Suppression of immune responses by nonimmunogenic oligodeoxynucleotides with high affinity for high-mobility group box proteins (HMGBs)
Suppression of immune responses by nonimmunogenic oligodeoxynucleotides with high affinity for high-mobility group box proteins (HMGBs)
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DOI：
10.1073/pnas.1108535108
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发表时间：
2011-06
期刊：
影响因子：
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通讯作者：
H. Yanai;S. Chiba;T. Ban;Yukana Nakaima;T. Onoe;K. Honda;H. Ohdan;T. Taniguchi
中科院分区：
文献类型：
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作者：
H. Yanai;S. Chiba;T. Ban;Yukana Nakaima;T. Onoe;K. Honda;H. Ohdan;T. Taniguchi
核酸激活先天免疫反应是宿主产生抗病原体反应的核心；然而，核酸也可能引发自身免疫等致病性反应的发生和/或加剧。我们之前已经证明，核酸感应细胞质和toll样受体的选择性激活取决于高迁移率的群盒蛋白（hmgb）对核酸的混杂感应。由此，我们推断具有高亲和力HMGB结合的非免疫原性核苷酸可能作为HMGB介导的疾病的抑制剂，特别是那些由核酸引发和/或加重的疾病。在这里，我们描述了一系列hmgb结合的非免疫原性寡脱氧核苷酸（ni-ODNs）。有趣的是，我们发现结合亲和力与核苷酸序列无关，而是依赖于脱氧核糖主干的长度和结构。我们进一步表明，这些ni- odn可以强烈抑制两类核酸敏感受体诱导的先天免疫反应的激活。在脓毒症和自身免疫小鼠模型中，我们还提供了一种被称为ISM ODN的ni-ODN对诱导适应性免疫反应的抑制作用的证据。我们讨论了有关hmgb在启动免疫反应中的关键作用以及这些ni- odn在治疗干预中的可能应用的研究结果。
The activation of innate immune responses by nucleic acids is central to the generation of host responses against pathogens; however, nucleic acids can also trigger the development and/or exacerbation of pathogenic responses such as autoimmunity. We previously demonstrated that the selective activation of nucleic acid-sensing cytosolic and Toll-like receptors is contingent on the promiscuous sensing of nucleic acids by high-mobility group box proteins (HMGBs). From this, we reasoned that nonimmunogenic nucleotides with high-affinity HMGB binding may function as suppressing agents for HMGB-mediated diseases, particularly those initiated and/or exacerbated by nucleic acids. Here we characterize an array of HMGB-binding, nonimmunogenic oligodeoxynucleotides (ni-ODNs). Interestingly, we find that binding affinity is rather independent of nucleotide sequence, but is instead dependent on length and structure of the deoxyribose backbone. We further show that these ni-ODNs can strongly suppress the activation of innate immune responses induced by both classes of nucleic acid-sensing receptors. We also provide evidence for the suppressive effect of an ni-ODN, termed ISM ODN, on the induction of adaptive immune responses and in mouse models of sepsis and autoimmunity. We discuss our findings in relation to the critical role of HMGBs in initiating immune responses and the possible use of these ni-ODNs in therapeutic interventions.