Dendritic cells generated in the presence of interferon-α and modulated with dexamethasone as a novel tolerogenic vaccine platform.

Abstract

Tolerogenic dendritic cells (tDCs) are considered a novel therapeutic tool in treating autoimmune diseases, allergies, and transplantation reactions. Among numerous pharmacological immune modulators, dexamethasone (Dex) is known to induce potent tolerogenicity in DCs generated from human monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4), and these cells (IL-4-DCs/Dex) are being appraised as a tDC-based platform in clinical settings. Interferon-α (IFNα) represents another powerful inducer of monocyte-derived DCs, which possess higher migratory activity and stability. However, the functions of IFN-DCs/Dex have not been sufficiently analyzed and there are no comparative studies of the tolerogenicity of IFN-DCs/Dex and IL-4-DCs/Dex. This study aimed to investigate the properties of IFN-DCs/Dex in comparison with IL-4-DCs/Dex. DCs were obtained by cultivation of an adherent fraction of peripheral blood mononuclear cells (MNCs) in the presence of GM-CSF and IFNα or IL-4 with subsequent lipopolysaccharide-driven maturation. Dex (10-6M) was added to the cultures at day 3. We showed that generation of IFN-DCs with Dex resulted in decrease in percentage of CD83+ and CD86+ DCs and increase in numbers of CD14+, B7-H1+, and Toll-like receptor 2 (TLR2+) DCs. Treatment with Dex downregulated pro-inflammatory cytokine production, reduced DC allostimulatory activity, and inhibited DC capacity to stimulate Th1/pro-inflammatory cytokine production, altogether evidencing the induction of a tolerogenic phenotype. As compared to IL-4-DCs/Dex, IFN-DCs/Dex were characterized by larger proportion of TLR2+ and CD14+ cells, higher production of IL-10 and lower TNFα/IL-10 ratio, more potent capacity to induce T cell anergy, and more efficiently skewed T cell cytokine balance towards Th2/anti-inflammatory profile. The data obtained indicate that potent tDCs could be generated by treating IFN-DCs with dexamethasone. The tolerogenic properties of IFN-DCs/Dex are better than or at least equal to those of the IL-4-DCs/Dex, as assessed by in vitro phenotypic and functional assays, suggesting these cells as a new tolerogenic vaccine platform.