Superior activity of the type C class of ISS in vitro and in vivo across multiple species
Superior activity of the type C class of ISS in vitro and in vivo across multiple species
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DOI：
10.1089/dna.2005.24.63
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发表时间：
2005-02-01
影响因子：
3.1
通讯作者：
Van Nest, G
中科院分区：
文献类型：
--
作者：
Marshall, JD;Fearon, KL;Van Nest, G
CpG-C是一类新的含CpG基序的免疫刺激序列（ISS），其包括5 '-TCG元件和含CpG的回文序列。CpG-C驱动所有已知的ISS活性，并且特别是来自浆细胞样树突细胞（PDCs）的IFN-α的有效增强剂。在我们对CpG-C序列要求的检查中，我们确定了最佳IFN-α诱导活性可以用较长的回文来实现。较长的回文也与双链（ds）形式的维持相关，尽管浓度和pH值的变化，表明通过ISS诱导的IFN-α合成的信号传导机制对ds寡脱氧核苷酸（ODNs）的偏好。这种相关性并不适用于ISS诱导的免疫反应的所有臂，因为我们没有观察到较长的回文CpG-C ODN会增加B细胞活性。我们进一步证明了CpG-C在体外灵长类动物系统中保留活性，并且当CpG-C体内施用于小鼠和灵长类动物时诱导几种细胞因子和IFN-α诱导基因的表达。总之，我们已经证明CpG-C在多个物种中发挥几种类型的免疫功能，因此这种新的类别是基于ISS的治疗策略的有吸引力的候选者。
CpG-C are a novel class of CpG motif-containing immunostimulatory sequences (ISS) that includes both a 5'-TCG element and a CpG-containing palindrome. CpG-C drive all known ISS activities and, in particular, are potent enhancers of IFN-alpha from plasmacytoid dendritic cells (PDCs). In our examination of CpG-C sequence requirements, we determined that optimal IFN-alpha-inducing activity could be achieved with longer palindromes. Longer palindromes also correlated with maintenance of the double-stranded (ds) form despite concentration and pH changes, indicating a preference for ds oligodeoxynucleotides (ODNs) by the ISS-induced signaling mechanism for IFN-alpha synthesis. This correlation did not hold for all arms of the ISS-induced immune response, since we did not observe increased B cell activity with the longer palindrome CpG-C ODNs. We further demonstrated that CpG-C retained activity in an in vitro primate system and induced the expression of several cytokines and IFN-alpha-inducible genes when CpG-C were administered in vivo to mice and primates. In conclusion, we have shown CpG-C to exert several types of immune functions across multiple species, and this novel class is thus an attractive candidate for ISS-based therapeutic strategies.