Untitled

Coelho, Valéria de Mello; Nguyen, Dong Van; Giri, Banabihari; Bunbury, Allyson; Schaffer, Eric; Taub, Dennis D.

doi:10.1186/1471-2172-5-2

Cited by 47 publications

(14 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NGcGM2 ganglioside is one of the major components of murine lymphocytes followed by NGcGD1a (31). Also, it has been reported that GM1 ganglioside expression is increased in CD4-CD8 + mature murine thymocytes in comparison with CD4 + CD8 À cells (32). As gangliosides are usually organized into lipid rafts where they modulate several signaling pathways, it is possible to speculate that these NGcGM3 differences could be correlated with different functions of this ganglioside in these murine lymphocyte subsets.…”

Section: Discussionmentioning

confidence: 96%

Anti-ganglioside antibody-induced tumor cell death by loss of membrane integrity

Roque-Navarro

Chakrabandhu

León

et al. 2008

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Gangliosides have been involved in multiple cellular processes such as growth, differentiation and adhesion, and more recently as regulators of cell death signaling pathways. Some of these molecules can be considered as tumor-associated antigens, in particular, N-glycolyl sialic acid -containing gangliosides, which are promising candidates for cancer-targeted therapy because of their low expression in normal human tissues. In this study, we provided the molecular and cellular characterization of a novel cell death mechanism induced by the anti-NGcGM3 14F7 monoclonal antibody (mAb) in L1210 murine tumor cell line but not in mouse normal cells (B and CD4 + T lymphocytes) that expressed the antigen. Impairment of ganglioside synthesis in tumor cells abrogated the 14F7 mAb cytotoxic effect; however, exogenous reincorporation of the ganglioside did not restore tumor cell sensitivity to 14F7 mAb-induced cytotoxicity. 14F7 F(ab ¶) 2 but not Fab fragments retained the cytotoxic capacity of the whole mAb. By contrary, other mAb, which recognizes N-glycolylated gangliosides, did not show any cytotoxic effect. These mAbs showed quite different capacities to bind NGcGM3-positive cell lines measured by binding inhibition experiments. Interestingly, this complementindependent cell death mechanism did not resemble apoptosis, because no DNA fragmentation, caspase activation, or Fas mediation were observed. However, NGcGM3 ganglioside-mediated 14F7 mAb-induced cell death was accompanied by cellular swelling, membrane lesion formation, and cytoskeleton activation, suggesting an oncosislike phenomenon. This novel mechanism of cell death lets us to support further therapeutic approaches using NGcGM3 as a molecular target for antibody-based cancer immunotherapy.

show abstract

Section: Discussionmentioning

confidence: 96%

Anti-ganglioside antibody-induced tumor cell death by loss of membrane integrity

Roque-Navarro

Chakrabandhu

León

et al. 2008

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Staining with CTx-B, commonly used to detect GM1a and visualize rafts, has demonstrated that CD8 + T cells express higher levels of GM1a in the rafts than CD4 + T cells (19). However, this toxin also reacts to other gangliosides including fucosylated-GM1a and extended-GM1b, both of which have a monosialo-ganglio-triose structure, Galβ1-3GalNAcβ1-4(SAα2-3)Galβ1- (6).…”

Section: Discussionmentioning

confidence: 99%

CD4 and CD8 T cells require different membrane gangliosides for activation

Nagafuku

Okuyama²,

Onimaru³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

116

View full text Add to dashboard Cite

Initial events of T-cell activation involve movement of the T-cell receptor into lipid rafts. Gangliosides are major components of lipid rafts. While investigating T-cell activation in ganglioside-deficient mice, we observed that CD4 + and CD8 + T cells required different ganglioside subsets for activation. Activation of CD4 + T cells from GM3 synthase-null mice, deficient in GM3-derived gangliosides, is severely compromised, whereas CD8 + T-cell activation is normal. Conversely, in cells from GM2/GD2 synthase-null mice, expressing only GM3 and GD3, CD4 + T-cell activation is normal, whereas CD8 + T-cell activation is deficient. Supplementing the cells with the corresponding missing gangliosides restores normal activation. GM3 synthase-null mice do not develop experimental asthma. Distinct expression patterns of ganglioside species in CD4 + T and CD8 + T cells, perhaps in uniquely functional lipid rafts, define immune functions in each T-cell subset. Control of ganglioside expression would offer a strategy targeting for specific T-cell subpopulations to treat immune diseases.

show abstract

“…Next, we investigated whether the LP5-induced decrease in CD3 was associated with lipid rafts, where CD90 is reportedly located [19]. T cells were treated with LP5 in the presence or absence of methyl-␤-cyclodextrin (M␤CD), which causes a depletion of membrane cholesterol [29,30].…”

Section: Lp5 Ab Induces the Down-modulation Of Cd3 Moleculesmentioning

confidence: 99%

“…In the mouse, CD90 is present on a variety of cell types including thymocytes and peripheral T cells. More recently, CD90 has been used as a marker for lipid rafts in murine T cells [19]. Both stimulatory and negative regulatory roles for CD90 during T cell activation were suggested from studies using CD90-deficient mice or anti-CD90 Abs [20][21][22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of T cell activation through down-regulation of TCR-CD3 expression mediated by an anti-CD90 Ab

et al. 2011

View full text Add to dashboard Cite

We are trying to develop new Abs that can manipulate CD4 T cell responses and are usable as immunosuppressive agents. To this end, we performed functional screening, in which we examined the effect of an Ab on the proliferation of mouse CD4 T cells upon activation. The Ab, LP5, inhibited the activation of CD4 T cells stimulated with an anti-CD3 Ab or peptide antigen. The Ab alone had no stimulatory effect on CD4 T cells. Biochemical experiments demonstrated that LP5 recognized the Thy-1 (CD90) molecule. Interestingly, the treatment of CD4 T cells with LP5 in vitro induced a temporary down-regulation of CD3 expression at the cell surface. TCR molecules were also affected. Other anti-CD90 Abs not inhibitory to CD4 T cell activation failed to induce a reduction in CD3. Experiments in vitro revealed that the down-regulation caused by LP5 is due to an accelerated endocytosis of cell surface CD3. In addition, it was shown that CD3 down-regulation before or in the early stages of T cell activation is critical for the induction of hyporesponsiveness. Experiments in vivo showed that pre-treatment of CD4 T cells with LP5 inhibited the rejection of semi-allogeneic bone marrow transplants. Based on these observations, we propose that CD3 down-regulation without any stimulatory activity against T cells could be one approach to inhibiting T cell activation, and CD90 would be an appropriate target.

show abstract

Untitled

Cited by 47 publications

References 34 publications

Anti-ganglioside antibody-induced tumor cell death by loss of membrane integrity

Anti-ganglioside antibody-induced tumor cell death by loss of membrane integrity

CD4 and CD8 T cells require different membrane gangliosides for activation

Inhibition of T cell activation through down-regulation of TCR-CD3 expression mediated by an anti-CD90 Ab

Contact Info

Product

Resources

About