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PubMed1995

Increased tumor cell reactivity and complement-dependent cytotoxicity with mixtures of monoclonal antibodies against different gangliosides.

Melanomas and other cancers of neuroectodermal origin express multiple cell-surface gangliosides in patterns that vary significantly even within the same tumor type. Monoclonal antibodies (mAb) against four of these gangliosides (GM2, GD2, 9-O-acetyl-GD3 and GD3) were tested alone and in combination on 14 tumor cell lines (7 melanomas, 3 neuroblastomas, 3 sarcomas and 1 astrocytoma) using flow cytometry and complement-dependent cytotoxicity (CDC) assays. Increased tumor cell recognition and CDC resulting from the combination of three or four mAb were found in 14/14 tested cell lines, and this was most striking when each mAb was used at suboptimal concentration. At these concentrations, the average mean fluorescence intensity of the 14 cell lines with individual mAb was between 3.0 and 6.8 and increased to 10.8 and 18.8 with the three- and four-mAb mixtures. The average percentage CDC-specific release with individual mAb was 2.0%-8.3%, and 12.3% and 16.6% with the three- and four-mAb combinations. The number of cell lines showing significant mean fluorescence intensity and CDC increased from 2-8/14 with single mAb to 13-14/14 with the mixtures of three or four mAb. Our experimental results support the rationale for active immunization with a polyvalent ganglioside vaccine or passive therapy with a combination of mAb to different gangliosides in patients with tumors of neuroectodermal origin. In addition, our studies have demonstrated that 9-O-acetyl-GD3 is a surprisingly effective target for immune attack, although it is a minor constituent of these cells.

Antibodies, Monoclonal↗
PubMed1993

Antitumor effects of a novel monoclonal antibody with high binding affinity to ganglioside GD3.

Ganglioside GD3, which is one of the major gangliosides expressed on the cell surface human tumors of neuroectodermal origin, has been studied as a target molecule for passive immunotherapy. We established ten kinds of anti-GD3 monoclonal antibodies (mAb) of the mouse IgG3 subclass by immunization with purified GD3 and melanoma cells. One of the established mAb, KM641, showed major reactivity with GD3 and minor reactivity with GQ1b out of 11 common gangliosides in an enzyme-linked immunosorbent assay. Immunostaining of gangliosides, separated on thin-layer chromatography plates, using KM641 revealed that most of the melanoma cell lines contained immunoreactive GD3 and GD3-lactone at a high level, but only the adrenal gland and the urinary bladder out of 21 human normal tissues had immunoreactive GD3. In immunofluorescence, KM641 bound to a variety of living tumor cell lines especially melanoma cells, including some cell lines to which another anti-GD3 mAb R24, established previously, failed to bind. High-affinity binding of KM641 to a tumor cell line was quantified by Scatchard analysis (Kd = 1.9 x 10(-8) M). KM641 exerted tumor-killing activity in the presence of effector cells or complement against melanoma cells expressing GD3 at a high level. Not only natural killer cells but also polymorphonuclear cells were effective as the effector cells in antibody-dependent cellular cytotoxicity. Intravenous injection of KM641 markedly suppressed the tumor growth of a slightly positive cell line, C24.22 (7.2 x 10(5) binding sites/cell), as well as a very GD3-positive cell line, G361 (1.9 x 10(7) binding sites/cell), inoculated intradermally in nude mice. KM641, characterized by a high binding affinity for GD3, has the potential to be a useful agent for passive immunotherapy of human cancer.

Animals↗
PubMed1994

Efficacy of tumor cell vaccine after incorporating monophosphoryl lipid A (MPL) in tumor cell membranes containing tumor-associated ganglioside.

Murine B16 melanoma expresses the ganglioside GM3. GM3 shed from tumor cells is immunosuppressive and promotes tumor growth. Reduction or elimination of the shed GM3 could be therapeutic, and the anti-GM3 antibodies may reduce and clear the shed ganglioside. To test this hypothesis, mice were challenged with tumor cells, with or without inducing anti-GM3 antibody response. Since gangliosides are poor immunogens and T-cell independent antigens, an adjuvant (monophosphoryl lipid A (MPL), a non-toxic lipid A of Salmonella), directed against B-cells, was employed. MPL was incorporated onto liposomes and into the surface membrane of B16 mouse melanoma cells; both are rich in GM3. C57BL/6J mice immunized with MPL-liposomes or MPL-B16 cells responded with elevated levels of anti-GM3 IgM. Non-immunized mice or mice immunized with B16 cells alone or ganglioside GM3 alone (without MPL) elicited poor anti-GM3 IgM response, confirming the GM3's immunologic crypticity and MPL's immunopotentiating effect. MPL's immunopotentiating effect was improved by coupling it to melanoma cell membranes. C57BL/6J mice were immunized with irradiated B16 alone or MPL alone or MPL-conjugated irradiated B16. After three weekly immunizations, each mouse received a challenge dose of viable syngeneic B16. Neither MPL alone nor B16 alone had a significant effect on tumor growth or host survival; however, administration of MPL-conjugated B16 cells significantly prevented tumor growth and prolonged survival. Our results indicate that MPL-incorporated B16 cells augment the anti-GM3 IgM response, which may reverse GM3-induced immunosuppression by eliminating tumor-derived GM3, and restore immunocompetence.

Adjuvants, Immunologic↗
PubMed1981

Interferon induces an antiviral state in ganglioside-deficient transformed mouse fibroblasts.

The antiviral activity of mouse fibroblast interferon against vesicular stomatitis virus was investigated in L-929 mouse fibroblasts and the ganglioside-deficient L-929 mutant cells (ATCC clone NCTC 2071). Although it has been widely reported that gangliosides serve as primary receptors for interferon at the cellular membrane, only a small difference in interferon sensitivity was observed between the wild-type L-929 and the ganglioside-deficient NCTC 2071 cells. It was not possible, however, to overcome this difference by administration of exogenous gangliosides.

Animals↗
PubMed1992

Are CSF or serum ganglioside antibodies related to peripheral nerve demyelination in neuroborreliosis, Guillain-Barré syndrome, or chronic inflammatory demyelinating polyradiculoneuropathy?

Cerebrospinal fluid (CSF) and serum IgG and IgM antibodies to seven gangliosides were determined in patients with neuroborreliosis (NB) (n = 20), Guillain-Barré syndrome (GBS) (n = 13), and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (n = 10). The incidence of elevated antibodies was highest in NB and lowest in CIDP. Correlation between CSF and serum antibodies was only observed for IgG antibodies to GM1, GD1b and GT1b in GBS. The strong IgM antibody reactivity to gangliosides in the CSF of NB patients may be involved in the variety of neurological disorders attributed to Borrelia burgdorferi infection. Since one CIDP and three GBS patients had serologic evidence of prior or concurrent borrelia infection, this infection may belong to the infections that can trigger GBS or CIDP. The lack of specific ganglioside antibody patterns in these four patients suggests that ganglioside antibodies are not the link between Borrelia burgdorferi infection and the demyelination of peripheral nerves in GBS and CIDP.

Adult↗
PubMed1977

Influence of trichloroacetic acid-phosphotungstic acid on the thin layer chromatographic mobility of gangliosides.

Trichloroacetic acid (TCA)-phosphotungstic acid (PTA) precipitation has been used as a faster procedure than dialysis for the isolation of gangliosides, but the TCA-PTA treatment causes striking abnormalities in the thin layer chromatographic mobilities of the gangliosides. However, a normal chromatographic pattern can be restored by treating the precipitated gangliosides with the tetrasodium salt of ethylenediamine tetraacetic acid followed by dialysis. Hence, TCA-PTA treatment does not appear to cause artifacts or hydrolysis of the gangliosides.

Brain Chemistry↗
PubMed1983

Effect of methylmercuric chloride on gangliosides of mouse neuroblastoma cells in culture.

The effect of methylmercuric chloride (CH3HgCl) on the levels of gangliosides in mouse neuroblastoma cells (NBP2) in culture was studied. The treatment of NB cells with low concentrations (0.1 microM and 0.2 microM) of CH3HgCl, which did not affect the growth rate or morphology, caused an increase in the level of the GM3 ganglioside without changing the level of other gangliosides. The treatment of NB cells with higher concentrations (0.5 microM and 1 microM) of CH3HgCl, which inhibited the growth of NB cells, caused a decrease in the level of GM3 and an increase in the level of GM2. These results show that alterations in the levels of specific gangliosides can be observed in cells which do not exhibit any detectable change in growth rate or morphology. This change may be associated with subtle changes in brain functions, including behavioral and psychological changes, after exposure to low concentrations of organic mercury.

Animals↗
PubMed1988

Human placenta gangliosides.

Gangliosides extracted from human placenta were composed of four major components (G1-G4), which were purified by silica beads column chromatography. The structures of these gangliosides were analyzed by exoglycosidase treatments, 400 MHz proton magnetic resonance spectroscopy and gas chromatography-mass spectrometry and were concluded to be as follows: (Formula: see text). Gangliosides containing more than 10 sugar residues were observed in addition to the above four major components. But ganglio-series gangliosides were undetectable in the placenta.

Amino Sugars↗
PubMedDate not supplied

Ganglioside treatment in diabetic peripheral neuropathy: a multicenter trial.

Ganglioside treatment was evaluated with a multicenter, randomized, double-blind, controlled, cross-over vs placebo trial in 140 insulin-treated diabetic subjects with peripheral neuropathy. The patients entered the study when they showed an impairment in at least two of the electroneurographic parameters, and were assigned to two protocols according to the presence and severity of their neurological symptoms. Ninety-seven diabetic subjects with no or mild symptoms were assigned to protocol I, whereas 43 symptomatic patients were assigned to protocol II. the treatment periods lasted 6 weeks with an intermediate washout period of 4 weeks. The treatment consisted in the daily i.m. administration of 20 mg gangliosides or of placebo. Electroneurographic parameters were recorded at the beginning and at the end of each treatment period, whereas clinical and metabolic data (mean daily plasma glucose, glycosuria and glycosylated hemoglobin) were evaluated every three weeks in protocol I and every two weeks in protocol II. No change in the metabolic parameters was observed throughout the trial period. However, the treatment induced a statistically significant improvement of paresthesias (protocol II) and of some electrophysiological parameters; in particular, ganglioside treatment improved MCV of peroneal nerve (p less than 0.03) in patients of protocol I, MCV o ulnar nerve (p less than 0.002) and SCV of median nerve (p less than 0.06) in patients of protocol II. Furthermore, 22 subjects of protocol II showed a 'drug preference' while 10 preferred placebo and 9 had no preference. In conclusion, ganglioside treatment seems to have a positive effect on diabetic peripheral neuropathy, improving both some symptoms and some electrophysiological parameters.

Adolescent↗
PubMedDate not supplied

Region distribution of the gangliosides in rat brain after chronic ethanol treatment.

In this study the effects of chronic ethanol administration on the regional distribution of brain gangliosides were investigated. A total of 36 60-d-old male Wistar rats weighing approximately 200 g was divided into two groups of 18 animals each. The ethanol-consuming group was offered drinking fluid (25% sucrose-32% ethyl alcohol, w/w) ad libitum, and the control group was given a sucrose solution isocaloric with the ethanol-sucrose solution. After 6 mo of chronic ethanol treatment, cerebral cortex, N. caudatus, hypothalamus, thalamus, and hippocampus were analyzed with respect to their ganglioside pattern (GM2, GM1, GD1a, GD1b, GT1b, and GQ). The results showed that there were highly significant effects of ethanol on hypothalamus GD1b and GT1b, thalamus GM1 and GD1a, and hippocampus GM1, GD1b, and GT1b ganglioside distribution. It was found that ethanol differently affected the gangliosides in these brain regions.

Animals↗
PubMed2005

Exogenous gangliosides, neuronal plasticity and repair, and the neurotrophins.

Gangliosides, a heterogeneous family of glycosphingolipids abundant in the brain, have been shown to affect neuronal plasticity during development, adulthood and aging. This review will examine old and recent evidence that exogenous gangliosides and in particular GM1, the prototype member of this family, exhibit multimodal neurotrophic effects. Since these compounds are a potential therapeutic tool for the treatment of various forms of acute or chronic neurodegenerative diseases, understanding the dynamic interplay of gangliosides and neuronal cells is essential in the effort to cure neurological disorders. Focus will be given to the novel and provocative hypothesis that gangliosides' neuroprotective properties may derive from their ability to mimic endogenous neurotrophic factors.

Gangliosides↗
PubMed1997

Quartz crystal microbalance investigation of the interaction of bacterial toxins with ganglioside containing solid supported membranes.

The binding of cholera toxin, tetanus toxin and pertussis toxin to ganglioside containing solid supported membranes has been investigated by quartz crystal microbalance measurements. The bilayers were prepared by fusion of phospholipid-vesicles on a hydrophobic monolayer of octanethiol chemisorbed on one gold electrode placed on the 5 MHz AT-cut quartz crystal. The ability of the gangliosides GM1, GM3, GD1a, GD1b, GT1b and asialo-GM1 to act as suitable receptors for the different toxins was tested by measuring the changes of quartz resonance frequencies. To obtain the binding constants of each ligand-receptor-couple Langmuir-isotherms were successfully fitted to the experimental adsorption isotherms. Cholera toxin shows a high affinity for GM1 (Ka = 1.8.10(8)M-1), a lower one for asialo-GM1 (Ka = 1.0.10(7)M-1) and no affinity for GM3. The C-fragment of tetanus toxin binds to ganglioside GD1a, GD1b and GT1b containing membranes with similar affinity (Ka approximately 10(6)M-1), while no binding was observed with GM3. Pertussis toxin binds to membranes containing the ganglioside GD1a with a binding constant of Ka = 1.6.10(6)M-1, but only if large amounts (40 mol%) of GD1a are present. The maximum frequency shift caused by the protein adsorption depends strongly on the molecular structure of the receptor. This is clearly demonstrated by an observed maximum frequency decrease of 99 Hz for the adsorption of the C-fragment of tetanus toxin to GD1b. In contrast to this large frequency decrease, which was unexpectedly high with respect to Sauerbrey's equation, implying pure mass loading, a maximum shift of only 28 Hz was detected after adsorption of the C-fragment of tetanus toxin to GD1a.

Cholera Toxin↗
PubMed2000

A longitudinal study of autoantibodies against central nervous system tissue and gangliosides in connective tissue diseases.

Our objective was to investigate longitudinally, antibodies against central nervous tissue (anti-CNS) derived from bovine brain and gangliosides GM 1, GD1a, GD1b, and GT1b in 91 patients with connective tissue diseases (systemic lupus erythematosus, n = 38; mixed connective tissue disease, n = 16; primary Sjogren's syndrome, n = 7; progressive systemic sclerosis, n= 13; polymyositis/dermatomyositis, n=4; overlap syndrome, n = 5; undifferentiated connective tissue disease, n = 8). Anti-CNS and anti-ganglioside antibodies, measured by enzyme-linked immunosorbent assay, were found in 73% and 63% of patients, respectively. Anti-CNS positive sera were also reactive in Western blotting in 74% of cases and recognized up to 14 different polypeptides from 29 to 130 kDa. Anti-CNS and anti-ganglioside antibodies reflected only in a limited extent the disease activity. In 27 of 58 patients, anti-CNS antibodies remained positive independently of disease activity and antibody levels did not correlate with the phases of exacerbations. A total of 36 of 60 anti-CNS-positive patients, in contrast to two of 22 anti-CNS-negative patients, had major neuropsychiatric manifestations (P < 0.001). Anti-ganglioside antibodies were not significantly associated with neuropsychiatric manifestations. In conclusion, our longitudinal data suggest that anti-CNS antibodies may be an important marker for the diagnosis of cerebral involvement in connective tissue diseases, but the pathogenic role of these autoantibodies remains to be determined.

Adolescent↗
PubMed2005

Uptake of [3H]-gangliosides by an intestinal protozoan, Giardia lamblia.

Because of their limited lipid synthesis ability it has been postulated that Giardia lamblia trophozoites depend on lipid remodeling reactions, to generate parasite-specific phospho and glycolipids. We have shown earlier that exogenous bile acids and lipid molecules are taken up by Giardia through active transport and by other mechanisms. Another report suggests that lipoprotein-like receptors may be present in this parasite that are involved in lipid endocytosis. In the present investigation, we asked whether and by what mechanism exogenous gangliosides can be taken up by Giardia. We found that ganglioside uptake was dependent, on time and concentration, but was not temperature- or carrier-dependent. Gangliosides encapsulated into liposomes were taken up much more effectively than non-encapsulated gangliosides. These results are consistent with a passive uptake process, facilitated by membrane fusion with lipid carriers, but not dependent on a catalytic carrier mechanism. This observation may have some therapeutic implications.

Animals↗
PubMed2005

Clinical evidences of GM3 (NeuGc) ganglioside expression in human breast cancer using the 14F7 monoclonal antibody labelled with (99m)Tc.

The relevance of certain gangliosides in tumour growth and metastatic dissemination has been well documented, reasons for considering these molecules as potential targets for cancer immunotherapy and diagnosis. GM3(NeuGc) ganglioside is particularly interesting due to its restrictive expression in normal human tissues according to immunohistochemical studies, using either polyclonal or monoclonal antibodies. But both immunohistochemical and biochemical methods have strongly suggested its over-expression in human breast tumours. Nevertheless, the lack of a direct evidence of this antigenic display in human breast cancer has kept the subject controversial. For the first time, we described herein the "in vivo" detection of GM3(NeuGc) ganglioside in human breast primary tumours using a radioimmunoscintigraphic technique with 14F7, a highly specific anti-GM3(NeuGc) ganglioside monoclonal antibody, labelled with (99m)Tc. In an open, prospective Phase I/II clinical trial, including women diagnosed in stage II breast cancer, the 14F7 monoclonal antibody accumulation in tumours at doses of 0.3 (n=5), 1 (n=5) and 3 mg (n=4) was evaluated. Noteworthy, the immunoscintigraphic study showed antibody accumulation in 100% of patients' tumours for the 1 mg dose group. In turn, the radioimmunoconjugate injected at doses of 0.3 mg or 3 mg of the antibody, was uptaken by 60 and 33.3% of breast tumours, respectively. "In vivo" immune recognition of GM3(NeuGc) in breast tumours reinforces the value of this peculiar target for cancer immunotherapy.

Adolescent↗
PubMed2001

Bovine milk gangliosides: changes in ceramide moiety with stage of lactation.

The stage of lactation is one of the most important factors that influence milk composition. Changes in fatty acids from triacylglycerols and phospholipids have already been reported. In this study, we looked for a lactational change in the ganglioside lipid moiety since ganglioside contents and patterns vary strongly with stage of lactation. Individual gangliosides from four stages were isolated, methanolized to cleave the bonds between individual constituents, and derivatized for gas-liquid chromatography and gas chromatography/mass spectrometry analyses. Ceramide components, both fatty acids (as methyl esters derivatives) and long-chain bases, were identified and quantified. The results pointed to a marked change in ceramide from colostrum to milk that was characterized by a dramatic decrease in saturated and the longest-chain fatty acids as well as an increase in 18:1 and 18:2. The major long-chain base along lactation was a recently described structure, 3-ethoxy-15:0 sphinganine. Other new long-chain base structures appeared in these gangliosides. All these changes suggest differences in the fluidity of the fat globule membrane, reflecting physiological variations in cows with respect to milk production.

Animals↗
PubMed1992

The characteristic negative Cotton effect of ganglioside lactones observed by circular dichroism spectrometry.

Circular dichroism spectrometry was applied to gangliosides and their lactones and revealed that the lactones have a characteristic strong negative Cotton effect around 235 nm. Four monolactones and two dilactones, which were formed from GM4, GD3, and GD1b, gave molar ellipticities at the wavelength in magnitude of 10(4), while their parent gangliosides, along with other gangliosides such as GM3, GM1, GD1a, GT1b, and GQ1b, showed no distinct feature. Two ganglioside esters, GM4-methyl ester and O-Ac-GT1b did not show the Cotton effect. The molar ellipticities had an additivity with respect to the number of lactone rings. The Cotton effect was attributed to the carbonyl group on the lactone ring.

Animals↗
PubMed1986

A new ganglioside in human meconium detected with antiserum against human milk sialyltetrasaccharide a.

Antiserum directed against the alditol derivative of the human milk monosialyloligosaccharide sialyltetrasaccharide a [D. F. Smith, P. A. Prieto, and B. V. Torres (1985) Arch. Biochem. Biophys. 241, 298-303] is used to detect a new ganglioside in human meconium by direct binding on nitrocellulose filters of the sialyl[3H]oligosaccharide alditol obtained from gangliosides after ozonolysis and alkali fragmentation. The sialyl[3H]oligosaccharide is purified by affinity chromatography on a column containing anti-sialyltetrasaccharide a antibodies. The affinity-purified sialyl[3H]oligosaccharide cochromatographs with the 3H-labeled alditol derivative of authentic sialyltetrasaccharide a from human milk. Results of sequential enzyme degradation of the pure sialyl[3H]oligosaccharide and cochromatography of the digestion products with standards are consistent with the presence in meconium of a monosialylganglioside with the structure NeuAc alpha 2-3Gal beta 1-3GlcNAc beta 1-3Gal beta 1-4Glc-ceramide. This ganglioside is presumably the biosynthetic precursor of the sialyl-Lea ganglioside [G. C. Hansson and D. Zopf (1985) J. Biol. Chem. 260, 9388-9392], which is also a component of human meconium.

Chromatography, Affinity↗