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PubMed1999

A human monoclonal antibody encoded by the V4-34 gene segment recognises melanoma-associated ganglioside via CDR3 and FWR1.

A heterohybridoma cell line producing the human monoclonal antibody (MoAb) MDT.1 has been established. The heavy chain of MoAb MDT.1 is encoded by the VH gene segment V4-34 (previously designated VH4-21), and the light chain is encoded by the V kappa 1-L12a gene segment, both in germline configuration. MDT.1 has reactivity against lipid A, double- and single-stranded DNA, red blood cell associated i antigen, and ganglioside antigens. In a panel of tumour cell lines, MDT.1 reacted specifically with melanoma cells and other tumour cells of neuroectodermal origin. Cellular recognition appears to be via tumour-associated ganglioside antigens, and may involve the minimal essential epitope NeuNac alpha 2-->3Gal beta 1-->-4Glc-. Binding to ganglioside antigen is inhibited by the monoclonal anti-idiotypic antibody 9G4. Since the 9G4 idiotope is located in framework region 1 (FWR1) of V4-34-encoded antibodies, this region is likely to be involved, either directly or indirectly, in ganglioside binding. The complementarity-determining region 3 (CDR3) of MDT.1 is arginine rich, with five out of 12 residues being arginine and these residues are candidates for interaction with the negatively charged ganglioside. The ability of MoAb MDT.1 to recognise ganglioside antigens is associated with potentially useful anti-tumour activity.

Amino Acid Sequence↗
PubMed1998

Anti-ganglioside antibody and neuropathy: review of our research.

Some patients developed Guillain-Barré syndrome (GBS) after the administration of bovine gangliosides. Patients with GBS subsequent to Campylobacter jejuni enteritis frequently have IgG antibody to GM1 ganglioside. Fisher's syndrome (FS), a variant of GBS, is associated with IgG antibody to GQ1b ganglioside. We showed the existence of molecular mimicry between GM1 and lipopolysaccharide (LPS) of C. jejuni isolated from a GBS patient, and that between GQ1b and C. jejuni LPSs from FS patients. Several lines of evidence suggest a pathogenic role for anti-ganglioside antibodies. Some patients developed sensorimotor polyneuropathy after anti-GD2 antibody administration. Anti-GM1 antibody can block motor nerve conduction. The molecular mimicry between infectious agents and gangliosides may function in the production of anti-ganglioside antibodies and the development of GBS and FS. Anti-GQ1b IgG antibody is detected also in Bickerstaff's brainstem encephalitis and acute ophthalmoparesis, which suggests that these conditions are categorized as autoimmune diseases related to FS. Since a tryptophan-immobilized column effectively adsorb anti-GQ1b IgG antibody, immunoadsorption with the column should be considered as an alternative form of plasmapheresis for the anti-GQ1b IgG antibody syndrome.

Antibodies↗
PubMed2000

Correlation of level of gangliosides in plasma with cancer in human patients.

Levels of gangliosides in the plasma of human patients with cancers of the breast, cheek, oesophagus, rectum, penis, bladder and skin, as analysed by thin layer chromatography and quantitative densitometric scanning, were found to increase many fold (ranging from 3.5 to 5.96 folds), compared to that of normal individuals. The ganglioside levels in the plasma of patients with benign tumors were comparable to that of normal individuals, thus suggesting correlation between increased ganglioside levels in the plasma and malignant growth in cancer patients. These increased levels of gangliosides in the plasma of Ca-breast, Ca-cheek and Ca-penis gradually increased with the advancement of the disease and showed some correlation with the increase in stage of the disease. The levels of gangliosides in the plasma of patients with Ca-breast and Ca-cheek were found to decrease significantly after surgical removal of the primary cancerous growth. The results indicated diagnostic as well as prognostic significance of plasma ganglioside levels in human cancers.

Adult↗
PubMed2001

[Detection of gangliosides in human milk with a high performance thin layer chromatography (HPTLC)].

OBJECTIVES: To determine the ganglioside composition in human milk during lactation, and to evaluate the biological significance. METHODS: The gangliosides extracted from 68 milk samples were examined with a high performance thin layer chromatography (HPTLC). RESULTS: The concentration of total lipid bound sialic acid was 7.8-10.4 microliters/ml. Four gangliosides were found and designated as GM3, GD3, GX1 and GX2, respectively. GX1 and GX2, which had not been described previously, were tentatively assumed to be gangliosides of the c-pathway because they did not react to the GA1 antibody after sialidase treatment. GD3 and GM3 were the major gangliosides in human milk (accounted for 50%-65%). CM3 decreased sharply at eight days postpartum. Both GM3 and GD3 changed significantly during lactation (GM3, r = 0.65, P < 0.01; GD3, r = -0.58, P < 0.01). CONCLUSIONS: Four gangliosides, GM3, GD3, GX1 and GX2 were found in human milk. Both GM3 and GD3 changed significantly during lactation.

Adult↗
PubMedDate not supplied

[Interaction of gangliosides with serotonin].

It has been shown that ganglioside micellae were able to reversible interaction with serotonin; the interaction is determined by their composition. Ganglioside and ganglioside-serotonin micellae were equal in sizes if pH, the ionic strength and the type of the buffer, the temperature and serotonin concentration were given. When the ganglioside micellae were saturated with serotonin the micallae became able to jumping reconstruction forming the structure able to bind more serotonin than the first one. As the serotonin concentration was increased CCM of mixed serotonin-ganglioside micellae was reached. It has been suggested that the reconstruction of the ganglioside micelle due to its interaction with serotonin can be considered as a model of a cooperative transfer of the postsynaptical membrane when a nervous impulse passes through a synapse.

Animals↗
PubMed1975

Further study on cerebral sphingolipids including gangliosides in two cases of juvenile amaurotic family idiocy (Spielmeyer-Vogt type) using a new analytical procedure of sphingolipids.

Sphingolipids isolated from cerebral grey and white matter of two patients with Juvenile Amaurotic Idiocy (Spielmeyer-Vogt Type) were studied. A new analytical procedure was attempted for the determination of sphingolipids, i.e., cerebroside, sulfatide, sphingomyelin and gangliosides were subjected to ozonolysis and reduced with NaBH4. Fatty alcohols thus derived from the double bond-containing long chain bases of the sphingolipids were analyzed by GLC as their TMS-derivatives using an internal standard. The new procedure was suitable for the analysis of small amounts of sphingolipids and could determine the amounts of C18 and C20 sphingosines. It was found that all individual gangliosides in both cases gave lower proportions of C20 sphingosine to the total long chain bases. Sphingomyelin in normal human grey matter contained a small but significant amount of C20 sphingosine, while the sphingomyelin of the two patient brains indicated a much lower proportion of C20 sphingosine in comparison with those of age-matched controls. Thus, this disease seemed to be related to a genetical defect in the metabolic regulation of the long chain bases of gangliosides and grey matter sphingomyelin. On the other hand, it was noted that the ganglioside pattern of grey matter in case-1 was entirely different from that of case-2. The grey matter gangliosides in case-1 were composed of 1.78% of GM2, 81.19% of GM1 and 17.02% of GD1b by the amounts of long chain bases, while the grey matter gangliosides in case-2 seemed to be similar to those of normal human brains. Also, unusual fatty acid compositions of galactosphingolipids (cerebrosides and sulfatides) were observed to a somewhat extent in the grey matter of case-1.

Adult↗
PubMed2003

Gangliosides expressed by the renal cell carcinoma cell line SK-RC-45 are involved in tumor-induced apoptosis of T cells.

It is now understood that the genetic plasticity of cancer cells can lead to alterations that confer selective growth advantages to the tumor, some of which play a role in immune escape. A number of mutations veiling tumor cells from host immune defenses have been well characterized but more recent studies suggest that a variety of tumors can also express products that are actually toxic for the immune effectors. A component of this tumor-induced T-cell death has been attributed to receptor-mediated apoptosis. Some tumors, however, synthesize soluble factors that mediate similar effects. In this regard, we previously showed that supernatants from explanted renal cell carcinoma (RCC) tumors sensitized normal T cells to activation induced cell death, and the responsible products had the features of gangliosides. We have also shown that renal tumor lines, including SK-RC-45, induce apoptosis of both Jurkat cells and normal T lymphocytes. Here, we used the ganglioside synthesis inhibitor PPPP to define the role of gangliosides in RCC cell line (SK-RC-45)-mediated T cell and Jurkat cell apoptosis and to elucidate the proapoptotic molecular events by which the glycosphingolipids produce their effects. The ganglioside-synthesizing SK-RC-45 line stimulated the TUNEL (terminal deoxynucleotidyl transferase-mediated nick end labeling) positivity of cocultured T cells by a mechanism that involved decreasing lymphocyte expression levels of Bcl-2 and Bcl-(XL), inducing cytochrome c release from their mitochondria and activating caspases 9 and 3. These proapoptotic events were partially or completely abrogated when tumor cells were pretreated with PPPP for 5 days before the SK-RC-45/T lymphocyte coincubation, a regimen that reduced tumor-associated ganglioside levels by 70-80%. Our results suggest that gangliosides may be key mediators of RCC-induced T-cell apoptosis and imply that they contribute to the T-cell dysfunction in the tumor microenvironment.

Apoptosis↗
PubMed2003

[Gangliosides in vitro effects on lymphocytes from patients with chronic Chagas disease stimulated with mitogens or heart or brain antigens].

In human Chagas'disease previous work has shown the occurrence of a T-lymphocyte CD4-positive population (a high producer of PAS-positive glycoproteins) with evidence suggesting a role in the formation of damages to the myocardium and neural structures in chagasic heart disease (ChHD). Other workers have taken such facts into consideration and have employed gangliosides (biological substances with neurotrophic and immunomodulatory properties) in chagasics with chronic cardiomyopathy and disautonomic signs, obtaining an Improvement in functional signs and a decrease in the number of PAS+ lymphocytes. In the present work we have studied the effect of mixed gangliosides (Cronassial on cell cultures of total leukocytes, or on mononuclear cells prepared through Ficoll-Hypaque. Blood was obtained from 14 patients with ChHD. Experiments were undertaken to assess the effect of policlonal mitogens Phytohaemagglutinin (Phy) and Concanavalin A (Con A) on blastic transformation, estimated by cell size and cytologic study. In addition, the production of PAS+ substances by the lymphocytes and blast were assessed. Gangliosides were added at final concentrations of 100 mg/ml or 200 mg/ ml. Cell viability was assessed by means of the Trypan blue test. With respect to blastic transformation, results showed a significant decrease in the cultures that received gangliosides 24 hours before mltogen administration, as compared with controls (p<0.001) (both for Phy and Con A). On the other hand, the production of lymphocytic PAS+ substances decreased in the cultures of chagasics in which gangliosides were added. Some of these results confirmed previous findings on the matter. The facts suggest that gangliosides can modulate some lymphocytic activities in chagasics.

Case-Control Studies↗
PubMed1991

[Gangliosides and cancer].

Gangliosides are glycosphingolipids which contain neuraminic acid. Although they are present in the plasma membranes of all cells, gangliosides are expressed differently, both quantitatively and qualitatively, in certain types of cancer. Modifications in ganglioside composition may account for some of the abnormal interactions between these tumor cells and their environment. Furthermore, some of the gangliosides are shed by tumor cells and may modify host immunity, thus contributing to the development of tumors. In cases of melanoma and neuroblastoma, the modifications in ganglioside expression are such that gangliosides may be used both as tumor markers and as targets for immunotherapy.

Antibody Formation↗
PubMedDate not supplied

Membrane gangliosides and immuno-mediated cytolysis in drug sensitive and treatment-induced multidrug resistant human ovarian cancer cells.

The pattern of cytoplasmic membrane gangliosides and two cellular features which have been reported to be related to the expression of different membrane gangliosides, namely adhesion to solid substrates and susceptibility to the lytic activity of immune effector cells, have been investigated in drug sensitive A2780 human ovarian cancer cells and in two treatment-induced multidrug resistant sublines (A2780-DX1 and A2780-DX3). The total membrane gangliosides content of A2780 sensitive cells was comparable to that of the two multidrug resistant (MDR) sublines, but the acquisition of the MDR phenotype was characterized by an increased expression of the polysialylated gangliosides (particularly the disialoganglioside GDIa) and decreased expression of the monosialoganglioside GM2. The kinetics of cellular adhesion (both to plastic culture dishes and to extracellular matrix coated dishes) were similar in the three cell lines, indicating that the gangliosides profile seems not to be relevant for cell adhesivity to the above mentioned substrates. When human peripheral blood lymphocytes in toto (PBL) and two lymphokine activated (LAK) T cell subpopulations (CD3+4-8- and CD3-16+) were used as effector cells against A2780 (sensitive) and A2780-DX3 (highly resistant) cells, cytolysis of target cells was more efficient against the A2780-DX3 subline, suggesting a possible role of the ganglioside GD1a as a target structure for LAK immunotherapy.

Antineoplastic Agents↗
PubMed1990

Immunomodulatory effects of human placenta gangliosides.

The immunomodulatory properties of the major gangliosides of human placenta were studied. All the gangliosides investigated suppressed the cytotoxic activity of human natural killer cells. The magnitude of the inhibitory effect depended on ganglioside structure. Gangliosides GM1, GM3, and GD3 were the most effective suppressors. Some of the placental gangliosides (GD3, GD1a, IV3NeuAc-nLc4Cer, VI3NeuAc-nLc6Cer) also inhibited lymphoblastic transformation, and one of them (GM3) strongly stimulated the Con-A-induced T-suppressor activity of human lymphocytes. It is suggested that the combined action of the placental gangliosides on maternal effector cells may be involved in the defence of the human embryo against the maternal immune system.

Cytotoxicity, Immunologic↗
PubMed1990

Shed tumor gangliosides and progression of human neuroblastoma.

Shedding of membrane gangliosides is characteristic of human and experimental tumors. Because some shed tumor gangliosides have potent tumor-enhancing properties, significant ganglioside shedding could influence tumor progression. We examined this possibility in a human tumor, neuroblastoma. Ganglioside shedding, measured as circulating tumor-derived GD2 ganglioside, and the outcome of 74 patients with advanced stage (III and IV) disease were studied. Progression-free survival (PFS) was inversely related to circulating GD2 levels at the time of diagnosis (P = .018). By Kaplan-Meier analysis, the quartile of patients having the highest circulating GD2 levels (greater than or equal to 568 pmol/mL) had a strikingly different outcome from the quartile of patients with the lowest (less than or equal to 103 pmol/mL) GD2 levels (P = .013): median PFS was shorter (9 v 28 months), and the long-term survival rate lower (2-year PFS of 24% v 70%). We conclude that more rapid disease progression and lower survival rate are associated with high circulating GD2 levels at diagnosis and speculate that shed neuroblastoma tumor gangliosides play a role in accelerating tumor progression.

Biomarkers, Tumor↗
PubMed1986

Interaction of gangliosides with fibronectin in the mobilization of capillary endothelium. Possible influence on the growth of metastasis.

Mobilization of the capillary endothelium is one of the first events observed during angiogenesis, and the study of conditions that control or influence the mobilization of the endothelium in vitro has been assumed to offer information relevant to the understanding of angiogenesis in vivo. In vitro mobilization of the bovine capillary endothelium was substantially enhanced by addition of gangliosides to the culture medium. Optimal mobilization was obtained when the endothelium incorporated the gangliosides first and was then seeded on fibronectin anchored to collagen type I. Preincubation of the capillary endothelium with gangliosides, trisialoganglioside in particular, doubled the amount of fibronectin bound to the cells and enhanced the migration about 5-fold. 'Blockage' of ganglioside binding with cholera toxin or gamma-interferon substantially reduced migration. Rabbit corneas, treated in vivo with a variety of angiogenesis effectors to induce neovascularization, consistently showed an increase in sialic acid content just prior to the time the tissue would be penetrated by the capillaries. This finding was interpreted to indicate that an increment of the ganglioside content of the capillary endothelial cell membranes may play a determinant role in the mobilization of the capillary endothelium in vivo as shown here to take place in vitro. Since the formation of a tumor from a micrometastasis requires formation of new capillaries and highly metastasizing tumors very frequently have high levels of sialic acid on the cell surface, it is hypothesized that production and shedding of gangliosides from the surface of neoplastic cells may be a factor in promoting angiogenesis and metastatic growth.

Animals↗
PubMed1987

Monoclonal antibody Leo Mel 3, which inhibits killing of human melanoma cells by anomalous killer cells, binds to a sugar sequence in GD2 (II3(NeuAc)2-GgOse3Cer) and several other gangliosides.

Human anomalous killer (AK) cells lyse freshly isolated human melanoma cells which are insensitive to human natural killer cell-mediated lysis. Monoclonal antibody Leo Mel 3, an IgM (k), produced by a hybridoma obtained from a mouse immunized with human melanoma cells, binds to melanoma cells and inhibits their conjugate formation with AK cells as well as their AK cell-mediated lysis. Other IgM antibodies from the same fusion that bind melanoma cells do not inhibit (Werkmeister, J. A., Triglia, T., Andrews, P., and Burns, G. F. (1985) J. Immunol. 135, 689-695). Leo Mel 3 binds several different gangliosides from melanoma cells, as determined by immunostaining thin layer chromatograms. Binding is abolished by treatment of the gangliosides with neuraminidase. In solid-phase radioimmunoassay, Leo Mel 3 binds strongly to ganglioside GD2 and less strongly to gangliosides GT3, GD3, and GQ1b. It does not bind to other gangliosides including GM1, GM2, GM3, GD1a, GD1b, and GT1b. Thus, the epitope recognized by antibody Leo Mel 3 is found in the sugar sequence of ganglioside GD2, GalNAc beta 1-4[NeuAc alpha 2-8NeuAc alpha 2-3]Gal beta 1-4Glc beta 1 .... This sequence may contain a target in melanoma cells recognized by AK cells.

Antibodies, Monoclonal↗
PubMed1987

Influence of gangliosides on primary and metastatic neoplastic growth in human and murine cells.

The influence of gangliosides on tumor growth and frequency of metastasis in vivo as well as on growth and motility of neoplastic cells in vitro was tested utilizing human and rodent cell populations. In mice receiving injections of a ganglioside mixture twice daily the tumor volume, the number of spontaneous metastases per animal, and the number of mice with metastasis was approximately double that of controls. Preincubation of neoplastic cells with the ganglioside mixture doubled the number of metastatic foci in the lungs of mice receiving the cells by i.v. injection. Addition of a ganglioside mixture to the culture medium enhanced motility of neoplastic cells about 3-fold. This finding was similar to that observed for capillary endothelium. The presence of gangliosides in the culture media for a 48-h incubation period about doubled the number of neoplastic cells as compared to controls; the same was observed for capillary endothelium. The data are interpreted to indicate that gangliosides improve growth and mobilization of capillary endothelium and neoplastic cells. Both events may concur in enhancing tumor growth in vivo, the first by improving angiogenesis, the second by direct action on the neoplastic cell population.

Animals↗
PubMed1989

[The analysis of gene-regulatory mechanism of ganglioside metabolism by gene transfection].

To investigate the genetic control on ganglioside metabolism, various oncogenes were directly transfected to rat 3Y1 cells, and the subsequent alteration in the ganglioside pattern was analysed. So-called "intranuclear" type oncogenes, the products of which are mainly expressed intranuclearly, ex. adeno E1 and myc, brought about specifically GD3 ganglioside with concomitant decrease in GM3. On the other hand, so-called "extranuclear" type oncogenes, the products of which are expressed extranuclearly (either on the cell membrane or in the cytoplasm), ex. ras and src, brought about SPG gangliosides but no GD3 expression was recognized. This result indicates that intracellular metabolic activities of oncogenes strongly affect the ganglioside metabolism, and that the sensitive points in the pathway of the ganglioside metabolism (synthesis) are not so various but rather restricted.

Animals↗
PubMed1989

Inhibition of platelet adhesion to fibronectin, fibrinogen, and von Willebrand factor substrates by complex gangliosides.

Gangliosides, which are complex glycosphingolipids containing sialic acid, are found in cell membranes and have been implicated in a variety of cell surface events including cellular adhesion. Complex gangliosides were observed to inhibit the adhesion of thrombin-activated platelets to substrates of fibronectin, von Willebrand factor, and fibrinogen. This adhesion, which is mediated by the glycoprotein IIb-IIIa complex, was differentially inhibited by gangliosides depending on the number of sialic acid residues present within the ganglioside. The observed order of effectiveness was GT1b greater than GD1a greater than GM1 greater than asialo-GM1. Another structurally related glycosphingolipid, globoside, exhibited little inhibitory activity. In contrast to the inhibition of platelet adhesion to von Willebrand factor mediated by the glycoprotein IIb-IIIa complex, gangliosides had no detectable effect on the ristocetin-dependent adhesion of platelets to von Willebrand factor mediated by glycoprotein Ib. These results suggest that the function of the glycoprotein IIb-IIIa complex may be modulated by gangliosides in a manner similar to that previously described for the closely related vitronectin receptor.

Blood Platelets↗
PubMed1989

Ganglioside composition in experimental tumors with different growth properties.

The composition of gangliosides was studied in four fibrosarcomas (FL, FLA, FLB, FLC) induced in the Lewis rat by Ferridextran, and in two clones of a spontaneous Lewis rat mammary sarcoma (C-1-SAM LEW and C-2-SAM LEW) and two supertransformed clones (S-174 and S-271) derived from these clones, using the B77 virus. The malignancy of the Lewis tumors was tested in terms of their ability to outgrow the RT-5 barrier in LEW.1x rats and expressed as the loss-rate of LEW.1x rats. As for the Ferridextran-induced tumors, the FL was the only one to have been rejected in nearly 100% of the LEW.1x recipients. Following presensitization with FL the other tumors were also rejected, though not at a rate of 100%. The rat loss-rate was: FL--0%, FLC--23.5%, FLB--36.5%, and FLA--82.6%. As malignancy increased, the composition of gangliosides showed signs of progressive simplification indicating a step-by-step repression of ganglioside biosynthesis involving first the disialoganglioside and subsequently also the monosialoganglioside pathways. Some less distinct decrease (but significant at the 5% level of probability) of gangliosides of the disialoganglioside pathway and an increase of the simplest ganglioside (GM3) were observed between the C-1 clone of SAM LEW and its S-174 supertransformant. However, the changes, especially in the C-2 clone and its supertransformant, were not such as would suggest a marked defect in the biosynthesis of gangliosides.

Animals↗