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PubMed1984

Modulation of the immune response by gangliosides. Inhibition of adherent monocyte accessory function in vitro.

Gangliosides are potent inhibitors of lymphoproliferative responses. Selectively greater inhibitory effects of gangliosides on antigen-induced (vs. mitogen-induced) proliferation have been documented; e.g., 50 nmol of highly purified bovine brain gangliosides (BBG)/ml caused greater than or equal to 87% inhibition of proliferative responses of human peripheral blood mononuclear cells (PBMC) to three soluble specific antigens (Candida, streptokinase-streptodornase, and tetanus toxoid) vs. less than or equal to 37% inhibition of responses to three nonspecific mitogens (phytohemagglutinin, concanavalin A, and pokeweed mitogen). The possibility that BBG interfere with adherent monocyte accessory function, upon which responses to soluble specific antigens are strictly dependent, was therefore considered. PBMC were separated into the adherent and nonadherent subpopulations, exposed to BBG, recombined, and their proliferative responses were measured. Unseparated PBMC preincubated for 48-72 h with 100 nmol BBG/ml and then washed to remove unbound BBG exhibited 73-76% inhibition of subsequent antigen-induced lymphoproliferation. Separate pretreatment of both adherent and nonadherent cell subpopulations in BBG under the same conditions resulted in similar (72-82%) inhibition, which was reproduced by preincubation of only the adherent cells in BBG. Preincubation of only the nonadherent cells in BBG was not inhibitory. Inhibition (a) was independent of whether gangliosides were added in solution or incorporated into liposomes, (b) was abrogated by adding untreated monocytes to cultures containing adherent cells that were preexposed to BBG (excluding the possibility that BBG was inducing suppression mediated by adherent cells), and (c) was reversible by further incubation of BBG-pretreated adherent cells in control medium. Together, these results delineate a mechanism by which gangliosides modulate lymphoproliferative responses--direct, noncytotoxic, and ultimately reversible inhibition of the accessory function of adherent monocytes.

Animals↗

PubMed1987

Gangliosides shed by tumor cells enhance tumor formation in mice.

The role of tumor cell membrane gangliosides in tumor formation was probed using a series of cloned murine AKR lymphoma cell lines. Tumor formation was directly related to high expression and shedding of membrane gangliosides. In vivo, as little as 1 pmol of purified total gangliosides of highly tumorigenic cells, injected intradermally with poorly tumorigenic cells (which lacked and did not shed gangliosides), markedly increased the tumorigenicity of these cells in syngeneic normal mice. Thus, gangliosides shed by tumor cells are a previously unrecognized, extremely potent enhancer of tumor formation in vivo.

AKR murine leukemia virus↗

PubMed1990

Altered expression of gangliosides in erythrocytes of paroxysmal nocturnal hemoglobinuria.

In paroxysmal nocturnal hemoglobinuria (PNH), impaired glycosyl-phosphatidylinositol (PI)-anchoring of membrane proteins such as decay-accelerating factor has been known to lead to increased susceptibility to complement. Moreover, abnormal expression of non-PI-anchoring glycoproteins such as C3b/C4b receptor (CR1) or glycophorin-alpha also has been shown in PNH. Therefore, we biochemically analyzed glycosphingolipids (GSL) as one of the membrane glycoconjugates of PNH erythrocytes. Erythrocytes of all seven PNH patients showed altered expression of sialosyl GSL (gangliosides) as compared with the control erythrocytes of healthy donors. Both a sialosylparagloboside (IV6NeuAc-nLc4Cer) among four major gangliosides and some minor gangliosides in normal erythrocytes variably disappeared in erythrocytes from the peripheral blood of PNH patients. As one of the possible mechanisms of altered expression of gangliosides in PNH erythrocytes, structural analysis suggested impaired sialylation of GSL. These results suggest not only the altered metabolism of gangliosides in PNH erythrocytes, but also a metabolic disorder of membrane glycoconjugates as a new feature of PNH.

Adult↗

PubMed1999

Renal cell carcinoma-derived gangliosides suppress nuclear factor-kappaB activation in T cells.

Activation of the transcription factor nuclear factor-kappaB (NFkappaB) is impaired in T cells from patients with renal cell carcinomas (RCCs). In circulating T cells from a subset of patients with RCCs, the suppression of NFkappaB binding activity is downstream from the stimulus-induced degradation of the cytoplasmic factor IkappaBalpha. Tumor-derived soluble products from cultured RCC explants inhibit NFkappaB activity in T cells from healthy volunteers, despite a normal level of stimulus-induced IkappaBalpha degradation in these cells. The inhibitory agent has several features characteristic of a ganglioside, including sensitivity to neuraminidase but not protease treatment; hydrophobicity; and molecular weight less than 3 kDa. Indeed, we detected gangliosides in supernatants from RCC explants and not from adjacent normal kidney tissue. Gangliosides prepared from RCC supernatants, as well as the purified bovine gangliosides G(m1) and G(d1a), suppressed NFkappaB binding activity in T cells and reduced expression of the cytokines IL-2 and IFN-gamma. Taken together, our findings suggest that tumor-derived gangliosides may blunt antitumor immune responses in patients with RCCs.

Carcinoma, Renal Cell↗

PubMed1995

Extraction and purification of gangliosides from plasma and fibroblasts before analysis by thin layer chromatography.

A procedure to extract and purify gangliosides from small volumes of plasma (0.6 mL), cerebrospinal fluid (1 mL) and fibroblasts is described. Gangliosides were extracted with chloroform/methanol and purified by means of reversed phase chromatography and gel filtration before analysis by thin layer chromatography. The procedure proved to be useful in confirming deficiency of lysosomal enzyme activity affecting ganglioside breakdown. The new procedure also appeared to be useful to monitor ganglioside catabolism in cultured fibroblasts loaded with ganglioside.

Adolescent↗

PubMed2005

Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice.

II3NeuAc-GgOse4Cer (GM1) gangliosidosis is an incurable lysosomal storage disease caused by a deficiency in acid beta-galactosidase (beta-gal), resulting in the accumulation of ganglioside GM1 and its asialo derivative GgOse4Cer (GA1) in the central nervous system, primarily in the brain. In this study, we investigated the effects of N-butyldeoxygalacto-nojirimycin (N B-DGJ), an imino sugar that inhibits ganglioside biosynthesis, in normal C57BL/6J mice and in beta-gal knockout (beta-gal-/-) mice from postnatal day 9 (p-9) to p-15. This is a period of active cerebellar development and central nervous system (CNS) myelinogenesis in the mouse and would be comparable to late-stage embryonic and early neonatal development in humans. N B-DGJ significantly reduced total ganglioside and GM1 content in cerebrum-brainstem (C-BS) and in cerebellum of normal and beta-gal-/- mice. N B-DGJ had no adverse effects on body weight or C-BS/cerebellar weight, water content, or thickness of the external cerebellar granule cell layer. Sphingomyelin was increased in C-BS and cerebellum, but no changes were found for cerebroside (a myelin-enriched glycosphingolipid), neutral phospholipids, or GA1 in the treated mice. Our findings indicate that the effects of N B-DGJ in the postnatal CNS are largely specific to gangliosides and suggest that N B-DGJ may be an effective early intervention therapy for GM1 gangliosidosis and other ganglioside storage disorders.

1-Deoxynojirimycin↗

PubMed1984

Characterization of monoclonal antibody 3G5 and utilization of this antibody to immobilize pancreatic islet cell gangliosides in a solid phase radioassay.

Monoclonal antibody 3G5, which was initially produced by immunization of mice with fetal rat brain, reacts specifically by indirect immunofluorescence with all cells of the pancreatic islets of human, rat, mouse, and bovine pancreas. This antibody reacts with the cell surface of isolated islet cells as well as the rat (RIN5F) insulinoma cell line. Antibody 3G5 reacts with islets, thyroid follicular cells, pituitary, and the adrenal medulla of a pattern similar to but distinct from those of antibody A2B5 and tetanus toxin, both of which react with complex gangliosides (sialic acid-containing glycosphingolipids). The antigen with which antibody 3G5 reacts also has the properties of ganglioside (neuraminidase sensitive, extracted into chloroform-methanol, partitioned into a methanol-water phase, soluble in water, and nondialyzable). Antibody 3G5, adsorbed to polyvinyl plates, can immobilize islet ganglioside micelles to which 125I-labeled 3G5, A2B5, and tetanus toxin all bind. The ability to immobilize micelles containing several complex gangliosides has led to a solid phase radioassay to detect antiganglioside antibodies. Monoclonal antibody 3G5 joins antibody A2B5 and tetanus toxin as markers for distinct complex gangliosides found on pancreatic islets and neurons.

Animals↗

PubMed1999

Growth- and development-dependent expression of gangliosides in rat hepatocytes and liver tissues.

Expression of gangliosides in the liver was examined in primary cultures of hepatocytes from adult rats and liver tissues from rats of different ages. Hepatocytes were isolated from 7-week-old rat liver and cultured in L-15 medium containing insulin, dexamethasone and 10% fetal bovine serum. Hepatocytes proliferated only on the first day, and then ceased proliferation. The content of GD3 and GD1a increased during the period of active proliferation and reached a nearly constant level, whereas GM1, GD1b, GT1b, and GQ1b gradually increased throughout culture. Addition of EGF to the culture medium caused significant increases in the content of GD3, and to a lesser degree of GM3, but exhibited little effect on the expression of other ganglioside species. The specific induction of GD3 and GM3 expression by EGF was reproduced under serum-free conditions, despite the lack of hepatocyte proliferation. Expression of gangliosides in cultured hepatocytes was also modulated by cell density; higher cell density brought about increased content of GM1, GD1a, GD1b, GT1b, and GQ1b with concomitant reduction of GM3 in cells. The composition of gangliosides in liver tissues demonstrated a unique developmental pattern. GD3 and GD1a were strongly expressed in E-16 embryonic tissue and rapidly decreased with increasing age. GD1b, GT1b, and GQ1b were found only in postnatal liver tissues. These findings suggest that the expression of gangliosides in rat hepatocytes and liver tissues are regulated by growth- and development-dependent factors.

Animals↗

PubMed1980

Aggregate formation of gangliosides at low concentrations in aqueous media.

The gangliosides GLac1, GGtri1 and GGtet1 in aqueous medium sediment in the ultracentrifuge as oligomeric aggregates independent of concentration at 10(-3)M to 10(-9)M with the sedimentation constants S20,W of 5.3, 7.5 and 10.0, respectively. If gangliosides dissolved in dimethylsulfoxide were diluted with water, this resulted in aggregates with lower sedimentation coefficients. In the presence of 1M tetramethylurea no sedimentation of gangliosides could be observed in the ultracentrifuge. A ganglioside analogue (gangliosidoide) with two hydrocarbon chains instead of the ceramide moiety shows a similar sedimentation behaviour as the native compound GGtet1. However, a ganglioside analogue with only one aliphatic hydrocarbon chain forms sedimenting aggregates only at concentrations exceeding 10(-3)M.

Brain↗

PubMed1985

Age- and hormone-dependent ganglioside patterns of rat hepatocytes in primary culture.

Using an improved procedure for the quantitative extraction of all glycolipids from small tissue samples the hepatic ganglioside pattern of rats was analysed during development. While this parameter remained fairly constant in adult animals, hepatocytes in primary culture showed drastic changes both in content and relative distribution among the various ganglioside species. The content of lipid-bound sialic acid increased several-fold during 6 days in monolayer and the pattern changed in favour of the higher sialylated forms. Dexamethasone delayed this transition and enhanced the content of GD1a and GM1 relative to GM3. The ganglioside content was also dependent on the density of hepatocytes in the primary culture. If the cell density was insufficient for formation of a confluent monolayer, higher ganglioside-sialic acid contents were found and the relative amount of GD3 increased after 3-4 days. These results support the notion that gangliosides are involved in cellular differentiation and cell-cell contact.

Aging↗

PubMedDate not supplied

Differentiation in murine mastocytoma induced by macrophage gangliosides.

In the membrane of mouse macrophages two gangliosides were detected which inhibit the division of murine mastocytoma P815 tumor cells. The two gangliosides were incorporated into the cytoplasmatic membrane of mastocytoma cells. The concentration necessary to achieve a complete inhibition of P815 tumor cell division is about 1 microM for both effective gangliosides. Macrophage ganglioside-induced inhibition of cell division is accompanied by morphological changes of the mastocytoma cells. While the cells are rounding, their diameter increases and serotonin and granules appear in the cytoplasm of the enlarged cells. Our findings suggest that macrophage gangliosides may differentiate mastocytoma cells into mast cells.

Animals↗

PubMed1989

Ganglioside treatment and improved axonal regeneration capacity in experimental diabetic neuropathy.

The efficacy of gangliosides in enhancing axonal regeneration and maturation in the early stages of diabetic neuropathy was assessed by quantitative analysis of immunostained serial sections of the sciatic nerve. Sprague-Dawley rats were made diabetic with a single injection of alloxan (100 mg/kg). One week later they were injected daily intraperitoneally with either a highly purified ganglioside mixture (10 mg/kg) or sterile saline for 4 wk. At the end of the treatment, sciatic nerves were crushed and allowed to regenerate for 1 wk without ganglioside treatment. The animals were then killed, and the nerves were frozen and processed for immunohistochemistry and electron microscopy. The number of regrowing axons was counted with a computerized image-analysis system on cross sections taken at predefined distances along the regenerating stump and stained with monoclonal antibody iC8 specific for the 145,000-Mr subunit of the neurofilaments. In untreated diabetic animals the number of axons able to regenerate and sustain elongation for greater than or equal to 13 mm from the crush point was reduced by 40% with respect to control rats. Ganglioside treatment was effective in compensating almost completely for this dramatic reduction. Electron microscopy confirmed that the immunofluorescence counts corresponded to regenerating axons containing neurofilaments. These results suggest that gangliosides are able to compensate for the derangements of axonal transport of cytoskeletal proteins reported in experimental diabetic neuropathy.

Alloxan↗

PubMedDate not supplied

Control by ganglioside GD1a of phospholipase A2 activity through modulation of the lamellar-hexagonal (HII) phase transition.

Ganglioside GD1a has a dual effect on the formation of the HII phase in mixtures of dioleoylphosphatidyl choline (DOPC)-dioleoylphosphatidylethanolamine (DOPE) (1:5). Below 1 mol% ganglioside in the mixture the formation of the HII phase is facilitated as indicated by a decrease of the lamellar-HII phase transition temperature; above 1 mol% the presence of ganglioside GD1a opposes formation of the HII phase and causes an increase of the phase transition temperature; the latter is completely abolished at 3 mol% GD1a or above. The rate of activity of phospholipase A2 against these mixtures showed a temperature variation in coincidence with the establishment of the lamellar-hexagonal II phase transition. In the presence of GD1a at 0.5 and 1 mol% in the mixture, the maximum activity shifted in correspondence with the ganglioside-induced displacement of the lamellar-hexagonal II phase transition. The temperature variation of the enzymatic activity did not show any maximum for pure DOPC of for DOPC-DOPE (1:5) mixtures containing 3 mol% GD1a or above, in which no lamellar-hexagonal II phase transition occurs. The effects of GD1a are probably due to the geometrical features of the ganglioside molecule that allow a composition-dependent compensation of the structural defects required for the formation of the HII phase which are detected by phospholipase A2.

Calorimetry↗

PubMed1995

Ganglioside extraction from erythrocytes: a comparison study.

Several methods for ganglioside extraction from erythrocytes have been compared. Our results show that ganglioside extraction is unfavourably affected by the addition of the solvents as a mixture and by the use of less polar solvents and by a lower total solvent-to-sample ratio. In accordance with our previous observation on cholesterol and phospholipids, the distribution of gangliosides could be uneven in an apparently monophasic extraction solvent mixture. The uneven distribution occurred during and also after the extraction (in filtration and centrifugation). In the recommended method using 19 volumes of methanol/chloroform (2:1) solvent in a one-step extraction, the above disadvantages in ganglioside extraction and quantification are kept under control. This method appears simple and it gives a high recovery of gangliosides.

Centrifugation↗

PubMed2003

Mechanisms of ganglioside inhibition of APC function.

Gangliosides shed by tumor cells exert potent inhibitory effects on cellular immune responses. Here we have studied ganglioside inhibition of APC function. When human monocytes were preincubated in 50 micro M highly purified ganglioside G(D1a), pulsed with tetanus toxoid (TT), and washed, the expected Ag-induced proliferative response of autologous normal T cells added to these monocytes was inhibited by 81%. Strikingly, there was also almost complete (92%) and selective inhibition of the up-regulation of the monocyte costimulatory molecule CD80, while I-CAM-1, LFA-3, HLA-DR, and CD86 expression were unaffected. Purified LPS-stimulated monocytes that had been preincubated in G(D1a) likewise showed inhibition of CD80 up-regulation (59%) as well as down-regulation of CD40 (54%) and impaired release of IL-12 and TNF-alpha (reduced by 59 and 51%). G(D1a)-preincubated human dendritic cells (DC) were also affected. They had reduced constitutive expression of CD40 (33%) and CD80 (61%), but not CD86, and marked inhibition of release of IL-6 (72%), IL-12 (70%), and TNF-alpha (46%). Even when pulsed with TT, these ganglioside-preincubated DC remained deficient in costimulatory molecule expression and cytokine secretion and were unable to induce a normal T cell proliferative response to TT. Finally, significant inhibition of nuclear localization of NF-kappaB proteins in activated DC suggests that disruption of NF-kappaB activation may be one mechanism contributing to ganglioside interference with APC expression of costimulatory molecules and cytokine secretion, which, in turn, may diminish antitumor immune responses.

Active Transport, Cell Nucleus↗

PubMed1998

Oncogene transgenic mice: an useful model to study in vivo the relationships between gangliosides and oncogenes.

Several studies have demonstrated that transfer of oncogenes in cultured cells reproducibly induces transmissible alterations in their ganglioside profile; the transfection of the same oncogene into different cell lines and the different localization of the oncogene product result in a different ganglioside expression. In the present study the modifications of the ganglioside pattern in mammary carcinomas induced in transgenic mice by the activated form of the rat neu oncogene have been investigated. Whereas control mammary tissues contain quite exclusively GM3, all neoplastic samples show a substantial decrease of this ganglioside, an accumulation in variable amount of GM3-derived species (GM1, GD3, GD1a, GD1b, GT and GQ) and the appearance of new, not yet identified, sialic acid containing molecules. Interestingly, three out of 10 tumors analyzed, even if histologically comparable to the others but with a larger dimension, show a significative difference as regard to the GM1, GD3 and GD1a content. Our data suggest that an activated oncogene may induce also in vivo a specific and transmissible alteration in the ganglioside pattern, but this distribution could be susceptible to further modifications during the tumor progression.

Animals↗

PubMed1999

GD3 ganglioside antibody augments tumoricidal capacity of canine blood mononuclear cells by induction of interleukin 12.

Monoclonal antibody R24 recognizes ganglioside GD3 expressed on the cell surfaces of some tumor cells and on a subset of human T lymphocytes. Binding of R24 to these lymphocytes induces proliferation, cytokine production, and activation of intracellular signaling pathways. In the current report, we investigated expression of gangliosides by canine mononuclear immune cells and studied the ability of antiganglioside antibody to activate these cells using tumor cell killing as a measure of activation. A subset of canine monocytes, but not lymphocytes, was found to express gangliosides GD3 and GD2 as determined by the binding of monoclonal antibodies R24 and 14.G2a, respectively. Only R24 augmented the tumoricidal potential of fresh canine peripheral blood mononuclear cells (PBMCs) against tumor cell lines that did not express surface gangliosides GD3 or GD2. The augmenting effect of R24 on PBMC-mediated tumor cytotoxicity required cooperation between monocytes and lymphocytes because there was no enhancement of cytotoxicity mediated by R24 combined with either monocytes or lymphocytes individually. The enhancing effect of R24 on canine PBMC-mediated tumor cytotoxicity was blocked by anti-interleukin (IL)-12 neutralizing antibody, suggesting that R24 binding to monocytes triggered IL-12 release, contributing to the observed tumor killing effects. Reverse transcription-PCR confirmed that the binding of R24 to canine monocytes induced transcription of mRNA for canine IL-12. These data indicate that monocytes can be activated for tumoricidal responses through a membrane structure associated with ganglioside GD3 triggered by the binding of R24 and that the mechanism for enhanced cytotoxicity is due to the production and secretion of IL-12.

Animals↗

PubMed1999

GT3 and its O-acetylated derivative are the principal A2B5-reactive gangliosides in cultured O2A lineage cells and are down-regulated along with O-acetyl GD3 during differentiation to oligodendrocytes.

Among the developmentally regulated antigens expressed on the surface of bipotential glial precursors isolated from neonatal rat brain are the gangliosides recognized by the monoclonal antibody A2B5. Immunostaining of thin layer chromatograms showed that oligodendrocyte-type 2 astrocyte (O2A) progenitors in culture express two ganglioside antigens that react strongly with the A2B5 antibody. Both ganglioside antigens are down-regulated as the cells differentiate to oligodendrocytes, corresponding to the disappearance of cell surface immunostaining by A2B5 in mature oligodendrocytes. By contrast, both gangliosides continue to be expressed when the cells differentiate to type-2 astrocytes. These two A2B5-reactive gangliosides in O2A lineage cells were identified as GT3 and O-acetyl GT3 by using the monoclonal antibody 18B8 that recognizes GT3 and an influenza C virus esterase that specifically removes O-acetyl moieties from sialic acids. Thin-layer chromatographic immunostaining with the JONES monoclonal antibody demonstrated that the progenitor cells in culture also express O-acetyl GD3, which is similarly down-regulated in oligodendrocytes, but retained in type-2 astrocytes. The 18B8 and JONES antibodies also immunostained the surface of O2A progenitors. Therefore, expression of GT3 and O-acetylation of GT3 and GD3 occur during the proliferative and migratory stages of glial cell development. Published 1999 Wiley-Liss, Inc.

Acetylation↗