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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：DNA聚合物共轭物通过Toll样受体9介导的途径进行免疫刺激

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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：包含未甲基化的CpG二核苷酸基序的寡脱氧核苷酸（ODN）是Toll样受体9的激动剂，目前正在通过促进I型免疫来研究用作疫苗佐剂。已经开发了几类ODN，它们的聚集倾向不同，从而改变了细胞因子谱和激活的细胞亚群。尽管聚集状态与细胞因子应答的变化相关，但尚不清楚这是否是由于可用于结合的ODN数量的变化和/或多个TLR9分子可能的结合所致。在这里，我们研究了通过ODN-聚（丙烯酸）（PAA）共轭物的合成，配体价对TLR9活化的作用。通过UV-可见光谱，质子核磁共振，凝胶渗透色谱和动态光散射来表征缀合物的组成和大小。鼠类巨噬细胞分泌的细胞因子的酶联免疫吸附试验表明，这些ODN-PAA聚合物缀合物在单独的TNF-α和IL-6释放浓度比单独使用ODN所需的浓度低100倍的情况下显示出增强的免疫刺激作用。比任何其他先前报道的多价ODN构建体更有效。显示化合价的增加显着增强了细胞因子的表达，特别是对于IL-6。 siRNA敲低表明这些聚合物结合物对TLR9具有特异性。我们的结果将化合价定义为关键设计参数，并将聚合物缀合定义为生产ODN免疫调节剂的有利策略。

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