Inproceedings: an article in a conference proceedings.
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Inhibition of dendritic cell maturation and function by low molecular weight dextran sulfate : PA-3216
Title of the conference
1st Joint Meeting of European National Societies of Immunology, under the auspices of EFIS, 16th European Congress of Immunology (ECI)
Paris, France, September 6-9, 2006
Background and Hypothesis: Activation of vascular endothelial cells (EC) is characterized by shedding of heparan sulfate (HS), which is an important regulator of intravascular coagulation and inflammation. Soluble HS is known to activate dendritic cells (DC) via Toll-like receptor 4 (TLR). Low molecular weight dextran sulfate (DXS, MW 5000) has been reported to inhibit the alternative, classical and lectin complement pathways as well as the coagulation cascade. Furthermore, DXS acts as an EC protectant, promoting accommodation in hamster-to-rat xenotransplantation. We therefore hypothesized that DXS might also be able to interfere with antigen presentation by blocking DC maturation, and that this effect may facilitate induction of immunological tolerance. Methods and Results: Human DC were propagated from monocytes with GM-CSF and IL-4 for 6 days. Immature DC were stimulated with different exogenous (LPS, LAM) and endogenous ligands (HS) of TLR to induce maturation. As shown by FACS analysis, addition of DXS during promoted DC maturation was able to dose-dependently prevent upregulation of molecules such as CD40, CD83, CD80/CD86 as well as ICAM-1. In the case of CD86, maturation induced by HS was totally inhibited with 5 mg/ml DXS (MFI ± SD; 61.3 ± 7.2 without DXS 8.2 ± 1.5 with DXS ; p<0.001; n=4). To exclude that the effect of HS was due to LPS contamination with LPS, Limulus anti LPS-factor was used, which had no effect. Mature DC function was examined by the ability to stimulate autologous T cells. DC-mediated T cell proliferation was significantly inhibited by DXS. In addition, DXS significantly inhibits HS induced secretion of IL-1β, IL-6 and TNF-α as assessed by multiplex suspension array in cell culture supernatant. Furthermore, DXS does not seem to influence differentiation of monocytes into immature DC as analyzed by the expression of CD14 and CD1a. Conclusions and Outlook: We have demonstrated that DXS is able to prevent phenotypic and functional maturation of human DC. Follow-up experiments will investigate if alterations of DXS treated DC are associated with a reduced translocation of NF-κB into the nucleus.
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