Modulation of toll-like receptor 9 responses through synthetic immunostimulatory motifs of DNA
Modulation of toll-like receptor 9 responses through synthetic immunostimulatory motifs of DNA
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DOI：
10.1196/annals.1281.005
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发表时间：
2003-01-01
期刊：
影响因子：
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通讯作者：
Kandimalla, ER
中科院分区：
文献类型：
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作者：
Agrawal, S;Kandimalla, ER
细菌、质粒和合成DNA在特定的序列环境中含有未甲基化的CpG二核苷酸，激活脊椎动物的先天免疫系统。模式识别受体(PRR)，Toll样受体9(TLR9)，识别CpG DNA并激活信号级联反应，导致大量细胞因子和趋化因子的分泌。我们广泛的结构-免疫刺激活性关系研究表明，许多人工合成的嘧啶(Y)和嘌呤(R)核苷酸被受体接受作为CpG二核苷酸中天然脱氧胞苷和脱氧鸟苷的替代品。这些研究允许开发合成的免疫刺激基序YPG、CPR和YPR，并建立了受体的核苷酸基序识别模式。CpG二核苷酸侧翼序列中的一些位点特异性化学修饰允许以可预测的方式调节免疫刺激效应。我们的研究还表明，TLR9可以识别和读取5‘端的CpG DNA序列。设计具有两个5‘端的寡核苷酸，免疫聚合物，导致具有不同细胞因子谱的强大的免疫调节剂。与天然CpG基序相比，含有合成免疫刺激基序的免疫聚合体产生不同的细胞因子诱导谱。重要的是，其中一些合成基序在小鼠和人类系统中都表现出最佳的活性，而不需要改变序列，这表明通过使用合成基序来推翻受体的物种依赖的特异性。本文综述了第二代免疫调节型寡核苷酸对TLR9受体结构识别和功能调控的研究现状及其作为广谱治疗药物的应用前景。
Bacterial, plasmid, and synthetic DNA containing unmethylated CpG dinucleotides in specific sequence contexts activate the vertebrate innate immune system. A pattern recognition receptor (PRR), toll-like receptor 9 (TLR9), recognizes CpG DNA and activates signaling cascade leading to the secretion of a number of cytokines and chemokines. Our extensive structure-immunostimulatory activity relationship studies showed that a number of synthetic pyrimidine (Y) and purine (R) nucleotides are accepted by the receptor as substitutes for natural deoxycytidine and deoxyguanosine in a CpG dinucleotide. These studies permitted development of synthetic immunostimulatory motifs YpG, CpR, and YpR and established the nucleotide motif recognition pattern of the receptor. A number of site-specific chemical modifications in the flanking sequences to the CpG dinucleotide permitted modulation of immunostimulatory affects in a predictable manner. Our studies also showed that TLR9 recognizes and reads the CpG DNA sequence from the 5'-end. Design of oligonucleotides with two 5'-ends, immunomers, resulted in potent immunomodulatory agents with distinct cytokine profiles. Immunomers containing synthetic immunostimulatory motifs produced different cytokine induction profiles compared with natural CpG motifs. Importantly, some of these synthetic motifs showed optimal activity in both mouse and human systems without requiring to change sequences, suggesting overriding the species-dependent specificity of the receptor by the use of synthetic motifs. In this article, we review current understanding of structural recognition and functional modulation of TLR9 receptor by second-generation immunomodulatory oligonucleotides and their potential application as wide spectrum therapeutic agents.