title: Mechanisms of ganglioside inhibition of APC function.
abstract: 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.
authors.affiliation: Glycobiology Program, Center for Cancer Research, Children's Research Institute, Washington, DC 20010, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Caldwell
authors.forename: Andreas
authors.initials: A
authors.lastname: Heitger
authors.forename: Weiping
authors.initials: W
authors.lastname: Shen
authors.forename: Yihui
authors.initials: Y
authors.lastname: Liu
authors.forename: Barbara
authors.initials: B
authors.lastname: Taylor
authors.forename: Stephan
authors.initials: S
authors.lastname: Ladisch
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000276:immunology; D017951:Antigen Presentation / Q000187:drug effects*; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018122:B7-1 Antigen / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002462:Cell Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005732:Gangliosides / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D018122:B7-1 Antigen; D016207:Cytokines; D005732:Gangliosides; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; C021298:ganglioside, GD1a