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The Journal of Immunology, 2003, 171: 1676-1683.
Copyright © 2003 by The American Association of Immunologists

Mechanisms of Ganglioside Inhibition of APC Function1

Sheila Caldwell, Andreas Heitger, Weiping Shen, Yihui Liu, Barbara Taylor and Stephan Ladisch2

Glycobiology Program, Center for Cancer Research, Children’s Research Institute, Washington, DC 20010

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 µM highly purified ganglioside GD1a, 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 GD1a 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%). GD1a-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-{kappa}B proteins in activated DC suggests that disruption of NF-{kappa}B 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.




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