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Liposome-Encapsulated CpG Oligodeoxynucleotides as a Potent Adjuvant for Inducing Type 1 Innate Immunity

¹ Division of Immunoregulation, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; ² Surgical Oncology, Cancer Medicine, Division of Cancer Medicine, Hokkaido University School of Medicine, Sapporo, Japan; and ³ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

Unmethylated cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG-ODNs) exhibit potent immunostimulating 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- (IFN-), whereas the same dose of unmodified CpG-ODN induced only low numbers of IFN-–producing NK cells (12.7%) and NKT cells (1.6%) to produce IFN-. In contrast with the NKT cell agonist -galactosylceramide, which induces both IFN- and IL-4 production by NKT cells, CpG-liposome only induced IFN- 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 1 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-specific 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.

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