Liposome-encapsulated CpG oligodeoxynucleotides as a potent adjuvant for inducing type 1 innate immunity
Liposome-encapsulated CpG oligodeoxynucleotides as a potent adjuvant for inducing type 1 innate immunity
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DOI：
10.1158/0008-5472.can-04-1691
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发表时间：
2004-12-01
期刊：
影响因子：
11.2
通讯作者：
Nishimura, T
中科院分区：
文献类型：
--
作者：
Suzuki, Y;Wakita, D;Nishimura, T
非甲基化胞嘧啶-硫代磷酸-鸟嘌呤寡脱氧核苷酸（CpG-ODNs）通过与抗原呈递细胞上表达的Toll样受体9（TLR 9）结合而显示出强的免疫刺激活性。在这里，我们表明，CpG-ODN封装在阳离子脂质体（CpG-liposomes）提高其纳入CD 11 c（+）树突状细胞（DCs）和诱导增强血清白细胞介素（IL）-12水平相比，未修饰的CpG-ODN。CpG-脂质体有效地激活自然杀伤（NK）细胞（84.3%）和NKT细胞（48.3%）以产生干扰素-γ（IFN-γ），而相同剂量的未修饰的CpG-ODN仅诱导少量的产生IFN-γ的NK细胞（12.7%）和NKT细胞（1.6%）产生IFN-γ。与诱导NKT细胞产生IFN-γ和IL-4的NKT细胞激动剂α-半乳糖神经酰胺相反，CpG-脂质体仅诱导NKT细胞产生IFN-γ。CpG-脂质体的这种有效的佐剂活性在TLR 9缺陷小鼠中不存在，表明CpG-脂质体在通过TLR 9刺激I型先天免疫中与CpG-ODN一样有效。除了TLR 9外，至少还有两个其他因素，即DC产生IL-12以及DC与NK或NKT细胞之间的直接接触，是CpG-脂质体诱导1型先天免疫所必需的。此外，通过与卵清蛋白（OVA）共包封的CpG-脂质体连接TLR 9引起OVA特异性CTL的诱导，其对表达OVA的肿瘤细胞表现出强的细胞毒性。这些结果表明，CpG脂质体单独或与肿瘤抗原蛋白联合应用为肿瘤的预防或治疗提供了一种有希望的方法。
Unmethylated cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG-ODNs) exhibit potent inummostimulating activity by binding with Toll-like receptor 9 (TLR9) expressed on antigen-presenting cells. Here, we show that CpG-ODN encapsulated in cationic liposomes (CpG-liposomes) improves its incorporation into CD11c(+) dendritic cells (DCs) and induces enhanced serum interleukin (IL)-12 levels compared with unmodified CpG-ODN. CpG-liposome potently activated natural killer (NK) cells (84.3%) and NKT cells (48.3%) to produce interferon-gamma (IFN-gamma), whereas the same dose of-unmodified CpG-ODN induced only low numbers of IFN-gamma-producing NK cells (12.7%) and NKT cells (1.6%) to produce IFN-gamma. In contrast with the NKT cell agonist a-galactosylceramide, which induces both IFN-gamma and IL-4 production by NKT cells, CpG-liposome, only induced IFN-gamma production by NKT cells. Such potent adjuvant activities of CpG-liposome were absent in TLR9-deficient mice, indicating that CpG-liposome was as effective as CpG-ODN in stimulating type I innate immunity through TLR9. In addition to TLR9, at least two other factors, IL-12 production by DCs and direct contact between DCs and NK or NKT cells, were essential for inducing type 1 innate immunity by CpG-liposome. Furthermore, ligation of TLR9 by CpG-liposome coencapsulated with ovalbumin (OVA) caused the induction of OVA-speciric CTLs, which exhibited potent cytotoxicity against OVA-expressing tumor cells. These results indicate that CpG-liposome alone or combined with tumor antigen protein provides a promising approach for the prevention or therapy of tumors.