Modulation of CD4 Th Cell Differentiation by Ganglioside GD1a In Vitro (original) (raw)
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Human tumor gangliosides inhibit murine immune responses in vivo
Cancer Research
Gangliosides which are shed by tumor cells clearly inhibit cellular immune responses in vitro. However, the immunosuppressive activity of these molecules have been more difficult to ascertain in vivo. Here we have adapted a murine model to determine the effects of tumor gangliosides In an in vivo microenvironment, the lymph node draining the site of stimu lation by allogeneic cell& In this model, allogeneic splenocytes (BALB/c) are s.c. Injected into C3H mice. The cellular Immune response in the draining popliteal lymph nodes 4 days later Is evidenced as an increase in lymph node mass (2-fold), lymphocyte number (6.fold), and lymphocyte DNA synthesis (6-fold). Purified human neuroblastoma gangliosides (10 nmol) coinjected with the sthnulating allogeneic cells significantly sup pressed this in vivo immune response. The increase In the lymph node mass was reduced by 65% (0.66 versus 1.89 mgJ, the Increase in lympho cyte number (4.0 x 10@cells/node) was almost completely Inhibited (1.1 x 106cells/node),and in vitro[3H]thymldine uptakeby the lympho. cytes recovered in vivo was reduced by 80%. In contrast to the Inhibition by tumor gangliosides, liposomes of cholesterol:lecithln were not inhibi tory. Thus, tumor gangliosides, specifically, modulate cellular immune responses in vivo, which may contribute to the observed enhancement of tumor formation by these molecules. Received 11/14/94; accepted 12/1/94. The costs of publicationof this articlewere defrayedin partby the paymentof page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicatethis fact.
Ganglioside GD1a impedes lipopolysaccharide-induced maturation of human dendritic cells
Cellular Immunology, 2002
Immunosuppressive membrane gangliosides are released by tumor cells and inhibit normal antigen presenting cell (APC) function. To better understand this process, we have studied the effect of gangliosides on lipopolysaccharide (LPS)-induced maturation of human dendritic cells (DCs). Immature DCs were generated in vitro from human peripheral blood monocytes and were exposed for 72 h to a highly purified ganglioside, G D1a . During the last 24 h, LPS was added to effect maturation. As assessed by fluorescence activated cell sorting (FACS) analysis, incubation in 50 lM G D1a significantly blunted the LPS-induced maturation of the dendritic cells. The expected up-regulation of expression of the co-stimulatory molecules CD80 and CD86 was ablated and that of CD40 was reduced, as were surface CD83 expression and intracellular CD208 production. In addition, ganglioside pretreatment of DC markedly inhibited the allostimulatory capacity and partially prevented the down-regulation of FITC-dextran uptake characteristic of LPS-activated DC. Furthermore, ganglioside-exposed DC also evidenced a broad down-regulation of the cytokine release that is normally initiated by LPS exposure, i.e., there was no increase in IL-1b, IL-6, IL-10, IL-12, or tumor necrosis factor (TNF)-a release. That a common mechanism may underlie these defects was suggested by the finding that G D1a exposure of DC also inhibited the nuclear binding of NF-jB that is normally induced by LPS. These results suggest that tumor gangliosides may blunt the anti-tumor immune response in vivo by binding and interfering with dendritic cell maturation.
Journal of Leukocyte Biology, 2005
Gangliosides, sialic acid-containing glycosphingolipids present in most cell membranes, are thought to participate in the maintenance of immune privilege and tumor-induced immunosuppression. However, the mechanisms responsible for their immunomodulatory activity remain poorly understood. The purpose of this study was to investigate whether gangliosides are able to modulate the balance of type-1/type-2 T cell responses and to characterize the cellular mechanisms involved. The effects of different gangliosides on anti-CD3-stimulated murine splenocytes and purified T cells were studied. The presence of gangliosides during T cell activation reduced the expression of interferon-␥ (IFN-␥) and enhanced that of interleukin (IL)-4, suggesting a shift toward a type-2 response. Intracellular cytokine staining demonstrated that gangliosides inhibited IFN-␥ production in CD4 ؉ , CD8 ؉ , and natural killer (NK)1.1 ؉ cell populations and enhanced IL-4 in CD4 ؉ T cells. The ganglioside-mediated enhancement in IL-4 production was independent of changes in endogenous IFN-␥, did not occur with cells from CD1d-deficient mice, and was partially inhibited by anti-CD1d antibodies. The inhibitory effects on IFN-␥ were independent of endogenous IL-4 or the presence of NKT cells and were unaffected anti-CD1d antibodies. These results suggest that gangliosides may modify the immunological environment by promoting immune deviation in favor of type-2 T cell responses.
HumanTumor GangliosidesInhibit MurineImmuneResponsesin Vivo1
Gangliosides which are shed by tumor cells clearly inhibit cellular immune responses in vitro. However, the immunosuppressive activity of these molecules have been more difficult to ascertain in vivo. Here we have adapted a murine model to determine the effects of tumor gangliosides In an in vivo microenvironment, the lymph node draining the site of stimu lation by allogeneic cell& In this model, allogeneic splenocytes (BALB/c) are s.c. Injected into C3H mice. The cellular Immune response in the draining popliteal lymph nodes 4 days later Is evidenced as an increase in lymph node mass (2-fold), lymphocyte number (6.fold), and lymphocyte DNA synthesis (6-fold). Purified human neuroblastoma gangliosides (10 nmol) coinjected with the sthnulating allogeneic cells significantly sup pressed this in vivo immune response. The increase In the lymph node mass was reduced by 65% (0.66 versus 1.89 mgJ, the Increase in lympho cyte number (4.0 x 10@cells/node) was almost completely Inhibited (1.1 x 106cells/node),and in vitro[3H]thymldine uptakeby the lympho. cytes recovered in vivo was reduced by 80%. In contrast to the Inhibition by tumor gangliosides, liposomes of cholesterol:lecithln were not inhibi tory. Thus, tumor gangliosides, specifically, modulate cellular immune responses in vivo, which may contribute to the observed enhancement of tumor formation by these molecules. Received 11/14/94; accepted 12/1/94. The costs of publicationof this articlewere defrayedin partby the paymentof page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicatethis fact.
Gangliosides inhibit the development from monocytes to dendritic cells
Clinical and Experimental Immunology, 2002
Dendritic cell (DC) development and function is critical in the initiation phase of any antigen-specific immune response against tumours. Impaired function of DC is one explanation as to how tumours escape immunosurveillance. In the presence of various soluble tumour-related factors DC precursors lose their ability to differentiate into mature DC and to activate T cells. Gangliosides are glycosphingolipids shed by tumours of neuroectodermal origin such as melanoma and neuroblastoma. In this investigation we address the question of whether gangliosides suppress the development and function of monocyte-derived DC in vitro . In the presence of gangliosides, the monocytic DC precursors showed increased adherence, cell spreading and a reduced number of dendrites. The expression of MHC class II molecules, co-stimulatory molecules and the GM-CSF receptor (CD116) on the ganglioside-treated DC was significantly reduced. Furthermore, the function of ganglioside-treated DC was impaired as observed in endocytosis, chemotactic and T cell proliferation assays. In contrast to monocytic DC precursors, mature DC were unaffected even when higher doses of gangliosides were added to the culture. With regard to their carbohydrate structure, five different gangliosides (GM2, GM3, GD2, GD3, GT1b), which are typically shed by melanoma and neuroblastoma, were tested for their ability to suppress DC development and function. Suppression was induced by GM2, but not by the other gangliosides. These data suggest that certain gangliosides impair DC precursors, implying a possible mechanism for tumour escape.
International journal of immunopharmacology, 1990
Cell membrane gangliosides have been shown to be involved in a number of biological processes including cell adhesion, signal transduction and ligand receptor interactions. In this paper we analyzed the effects of a mixture of bovine brain gangliosides, currently in clinical use, on cell mediated immune responses in vitro. We show here that exogenous gangliosides inhibit mitogen and alloantigen induced lymphoproliferation. On the other hand effects on antigen induced blastogenesis were exquisitely dose dependent in that while high doses of gangliosides inhibited lymphoproliferation, probably by interfering in interleukin 2 receptor interactions, lower doses significantly enhanced antigen induced responsiveness. We also report that gangliosides inhibit the generation of lymphokine activated killer cells. Altogether, these data underline the immunoregulatory potential and the polymorphism of effects of exogenous gangliosides.
Gangliosides involved in activation of rat T lineage cells
Biochimica et biophysica acta, 1997
Gangliosides have long been known to be involved in T-cell activation. In our previous studies, a unique GMlb-derived ganglioside, GD1c(NeuGc,NeuGc), was shown to be the predominant ganglioside in rat thymocytes and T-cells. Upon the activation of the thymocytes, the amount of GD1c(NeuGc,NeuGc) increases remarkably, and additionally a novel species of GD1b, GD1b(NeuGc,NeuGc), appears as the other major ganglioside (Nohara, et al. (1993) J. Biol. Chem. 268, 24997-25000). In the present study, monoclonal antibodies (MAbs) against these two gangliosides have been generated. The MAb AC1 established by immunizing mice with purified GD1c(NeuGc,NeuGc) reacted strongly with GD1c(NeuGc,NeuGc) and weakly with GD1b(NeuGc,NeuGc) by enzyme-linked immunosorbent assay (ELISA). The other MAb AB1 obtained by immunization with GD1b(NeuGc,NeuGc) showed a strong binding activity to GD1b(NeuGc,NeuGc) and no reactivity to GDlc(NeuGc,NeuGc) by ELISA. Flow cytometry analyses using these MAbs have revealed ...