Background

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.

Results

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 (10⁻⁶ M) 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.

Conclusions

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.

中文翻译：

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树突状细胞在干扰素-α的存在下产生，并被地塞米松调节为一种新型的致耐受性疫苗平台。

背景

致耐受性树突状细胞（tDC）被认为是治疗自身免疫性疾病，过敏和移植反应的新型治疗工具。在众多药理免疫调节剂中，地塞米松（Dex）可以诱导人单核细胞与粒细胞-巨噬细胞集落刺激因子（GM-CSF）和白细胞介素4（IL-4）以及这些细胞（IL）产生的强耐受性-4-DC / Dex）在临床环境中被评估为基于tDC的平台。干扰素-α（IFNα）代表另一种强大的单核细胞衍生DC诱导剂，具有更高的迁移活性和稳定性。但是，尚未充分分析IFN-DCs / Dex的功能，并且没有对IFN-DCs / Dex和IL-4-DCs / Dex的致耐受性的比较研究。

结果

DCs是通过在GM-CSF和IFNα或IL-4存在下培养外周血单核细胞（MNC）的粘附级分并随后进行脂多糖驱动的成熟而获得的。 在第3天将Dex（10 ^-6 M）添加到培养物中。我们显示，带有Dex的IFN-DC的产生导致CD83 ⁺和CD86 ⁺ DC的百分比降低，而CD14 ⁺，B7-H1 ^+的数量增加和Toll样受体2（TLR2 ⁺）DC。Dex的治疗下调了促炎细胞因子的产生，降低了DC的同素刺激活性，并抑制了DC刺激Th1 /促炎性细胞因子的产生，从而证明了耐受性表型的诱导。与IL-4-DCs / Dex相比，IFN-DCs / Dex具有以下特点：TLR2 ⁺和CD14 ⁺细胞比例更大，IL-10产量更高，TNFα/ IL-10比值更低，诱导T的能力更强细胞无反应，并且更有效地使T细胞细胞因子平衡偏向Th2 /抗炎状态。

结论

获得的数据表明通过用地塞米松处理IFN-DC可以产生有效的tDC。通过体外表型和功能测定评估，IFN-DCs / Dex的耐受性优于或至少等于IL-4-DCs / Dex的耐受性，表明这些细胞是一种新的耐受性疫苗平台。