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首页> 外文期刊>Vaccine >Differential effects of monophosphoryl lipid A and cytokine cocktail as maturation stimuli of immunogenic and tolerogenic dendritic cells for immunotherapy.
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Differential effects of monophosphoryl lipid A and cytokine cocktail as maturation stimuli of immunogenic and tolerogenic dendritic cells for immunotherapy.

机译：单磷酰脂质A和细胞因子鸡尾酒作为免疫原性和耐受性树突状细胞成熟刺激的免疫疗法的差异作用。

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Immunotherapy using monocyte-derived dendritic cells (MDDC) is increasingly being considered as alternative therapeutic approach in cancer, infectious diseases and also in autoimmunity when patients are not responsive to conventional treatments. In general, generation of MDDC from monocytes is induced in the presence of GM-CSF and IL-4, and a maturation stimulus is added to the culture to obtain mature DCs suitable for therapy. For DC maturation, different combinations of pro-inflammatory mediators and Toll-like receptor ligands have been tested, obtaining DCs that differ in their properties and the type of immune response they promote. Therefore, it is necessary to find an optimal cytokine environment for DC maturation to obtain a cellular product suitable for DC-based immunotherapeutic protocols. In this study, we have evaluated in vitro the effects of different maturation stimuli on the viability, phenotype, cytokine profile, stability and functionality of immunogenic and tolerogenic (1 alpha ,25-dihydroxyvitamin D3-treated) MDDC. Maturation was induced using the clinical grade TLR4-agonist: monophosphoryl lipid A (LA), compared to the traditional cytokine cocktail (CC; clinical grade TNF- alpha , IL-1 beta , PGE2) and a combination of both. Our results showed the combination of CC + LA rendered a potent immunogenic DC population that induced the production of IFN- gamma and IL-17 in allogeneic co-cultures, suggesting a Th17 polarization. Moreover, these immunogenic DCs showed a high surface expression of CD83, CD86, HLA-DR and secretion of IL-12p70. When aiming to induce tolerance, using LA to generate mature TolDC did not represent a clear advantage, and the stability and the suppressive capability exhibited by CC-matured TolDC may represent the best option. Altogether, these findings demonstrate the relevance of an appropriate maturation stimulus to rationally modulate the therapeutic potential of DCs in immunotherapy.
机译：当患者对常规治疗无反应时，使用单核细胞来源的树突状细胞（MDDC）进行的免疫治疗已被越来越多地视为癌症，传染病以及自身免疫性的替代治疗方法。通常，在存在GM-CSF和IL-4的情况下诱导单核细胞产生MDDC，并向培养物中添加成熟刺激物以获得适合于治疗的成熟DC。对于DC成熟，已经测试了促炎性介质和Toll样受体配体的不同组合，从而获得了DC的性质和它们促进的免疫反应类型不同的DC。因此，有必要找到DC成熟的最佳细胞因子环境，以获得适用于基于DC的免疫治疗方案的细胞产品。在这项研究中，我们评估了体外不同成熟刺激对免疫原性和耐受性（1 alpha，25-dihydroxyvitamin D 3的存活率，表型，细胞因子谱，稳定性和功能性的影响处理）的MDDC。与传统的细胞因子混合物（CC;临床等级TNF-α，IL-1 beta，PGE2）和两者的组合相比，使用临床等级的TLR4-激动剂：单磷酰脂质A（LA）诱导成熟。我们的结果表明CC + LA的结合产生了强大的免疫原性DC种群，该种群诱导了同基因共培养物中IFN-γ和IL-17的产生，表明Th17极化。此外，这些具有免疫原性的DC表现出CD83，CD86，HLA-DR的高表面表达和IL-12p70的分泌。当试图诱导耐受性时，使用LA生成成熟的TolDC并不代表明显的优势，而CC成熟的TolDC表现出的稳定性和抑制能力可能是最佳选择。总之，这些发现证明了适当的成熟刺激与合理调节DC在免疫疗法中的治疗潜力的相关性。

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