Liposome-encapsulated CpG oligodeoxynucleotides as a potent adjuvant for inducing type 1 innate immunity.
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-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 alpha-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 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.
Suzuki
Yoshinori
Y
Division of Immunoregulation, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Wakita
Daiko
D
Chamoto
Kenji
K
Narita
Yoshinori
Y
Tsuji
Takemasa
T
Takeshima
Tsuguhide
T
Gyobu
Hiroshi
H
Kawarada
You
Y
Kondo
Satoshi
S
Akira
Shizuo
S
Katoh
Hiroyuki
H
Ikeda
Hiroaki
H
Nishimura
Takashi
T
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology; D018899:CpG Islands / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000097:blood / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008081:Liposomes / Q000008:administration & dosage / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D008081:Liposomes; D009841:Oligonucleotides; D018664:Interleukin-12; D007371:Interferon-gamma; D010047:Ovalbumin