Antigens, Differentiation, Myelomonocytic↗
PubMed1989

Ganglioside-modulated protein phosphorylation in muscle. Activation of phosphorylase b kinase by gangliosides.

Gangliosides have profound effects on protein phosphorylation in skeletal muscle. Addition of GT1b to guinea pig muscle extract stimulated the phosphorylation of a 98-kDa protein 4-8-fold. In contrast, Ca2+ stimulated the phosphorylation of this protein and two other proteins with apparent Mr of 107,000 and 145,000, respectively. Addition of GT1b in the presence of Ca2+ further enhanced the phosphorylation of the 98-kDa protein but completely inhibited the phosphorylation of both the 107- and the 145-kDa proteins. The nature of the ganglioside-modulated 98-kDa protein has been characterized. Results on the pH activity profiles and the requirements of Ca2+ for phosphorylation suggest that this phosphoprotein may correspond to glycogen phosphorylase. Phosphorylation of purified rabbit muscle phosphorylase b by nonactivated phosphorylase kinase was stimulated by GT1b. This stimulation was in part due to an activation of the kinase activity. Autophosphorylation of highly purified phosphorylase kinase was increased 4-10-fold in the presence of GT1b. Polysialogangliosides were more potent than monosialogangliosides in stimulating the autocatalytic activity, whereas asialo-GM1, colominic acid, N-acetylneuraminic acid, and phosphatidylserine were ineffective. The effects of gangliosides were dose-dependent. At physiological pH, the concentrations of GT1b required for half-maximal stimulation of the autophosphorylation of phosphorylase kinase were 6.4 microM in the absence of Ca2+ and 1.3 microM when the divalent cation was present. These findings suggest that gangliosides may play a role as biomodulators in the regulation of glycogenolysis in muscle.

Animals↗
PubMed2001

The effect of cold stress on ganglioside fatty acid composition and ganglioside-bound sialic acid content of rat brain subcellular fractions.

The effect of cold stress on the ganglioside fatty acid composition and sialic acid content of brain subcellular fractions and homogenate of rats was studied, the animals were kept in a cold room with 12h light-dark cycles at 3 and 10 degrees C for 2 weeks. (1) The rat brain homogenate, synaptosomes and myelin of rats exposed to 3 degrees C contained significantly higher amounts of ganglioside-bound sialic acid per mg of protein than these fractions of control rats kept at 23 degrees C; the differences were less pronounced in rats exposed to 10 degrees C. (2) A small, but significant, diminution of relative palmitic acid content and an increase of stearic acid content was found to take place in gangliosides from rat brain synaptosomes, synaptosomal plasma membranes and homogenate as a result of the exposure of animals to 3 degrees C and to a lesser extent to 10 degrees C. (3) The content of unsaturated fatty acids in gangliosides from brain subcellular fractions was approximately the same in cold exposed and control rats.

Journal Article↗
PubMed1996

In vivo growth conditions suppress the expression of ganglioside GM2 and favour that of lacto series gangliosides in the human glioma D-54MG cell line.

The human glioma D-54MG cell line grown in vitro primarily expresses ganglio series gangliosides, particularly GM2. Subcutaneous injection of these cells into nude mice produced xenografts with an increased content of the human glioma-associated lacto series gangliosides, primarily 3'-isoLM1, an alteration that was dose dependent, with the highest dose (1 x 10(8)) resulting in a phenotype that was most like that of the inoculum. After one passage in vivo, the lacto series dominated and reached a proportional level that was kept throughout the 10 passages. The mRNA levels of the GM2-synthase clearly coincided with GM2 expression and was 20 times higher in cells grown in vitro than in those grown in vivo. These results support the view that ganglioside expression in human gliomas is strongly influenced by environmental factors.

Animals↗
PubMed1997

Synthesis of ganglioside GM1 containing a thioglycosidic bond to its labeled ceramide(s). A facile synthesis starting from natural gangliosides.

Capitalizing on the readily available ganglioside, GM1, we have devised a simple synthesis of labeled GM1 analogues with sulfur in place of oxygen in their linkage to the ceramide residue (SGM1). The sugar moiety of ganglioside GM1 was released by ozonolysis and subsequent alkaline fragmentation in good yield. During acetylation of the ganglioside sugar, the carboxyl group of the sialic acid residue lactonized with the 2-hydroxyl group of the inner galactose moiety (galactose II). The resulting sialoyl-II2-lactone of pentadeca-O-acetyl-monosialogangliotetraose could be readily transformed into the alpha-glycosyl bromide. Subsequent treatment of this glycosyl bromide with potassium thioacetate afforded the sialoyl-II2-lactone of tetradeca-O-acetyl-1-S-acetyl-1-thio-beta-monosialogangliotetra ose. The latter could be condensed with (2R, 3R, 4E)-3-O-benzoyl-2-dichloroacetamido-1-iodo-4-octadecen -3-ol in methanolic sodium acetate to afford a protected lyso-SGM1 derivative. One-step removal of the protecting groups under alkaline conditions gave beta-monosialogangliotetraosyl thiosphingosine. This lyso-SGM1 was converted into labeled analogues of SGM1 using the N-succinimidoyl derivative of radiocarbon-labeled octanoic and octadecanoic acid, respectively. Subsequent actions of GM1-beta-galactosidase, beta-hexosaminidase A, sialidase and again GM1-beta-galactosidase on these labeled analogues of SGM1 in the presence of taurodeoxycholate produced the respective analogues of GM2, GM3, lactosylceramide and glucosylceramide, respectively.

Carbohydrate Conformation↗
PubMed1987

Inactivation of GM1-ganglioside beta-galactosidase by a specific inhibitor: a model for ganglioside storage disease.

This study was designed to establish an in vitro model with biochemical and morphological similarities to the human neurodegenerative disease GM1 gangliosidosis. Utilizing a specific inactivator of the lysosomal enzyme GM1-ganglioside beta-galactosidase (beta-D-galactopyranosylmethyl-p-nitrophenyltriazene [beta-GalMNT]) and neuroblastoma X glioma hybrid cells (NG108-15), we suppressed beta-galactosidase activity for up to 72 hours. Coincidental with suppression of this enzyme to levels less than 1% of control, we found up to a nine-fold accumulation of its substrate, the GM1-ganglioside, and the ultrastructural appearance of membranous cytoplasmic bodies. beta-GalMNT treatment suppressed growth but had little effect on the specific activity of choline acetyltransferase, lactate dehydrogenase, or other lysosomal enzymes including galactosylceramidase. This model should permit studies of the neurophysiological effects of increased ganglioside accumulation and their reversibility.

Brain↗
PubMed1983

Ganglioside-basic protein interaction: protection of gangliosides against neuraminidase action.

The ability of acidic phospho- and sphingolipids to interact with basic proteins was studied by double diffusion analysis. The phospholipids, tri- and diphosphoinositide, and the sphingolipid, sulfatide, interacted with myelin basic protein as evidenced by precipitin line formation. Of the sialoglycosphingolipids (gangliosides) tested, only the myelin-specific monosialoganglioside, GM4, formed a precipitin line with myelin basic protein. In addition, myelin basic protein retarded the activity of Clostridium perfringens neuraminidase against GM4 and the disialoganglioside, GD1b. Examination of purified rat brain myelin suggested the presence of a neuraminidase activity intrinsic to myelin. This finding, in concert with ganglioside-myelin basic protein complexes which selectively protect against neuraminidase, may provide a physiological explanation for the simplified ganglioside pattern found in myelin.

Animals↗
PubMed1986

Ganglioside GM1, a molecular target for immunological and toxic attacks: similarity of neuropathological lesions induced by ganglioside-antiserum and cholera toxin.

Ganglioside-antisera, the ganglioside GM1-ligands, cholera toxin (CT), and CT subunit B, respectively, were injected into the lumbosacral subarachnoid space of normal rats. The cytotoxic effects of the injected compounds on the peripheral and central nervous system were investigated by light and electron microscopy; the severity of CNS lesions was evaluated by quantitation of macrophages containing debris. In contrast to control sera and GM2-antiserum, antisera against a mixture of the major brain gangliosides GM1, GD1a, GD1b, and GT1b (MaBG) or against GM1 induced demyelination in spinal roots and spinal cord, as well as alterations of astroglia. CT induced the same cytotoxic effects as MaBG- and GM1-antisera, whereas CT subunit B was without effect. The ineffectiveness of GM2-antiserum is obviously due to the very low concentration of the specific binding target, GM2, on cell surfaces; that of CT subunit B to the lack of the cytotoxic operator, subunit A. Our results indicate that a similar pattern of neuropathological lesions may be effected by different cytotoxic mechanisms through attachment of the cytotoxic agent onto the cell surface via a common target molecule, and further substantiate the role of GM1-antibodies in the pathogenesis of demyelination.

Animals↗
PubMed1992

Anti-GM3-lactam monoclonal antibodies of the IgG type recognize natural GM3-ganglioside lactone but not GM3-ganglioside.

Immunization of mice with a synthetic GM3-lactam-BSA (bovine serum albumin) conjugate (designed to emulate the corresponding natural GM3-lactone conjugate), followed by fusion of splenocytes with myeloma cells, gave rise to more than 300 monoclonal hybridomas producing antibodies to GM3-lactam-BSA, which did not react with Glc-BSA and BSA. Eight antibody clones were randomly chosen from the positive 300 hybridomas. The eight clones, all belonging to the IgG class, were unreactive against GM3-ganglioside, whereas two antibodies (P5-1 and P5-3, both IgG1, kappa) reacted with GM3-ganglioside lactone. Binding of these two antibodies to the GM3-lactam-BSA conjugate was inhibited by soluble glycosides of GM2-, GM3-, and GM4-lactam and by GM3- and GM4-lactam, respectively, but not by Gb3 or asialo-GM1 and GM2-saccharides. A third antibody (P3; IgG2b, kappa) was inhibited by GM2-, GM3-, and GM4-lactam, but did not recognize GM3-ganglioside lactone.

Animals↗
PubMed1999

High levels of GM(1)-ganglioside and GM(1)-ganglioside beta-galactosidase in the parotid gland: a new model for secretory mechanisms of the parotid gland.

A new model for the subcellular basis of parotid secretion is presented in this article. GM(1)-ganglioside, typically found in neural tissues, is shown to be abundant in the parotid gland. This ganglioside may play a central role in membrane turnover mechanisms underlying exocytosis/endocytosis in its role as a promoter of membrane fusion or a fusogen. The lysosome and lysosomal hydrolases also play a central role in this model in catabolism of GM(1)-ganglioside. Consequently, high levels of the lysosomal hydrolase acidic beta-galactosidase are demonstrated in the salivary gland. GM(1)-gangliosidosis of the parotid glands, as described in mice, appears to be the first single-gene heritable disease found so far in the salivary glands.

Adenoma, Pleomorphic↗
PubMed1997

Interaction between botulinum neurotoxin type A and ganglioside: ganglioside inactivates the neurotoxin and quenches its tryptophan fluorescence.

This study found that ganglioside quenched the tryptophan fluorescence of botulinum neurotoxin type A (BoNT A), accompanied by the inactivation of the toxin under low ionic strength conditions. This finding suggests that the ganglioside-binding site of BoNT A contains tryptophan residues. The quantum yield (a conformation parameter) in BoNT A under high ionic strength conditions differed from that under low ionic strength. This observation indicates that high ionic strength may alter the conformation of BoNT A, resulting in failure of the interaction between BoNT A and ganglioside.

Botulinum Toxins, Type A↗
PubMed1979

Gangliosides of human erythrocytes. A novel ganglioside with a unique N-acetylneuraminosyl-(2 leads to 3)-N-acetylgalactosamine structure.

A novel ganglioside having both N-acetylgalactosamine and N-acetylglucosamine was isolated from human erythrocyte membranes. Its structure was characterized by successive exoglycosidase treatment, methylation analysis, and direct-probe mass spectrometry of permethylated intact and desialylated glycolipid. The core structure of the ganglioside was found to be N-acetylgalactosaminyl paragloboside with sialosyl substitution by 2 leads to 3 linkage at the terminal GalNAc residue: NeuNAc alpha 2 leads to 3 GalNAc beta 1 leads to -3Gal beta 1 leads to 4 GlcNAc beta 1 leads to 3 Gal beta 1 leads to 4Glc leads to Cer. The ganglioside was characterized by the presence of a ceramide with myristic acid as the major component.

Acetylgalactosamine↗
PubMed1996

Distinctive ganglioside patterns revealed by anti-ganglioside antibody binding to differentiating CG-4 oligodendrocytes.

Oligodendrocytes are central nervous system glial cells responsible for myelination of neuronal axons. During brain development oligodendrocyte progenitor cells progress through a series of morphologically and immunohistochemically distinct differentiation steps leading to mature myelin-producing oligodendrocytes. Much of this same differentiation sequence is expressed in vitro by primary oligodendrocyte progenitor cells, and by the clonal progenitor cell line CG-4. We report the use of highly specific monoclonal antibodies against GM1, GD1a, GD1b, GT1b, and GQ1b to determine major brain ganglioside expression and morphological distribution during CG-4 differentiation in vitro. Prominent anti-GD1b antibody stained defined a highly arborized intermediate stage of oligodendrocyte differentiation. In contrast, anti-GT1b antibody bound to discrete patches on the cell bodies of early progenitor cells and more mature oligodendrocytes, and to sites of progenitor arborization. The other anti-ganglioside antibodies tested did not bind above background levels. Cells with anti-GD1b antibody binding and morphology similar to those in differentiating CG-4 cells were detected in rat brain primary cell cultures enriched in oligodendrocyte precursors. The remarkably distinctive ganglioside immunoreactivity on differentiating oligodendrocytes suggests the possibility of a functional role for their surface expression.

Animals↗
PubMed1985

Bioactive gangliosides. IV. Ganglioside GQ1b/Ca2+ dependent protein kinase activity exists in the plasma membrane fraction of neuroblastoma cell line, GOTO.

A ganglioside-stimulated protein phosphorylation system was discovered in plasma membrane fractions of human neuroblastoma cells (GOTO). Gangliosides (GQ1b, GT1a, GT1b, GD1a, GD1b, GD3, and GM1) could stimulate this system. GQ1b showed the most effective stimulation among these gangliosides. The substrate specificity was rather broad. Not only some (de novo) proteins of the membranes but also purified histones and tubulin were phosphate-acceptable. This protein phosphorylation system specifically depended upon Ca2+ (optimum concentration: 50-100 microM). The optimum pH was 7.0-7.5. GQ1b/Ca2+ could not directly activate well known protein kinases (Ca2+/phospholipid-activated protein kinase, Ca2+/calmodulin-activated protein kinase, and cyclic nucleotide-dependent protein kinases). Furthermore, GQ1b could replace neither phospholipids nor calmodulin. Thus, an unknown, new type of protein kinase(s) may be involved in this system. Alternatively, GQ1b may activate some known protein kinase(s) in cooperation with another unknown factor which may be removed during the preparation of the partially purified known protein kinase used in this experiment.

Animals↗