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首页> 外文期刊>Acta biomaterialia >DNA-polymer conjugates for immune stimulation through Toll-like receptor 9 mediated pathways
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DNA-polymer conjugates for immune stimulation through Toll-like receptor 9 mediated pathways

机译：用于免疫刺激的DNA-聚合物缀合物通过Toll样受体9介导的途径

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摘要

Oligodeoxynucleotides (ODNs) containing unmethylated CpG dinucleotide motifs are agonists of Toll-like receptor 9 and are currently being investigated for use as vaccine adjuvants through the promotion of type I immunity. Several classes of ODN have been developed which differ in their propensity to aggregate, which in turn alters cytokine profiles and cellular subsets activated. Although aggregation state is correlated with the change in cytokine response, it is unknown if this results from a change in the number of ODNs available for binding and/or the possible engagement of multiple TLR9 molecules. Here, we examined the role of ligand valency on the activation of TLR9 through the synthesis of ODN-poly(acrylic acid) (PAA) conjugates. The compositions and size of the conjugates were characterized by UV-vis spectroscopy, proton nuclear magnetic resonance, gel permeation chromatography and dynamic light scattering. Enzyme-linked immunosorbent assays of cytokine secretion by murine-like macrophages indicate that these ODN-PAA polymer conjugates show enhanced immunostimulation at 100-fold lower concentrations than those required for ODN alone, for both TNF-α and IL-6 release, and are more potent than any other previously reported multivalent ODN constructs. Increasing valency was shown to significantly enhance cytokine expression, particularly for IL-6. Knockdown by siRNA demonstrates that these polymer conjugates are specific to TLR9. Our results define valency as a critical design parameter and polymer conjugation as an advantageous strategy for producing ODN immunomodulatory agents.
机译：含有未甲基化的CpG二核苷酸基序的寡脱氧核苷酸（ODNS）是Toll样受体9的激动剂，目前正在研究通过促进I型免疫力作为疫苗佐剂。已经开发了几类ODN，其倾向于骨料倾向，其反而改变了激活的细胞因子曲线和细胞亚群。尽管聚集状态与细胞因子响应的变化相关，但如果这是由可用于结合和/或多个TLR9分子的可能接合的ODN的变化来相关。在这里，我们通过合成Odn-poly（丙烯酸）缀合物来检查配体utence对TLR9活化的作用。通过UV-Vis光谱，质子核磁共振，凝胶渗透色谱和动态光散射的组合物和尺寸的特征表征。用鼠样巨噬细胞的细胞因子分泌的酶联免疫吸附测定表明，这些ODN-PAA聚合物缀合物在100倍的较低浓度下显得增强的免疫刺激，而不是单独的ODN所需的免疫刺激，用于TNF-α和IL-6释放，并且是比任何其他先前报道的多价odn结构更有效。较高的桂增强显着增强细胞因子表达，特别是对于IL-6。 SiRNA敲低证明这些聚合物缀合物特异于TLR9。我们的结果定义了价值作为关键设计参数和聚合物缀合，作为生产ODN免疫调节剂的有利策略。

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