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PubMed2003

Induction of cellular immunity by anti-idiotypic antibodies mimicking GD2 ganglioside.

Gangliosides are potentially useful targets for tumor destruction by antibodies. However, the role of gangliosides in T cell-mediated immunity to tumors is unclear. We produced three murine monoclonal anti-idiotypic antibodies (Ab2) against a monoclonal antibody (Ab1) that binds strongly to melanoma-associated GD2 ganglioside and weakly to GD3 ganglioside. All three Ab2 induced anti-anti-idiotypic antibodies (Ab3) with Ab1-like binding specificity to tumor cells and antigen in rabbits. The Ab3 specifically bound to GD2(+) tumor cells and isolated GD2, and shared idiotopes with the Ab1. Two of the three Ab2 induced GD2-specific delayed-type hypersensitivity responses in BALB/c and C57BL/6 mice, but not in C57BL/6/CD4(-/-) mice. Peripheral blood mononuclear cells (PBMC) from a melanoma patient proliferated specifically in response to in vitro stimulation with Ab2. Proliferation was accompanied by Th1-type cytokine production. Our studies demonstrate the induction of ganglioside-specific T cell-dependent immunity by Ab2 in mice. These T cells showed specific reactivity to ganglioside expressed by tumor cells.

Animals↗
PubMed1983

Recognition by two-dimensional thin-layer chromatography and densitometric quantification of alkali-labile gangliosides from the brain of different animals.

A simple method for recognition and quantification of alkali-labile gangliosides is described. The method was worked out using authentic alkali-labile gangliosides in pure form (9-O-Ac-GT1b; 9-O-Ac-GQ 1b; lactone form of GD 1b) and applied to ganglioside mixtures from the brain of mouse, rat, rabbit, pig, and pigeon. The method consists of two-dimensional thin-layer chromatography on silica gel high-performance thin-layer chromatography plates employing the same solvent, chloroform/methanol/0.2% aqueous CaCl2, 50/40/10, for both runs. Prior to the second run the plate is exposed at room temperature for 5 h to ammonia vapors in order to split alkali-labile linkages. At the end of chromatography alkali-stable gangliosides appear lined along a diagonal starting from the origin; the spots corresponding to alkali-labile gangliosides lie out of the diagonal and can be individually detected and quantified on the basis of their sialic acid content. Up to 15 different spots, corresponding to as many alkali-labile gangliosides, can be recognized by this procedure.

Animals↗
PubMed1986

A radiometric assay for ganglioside sialidase applied to the determination of the enzyme subcellular location in cultured human fibroblasts.

A radiometric method for the assay of ganglioside sialidase in cultured human fibroblasts was set up. As substrate, highly radioactive (1.28 Ci/mmol) ganglioside GDla isotopically tritium-labeled at carbon C-3 of the long chain base was employed; the liberated, and TLC separated [3H]GM1 was determined by computer-assisted radiochromatoscanning. Under experimental conditions that provided a low and quite acceptable (4-5%) coefficient of variation, the detection limit of the method was 0.1 nmol of liberated GM1, using as low as 10 micrograms of fibroblast homogenate as protein. The detection limit could be lowered to 0.02-0.03 nmol, adopting conditions that, however, carried a higher analytical error (coefficient of variation over 10%). The content of ganglioside sialidase in human fibroblasts cultured in 75-cm2 plastic flasks was 5.8 +/- 2.5 (SD) nmol liberated GM1 h-1 mg protein-1. Subfractionation studies performed on fibroblast homogenate showed that the ganglioside sialidase was mainly associated with the light membrane subfraction that was rich in plasma and intracellular membranes. This subfraction displayed almost no sialidase activity on the artificial substrate 4-methylumbelliferyl-D-N-acetylneuraminic acid. A small but measurable ganglioside sialidase activity was also present in the lysosome-enriched subfraction, which contained a very high sialidase activity on the above artificial substrate. All this supports the hypothesis that human fibroblasts contain sialidases with different subcellular location and substrate specificity. Particularly, the sialidase acting on gangliosides seems to have two sites of subcellular location, a major one at the level of plasma membranes and/or intracellular organelles functionally related with the plasma membranes and a minor one in the lysosomes.

Cells, Cultured↗
PubMed1984

Inhibition of adenylate cyclase activity of human thyroid membranes by gangliosides.

Gangliosides inhibit basal, thyrotropin-induced and fluoride-induced adenylate cyclase activity of human thyroid membranes in physiological conditions. In contrast neutral glycolipids, phospholipids and neuraminic acid containing oligosaccharides show no effect. The efficacy of inhibition is more dependent upon the position of the sialic acid residues than upon their absolute number. In general gangliosides with disialyl groups are more inhibitory than those with single sialyl moieties. The inhibitory effects of the individual gangliosides on the two modes of stimulation are parallel. This parallelism suggests that the inhibitory effect is located at the postreceptor level and that the gangliosides interact directly with the adenylate cyclase system. A possible role of thyroid membrane gangliosides as suppressive cofactors of adenylate cyclase is discussed in relation to recent findings of stimulating anti-ganglioside antibodies in Graves' disease.

Adenylyl Cyclase Inhibitors↗
PubMed1985

Ganglioside alterations in stimulated murine macrophages.

A two-dimensional thin-layer chromatographic technique has been used to separate and display gangliosides from murine peritoneal macrophages in different functional states. Resident macrophages have a relatively simple ganglioside pattern with about 15 resorcinol-positive spots. Gangliosides from resident cells contained mostly (90%) N-glycolylneuraminic acid. Thioglycolate-elicited and Corynebacterium parvum-activated macrophages have much more complex patterns with about 40 resorcinol-positive spots. Although ganglioside sialic acid content of stimulated macrophages was only slightly higher than that of resident cells, it consisted of nearly equal amounts of N-acetyl- and N-glycolylneuraminic acid. The shift in the ganglioside sialic acid type and the expression of different gangliosides in macrophages upon stimulation may help explain some of the differences in function and responsiveness noted in these macrophage populations.

Animals↗
PubMed1986

Inhibitory effects of gangliosides on immune reactions of antibodies to neutral glycolipids in liposomes.

Specific immune damage to liposomes containing Forssman or globoside glycolipid was inhibited when the liposomes also contained ganglioside. The activity of a human monoclonal Waldenström macroglobulin antibody to Forssman glycolipid was inhibited by each of three gangliosides tested, GM3, GD1a and GD1b. Inhibition of the monoclonal antibody was dependent on the amount of ganglioside in the liposomes, and was diminished by reducing the relative amount of ganglioside. Inhibition also correlated positively with the number of ganglioside sialic acid groups, with inhibition by GT1b greater than GD1a greater than GM3. Naturally occurring human antibodies to globoside glycolipid were detected in 18% (9 out of 50) of normal human sera tested. Immune damage to liposomes induced by each of the three highest-reacting human anti-globoside sera was blocked by liposomal GM3. We conclude that gangliosides can strongly influence immune damage to membranes induced by antibody interactions with adjacent neutral glycolipids.

Antibodies, Monoclonal↗
PubMed1988

Effect of exogenous gangliosides on the lipid composition of chick neurons in culture.

When exogenous gangliosides are added to the growth medium of neuronal cell cultures they are inserted into their plasma membranes and are afterwards metabolized in the cytoplasmic interior. The action of exogenous gangliosides brings important morphological and biochemical changes to neurons in culture. The present report shows that the treatment with exogenous gangliosides of a primary culture of chick neurons modified the distribution of fatty acids in phosphatidylinositol (PI), mainly that of arachidonic acid and the fatty acids of the (n - 3) series without affecting the other phospholipids. The composition of neutral lipids did not change but their content was increased up to 2-3-fold depending upon the concentration of gangliosides. The change of the growth medium from one containing fetal calf serum to a chemically defined one reduced dramatically the content of free fatty acids while the addition of gangliosides raised this content to normal levels. The increase in the amount of diacylglycerol (DG) confirmed the finding that gangliosides stimulate phosphoinositide degradation. Finally the fatty acid composition of DG suggests indirectly that this compound might be produced also by degradation of phosphatidylcholine and not only of PI.

Animals↗
PubMed1990

Modification of the adenylate cyclase activity of bovine thyroid plasma membranes by manipulating the ganglioside composition with a nonspecific lipid transfer protein.

Gangliosides (GM1, GT1b, GD3) were incorporated in bovine thyroid plasma membranes using the nonspecific lipid transfer protein from beef liver. The transfer of GT1b or GD3 in the presence of 16 units of transfer protein was twice as high as that of GM1. However, taking into account the spontaneous exchange (approximately 8% for GT1b or GD3 and 1% for GM1) the transfer protein seemed to be more effective for GM1. Incorporation of these gangliosides in bovine thyroid plasma membranes caused a concentration dependent inhibition of the TSH-stimulated adenylate cyclase activity. The forskolin-stimulated adenylate cyclase activity was not significantly affected by ganglioside modification of the plasma membranes, indicating that the gangliosides do not act at the level of the catalyst of adenylate cyclase. Binding experiments on the other hand revealed that TSH binding to bovine thyroid plasma membranes was inhibited with the same order of efficacy (GT1b greater than GD3 greater than GM1) and to the same extent as their inhibitory effect on TSH stimulation. Therefore, this indicates that the ganglioside induced drop in TSH binding might be an important factor in the decrease in TSH-stimulated adenylate cyclase activity. Incorporation of GT1b or GD3 (approximately 11 nmol) in bovine thyroid plasma membranes, however, also induced a substantial decrease in cholera toxin-stimulated adenylate cyclase activity (approximately 30%) and to a lesser degree a decrease in NaF-stimulated activity (approximately 17%), whereas GM1 incorporation did not significantly affect these stimulated activities. These latter inhibitory effects were paralleled by changes in fluorescence steady-state anisotropy: GT1b modification of the plasma membranes provoked a slight increase in TMA-DPH anisotropy, whereas the anisotropy of DPH was substantially enhanced after incorporation of GD3 or GT1b. These results suggest that gangliosides might also interfere with the coupling between the alpha-subunit of the stimulatory GTP-binding regulatory protein and the catalyst of the adenylate cyclase system by affecting the membrane fluidity.

Adenylyl Cyclases↗
PubMed1975

Gangliosides of chemically and virally transformed rat embryo cells.

The gangliosides of control rat embryo cells, 3-methylcholanthrene, Rauscher leukemia virus, and combined 3-methylcholanthrene-Rauscher leukemia virus transformants were examined using [14 C]glucosamine as a tracer. All four cell lines exhibited a complex pattern of gangliosides. While N-acetylgalactosaminyl-(N-acetylneuraminyl)-galactosyl-glucosyl-ceramide was the major ganglioside in the control cell line, N-acetylneuraminyl-galactosyl-glucosyl-ceramide was the major ganglioside in the three transformants. The 3-methylcholanthrene transformant possessed a ganglioside pattern different from that of the Rauscher leukemia virus transformant. Hydrolysis of the gangliosides indicated that galactosamine, N-acetyl-and N-glycolylneuraminic acid were the labeled components in all cell lines.

Acetylgalactosamine↗
PubMed1980

Separation of gangliosides on a new type of anion-exchange resin.

A new anion exchange resin, Spherosil-DEAE-Dextran, consisting of porous glass beads covered with cross-linked DEAE-Dextran, was used in the separation of gangliosides. The gangliosides were eluted from the resin with a discontinuous gradient of potassium acetate in methanol, separating the gangliosides quantitatively into mono-, di, tri-, tetra- and pentasialoganglioside fractions. The new resin was found to have higher binding capacity, to show less unspecific adsorption and to give a better separation of the higher oligosialogangliosides than did DEA-Spherosil, QAE-Sephadex, DEAE-Sephadex and DEAE-Sepharose. Anion exchange chromatography improved discrimination between closely allied gangliosides as well as quantification and identification of individual gangliosides, especially the minor ones. The new procedure was used in the separation of the gangliosides in human infant forebrain and cerebellum.

Adult↗
PubMed1985

Monoclonal antibodies raised against NeuAc alpha 2-6neolactotetraosylceramide detect carcinoma-associated gangliosides.

Monoclonal antibodies wee obtained by the immunization of mice with 6'LM1 (IV6NeuAc-nLcOse4Cer) adsorbed to Salmonella minnesota. The monoclonal antibodies showed a specificity for gangliosides with a terminal NeuAc alpha 2-6Gal substitution, which was demonstrated in solid-phase binding assay and in liposome inhibition assay. Gangliosides with a NeuAc alpha 2-6Gal substitution were minor components of different normal tissues. However, these gangliosides were enriched in carcinomas of many tissues, and were particularly enriched in most colorectal carcinomas and in lung carcinomas. 6'LM1 is a characteristic ganglioside in fetal intestinal mucosa (meconium). This ganglioside and other gangliosides with a terminal NeuAc alpha 2-6Gal substitution might represent oncofetal antigens expressed in carcinomas owing to an activation of a "fetal' sialyltransferase.

Animals↗
PubMed1988

Specific staining on thin-layer chromatograms of glycosphingolipids of neolacto series and gangliosides with a terminal N-acetylneuraminyl residue by different procedures with wheat germ agglutinin.

Sensitive staining methods with wheat germ agglutinin were developed for the detection of glycosphingolipids of neolacto series (A) and gangliosides with a terminal N-acetylneuraminyl residue (B) on thin-layer chromatograms. (A) Neolacto series glycosphingolipids were treated by beta-galactosidase on the chromatograms in the presence of taurodeoxycholate. Then the chromatograms were incubated with biotinated wheat germ agglutinin followed by incubation with a complex of avidin and biotinated horseradish peroxidase, and the reaction was detected by 4-chloro-1-naphthol. In the case of gangliosides, sialidase treatment on the chromatograms was performed before the beta-galactosidase treatment. The sensitivity of the method for Lc3Cer, nLc4Cer, sialyl-nLc4Cer, and sialyl-nLc6Cer was 4 pmol, 7.6 pmol, 2.9 pmol and 1.4 pmol, respectively. (B) The gangliosides on the chromatograms were oxidized by periodic acid and reduced by NaBH4. Then the chromatograms were stained with wheat germ agglutinin as mentioned above. As little as 0.5 pmol of GM3, NeuAc-nLc4Cer, and NeuAc-nLc6Cer was detected by this method, whereas the detected limits for these gangliosides were 10 pmol, 10 pmol and 2 pmol, respectively, when periodate oxidation was omitted. GM4, GD3 and GD1a were an order less reactive than GM3, GM2, GM1 or GD1b were not stained under the same condition. In contrast to NeuAc-containing gangliosides, any gangliosides with N-glycolylneuraminic acid were not stained by the method in (B).

Chromatography, Thin Layer↗
PubMed1992

Isolation of complex gangliosides from human brain.

A simple procedure that enables the isolation of ganglioside GQ1b and other complex gangliosides from the human brain is described. The tissue was extracted with a mixture of chloroform, methanol, and water, and the extract purified twice by means of silica gel column chromatography and preparative HPTLC. Phase partition and ion exchange chromatography were omitted. The silica gel chromatography was based on a two step developing system, which provided an efficient separation of oligosialogangliosides. The yields of chromatographically homogenous fractions of ganglioside GQ1b isolated from the whole cerebrum, cerebellar cortex and occipital grey matter of a 60-year-old woman were 62, 138 and 110 nmol SA per g of fresh tissue. The problem of co-extraction of protein-positive material with gangliosides into the organic solvents is discussed. Chromatographic search of gangliosides in different regions of the human brain revealed the presence of small quantities of more complex gangliosides than GQ1b.

Brain Chemistry↗
PubMed1987

Ganglioside-induced enhancement of behavioral recovery after bilateral lesions of the entorhinal cortex.

Previous research has shown that exogenous gangliosides improve recovery of learned alternation after unilateral lesions of the entorhinal cortex. Since this recovery is thought to depend upon axonal sprouting, it has been hypothesized that ganglioside-induced improvement may be due to enhanced sprouting. The present study examined the effects of ganglioside treatments on learned alternation after bilateral entorhinal lesions. Whereas control rats exhibited a severe impairment postoperatively, ganglioside-treated (50 mg/kg total brain gangliosides; i.m.) rats committed significantly fewer errors and perseverative errors, and reached criterion sooner. The two groups exhibited comparable rates of daily improvement in performance. Since bilateral entorhinal lesions preclude the sprouting which is important for recovery of alternation, the ganglioside-induced improvement observed in the present study appears to be independent of sprouting.

Animals↗
PubMed1988

A monoclonal antibody, WCC4, recognizes a developmentally regulated ganglioside containing alpha-galactose and alpha-fucose present in the rat nervous system.

A monoclonal antibody, WCC4, raised against PC12 cells, recognizes a ganglioside which is present in low concentrations in the postnatal rat nervous system. The antigen is also present in the adrenal and kidney, as determined immunohistochemically, but is not detectable in liver or spleen. A neutral glycosphingolipid is also immunoreactive. In the present report, the chemical characterization of this ganglioside, isolated from PC12 cells, and the anatomical distribution of the antigens recognized by the WCC4 antibody are described. By enzymatic cleavage of terminal saccharide moieties, the ganglioside is identified as alpha-galactosyl, (alpha-fucosyl) GM1. The ganglioside increases in concentration postnatally to day 35 (P35) and is present in a slightly diminished concentration in the adult. Immunohistochemical studies revealed that this glycolipid is also present on neuronal cell soma throughout the cerebrum, cerebellum and spinal cord. It is expressed in highest concentration in the molecular layer of the dentate gyrus and is also present in the olfactory bulb, the molecular layer of the hippocampus, the piriform cortex, the olfactory tubercle and the entorhinal cortex. The dentate molecular layer receives most of its innervation from neurons in the entorhinal cortex, and gangliosides are known to have an effect on plasticity following entorhinal cortical lesions. Therefore, the WCC4 antibody should prove to be a useful tool for the study of the role of endogenous gangliosides in this region of the nervous system.

Adrenal Gland Neoplasms↗
PubMed1993

Alterations and recovery of rat brain gangliosides and glycosidases following long-term exposure to alcohol and rehabilitation during development.

The present study examines effects of continuous exposure to alcohol during gestation, lactation and postweaning periods and rehabilitation on gangliosides and their catabolizing enzymes in whole brain (WB), cerebrum (C), cerebellum (CB) and brain stem (BS) of 63-day-old rats. Continuous exposure to alcohol was found to cause significant deficits in the body and brain weights. On the other hand, the concentration of total ganglioside in whole brain, cerebrum, cerebellum and brain stem showed an increase following exposure to alcohol. In agreement with the increased ganglioside concentration the activities of sialidase, beta-galactosidase, beta-glucosidase and beta-hexosaminidase, which are likely to be involved in the catabolism of gangliosides, showed reductions due to alcohol. Alcohol was also found to alter the proportions of individual gangliosides and the changes were found to be region-specific. However; the alcohol-induced alterations were reversed, at least to some extent, upon abstinence from alcohol. Body weights of control (CT), alcoholic (AC) and rehabilitated (AR) rats were 164 +/- 2, 107 +/- 7 and 139 +/- 3 (mean +/- S.E.M.), respectively. Decrease in tissue weight was significant in whole brain, cerebrum and brain stem but not in cerebellum. In AR rats significant deficits in tissue weights persisted in cerebrum and almost a complete recovery was observed in brain stem. On the other hand, the increase in the concentration of gangliosides in WB, C, CB and BS of AC rats amounted to 23, 19, 19 and 53% of controls, respectively. The corresponding values for the AR rats were 12, 14, 3 and 5%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Rat cerebellar granule cells in culture associate and metabolize differently exogenous GM1 ganglioside molecular species containing a C18 or C20 long chain base.

A study has been made of the association properties of the two GM1 ganglioside molecular species GM1-C18 and GM1-C20 (containing C18 and C20 long chain bases, respectively) to rat cerebellar granule cells in culture. Both gangliosides recognized, to the same extent, and associated with them to give a form of association, the trypsin-labile form. This form was removed by treatment with trypsin enzyme. Both gangliosides associated stably with the cells to become components of the cell membranes. Although similar amounts of the two gangliosides entered the cells, being then metabolized, the time course of the association was different for the two gangliosides: after 15 h of ganglioside-cell incubation the amount of GM1-C18 inserted into the cell membrane was 2.43 times higher than that of GM1-C20.

Animals↗
PubMed1983

Association of ganglioside-protein conjugates into cell and Sendai virus. Requirement for the HN subunit in viral fusion.

A method is described for preparing a covalent conjugate of proteins, in particular antibodies and their fragments, with gangliosides in the micellar form. The protein-ganglioside conjugate is associated with ganglioside micelles and can be separated from free protein by molecular sieve chromatography. Conjugates can irreversibly transfer from the micelle to a cell membrane of choice, and the protein portion be identified as a new surface antigen. The successful application of this methodology has been demonstrated with three biological systems. Rabbit IgG-ganglioside conjugate has been transferred to human or sheep erythrocytes, which have been hemagglutinated with goat anti-rabbit IgG. Erythrocytes modified with ganglioside-anti-H2Kk have been shown to adhere to monolayers of L929 mouse fibroblasts which express H2Kk-antigen. Mouse monoclonal anti-glycophorin ganglioside conjugate can associate with Sendai virus and confer upon the virus the ability to agglutinate and hemolyse desialylated human erythrocytes. Using the anti-glycophorin conjugate, we demonstrated that the HN subunit, which is normally responsible for viral binding, appears also to be essential for fusion activity, because its destruction eliminates hemolysis and fusion, but not agglutination, by the conjugate-modified virus.

Animals↗