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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Immunomodulatory oligonucleotides containing a cytosine-phosphate-2′-deoxy-7-deazaguanosine motif as potent Toll-like receptor 9 agonists
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Immunomodulatory oligonucleotides containing a cytosine-phosphate-2′-deoxy-7-deazaguanosine motif as potent Toll-like receptor 9 agonists

机译：含有胞嘧啶磷酸酯2'-脱氧-7-脱氮鸟苷基序作为强效Toll样受体9激动剂的免疫调节寡核苷酸

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摘要

Bacterial DNA and synthetic oligomers containing CpG dinucle-otides activate the immune system through Toll-like receptor (TLR) 9. Here, we compare the immunostimulatory activity of three immunomers with different nucleotide sequences containing a synthetic cytosine-phosphate-2′-deoxy-7-deazaguanosine dinucleotide (CpR), called immunomodulatory oligonucleotides (IMOs), in mouse, human, and monkey systems. IMOs induced IL-12 and IFN-γ secretion more than a control non-CpG IMO in mice. All three IMOs activated HEK293 cells expressing TLR9 but not TLR3, -7, or -8. IMOs induced human B-cell proliferation and enhanced expression of CD86 and CD69 surface markers on B cells. The three IMOs induced CD86 expression on human plasmacytoid dendritic cells, but only IMOs that contained a 5′-terminal TCR nucleotide sequence induced IFN-α secretion. A sequence that forms a duplex structure also was required for IFN-α induction in human peripheral blood mononuclear cell cultures. IMOs induced chemokine and cytokine gene expression in human peripheral blood mononuclear cells. In monkeys, all three IMOs induced transient changes in peripheral blood leukocytes and lymphocytes and activated B and T lymphocytes. All three IMOs induced IFN-α in vivo in monkeys; the IMO sequence that forms a stable secondary structure induced the highest levels of IFN-α. These studies are, to our knowledge, the first comprehensive studies to compare the activity of IMOs containing synthetic stimulatory CpR dinucleotides in mouse, monkey, and human systems. These results suggest that IMOs induce strong and rapid immunostimulation and that the CpR dinucleotide is recognized by TLR9, leading to immune-cell activation and cytokine secretion in vitro and in vivo.
机译：细菌DNA和含有CpG二核苷酸的合成寡聚物通过Toll样受体（TLR）9激活免疫系统。在这里，我们比较了三种具有不同核苷酸序列的含有合成胞嘧啶-磷酸-2'-脱氧-核苷酸的免疫单体的免疫刺激活性。在小鼠，人和猴系统中的7-脱氮鸟苷二核苷酸（CpR），称为免疫调节性寡核苷酸（IMO）。在小鼠中，IMO比诱导的非CpG IMO诱导的IL-12和IFN-γ分泌更多。这三个IMO都激活了表达TLR9但不表达TLR3，-7或-8的HEK293细胞。 IMOs诱导人B细胞增殖，并增强B细胞上CD86和CD69表面标记的表达。这三个IMO诱导了人浆细胞样树突状细胞上CD86的表达，但是只有包含5'-末端TCR核苷酸序列的IMO诱导了IFN-α的分泌。在人外周血单核细胞培养物中诱导IFN-α也需要形成双链体结构的序列。 IMOs诱导人外周血单核细胞中趋化因子和细胞因子基因的表达。在猴子中，所有三个IMO都诱导外周血白细胞和淋巴细胞以及活化的B和T淋巴细胞发生瞬时变化。这三种IMO均在猴体内诱导IFN-α；形成稳定二级结构的IMO序列诱导了最高水平的IFN-α。就我们所知，这些研究是比较小鼠，猴和人系统中包含合成刺激性CpR二核苷酸的IMO活性的首个综合研究。这些结果表明，IMOs诱导了强烈而快速的免疫刺激，并且CpR二核苷酸被TLR9识别，从而导致体内外免疫细胞活化和细胞因子分泌。

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