title: Nonagonistic Dectin-1 ligand transforms CpG into a multitask nanoparticulate TLR9 agonist.
abstract: CpG DNA, a ligand for Toll-like receptor 9 (TLR9), has been one of the most promising immunotherapeutic agents. Although there are several types of potent humanized CpG oligodeoxynucleotide (ODN), developing "all-in-one" CpG ODNs activating both B cells and plasmacytoid dendritic cells forming a stable nanoparticle without aggregation has not been successful. In this study, we generated a novel nanoparticulate K CpG ODN (K3) wrapped by the nonagonistic Dectin-1 ligand schizophyllan (SPG), K3-SPG. In sharp contrast to K3 alone, K3-SPG stimulates human peripheral blood mononuclear cells to produce a large amount of both type I and type II IFN, targeting the same endosome where IFN-inducing D CpG ODN resides without losing its K-type activity. K3-SPG thus became a potent adjuvant for induction of both humoral and cellular immune responses, particularly CTL induction, to coadministered protein antigens without conjugation. Such potent adjuvant activity of K3-SPG is attributed to its nature of being a nanoparticle rather than targeting Dectin-1 by SPG, accumulating and activating antigen-bearing macrophages and dendritic cells in the draining lymph node. K3-SPG acting as an influenza vaccine adjuvant was demonstrated in vivo in both murine and nonhuman primate models. Taken together, K3-SPG may be useful for immunotherapeutic applications that require type I and type II IFN as well as CTL induction.
authors: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation, Osaka 567-0085, Japan.
authors: Kouji
authors: K
authors: Kobiyama
authors: Taiki
authors: T
authors: Aoshi
authors: Hirotaka
authors: H
authors: Narita
authors: Etsushi
authors: E
authors: Kuroda
authors: Masayuki
authors: M
authors: Hayashi
authors: Kohhei
authors: K
authors: Tetsutani
authors: Shohei
authors: S
authors: Koyama
authors: Shinichi
authors: S
authors: Mochizuki
authors: Kazuo
authors: K
authors: Sakurai
authors: Yuko
authors: Y
authors: Katakai
authors: Yasuhiro
authors: Y
authors: Yasutomi
authors: Shinobu
authors: S
authors: Saijo
authors: Yoichiro
authors: Y
authors: Iwakura
authors: Shizuo
authors: S
authors: Akira
authors: Cevayir
authors: C
authors: Coban
authors: Ken J
authors: KJ
authors: Ishii
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D018899:CpG Islands / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007369:Interferon Inducers / Q000494:pharmacology; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D053758:Nanoparticles / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D012566:Sizofiran / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D000099181:Dectin-1
chemical_list: D000276:Adjuvants, Immunologic; D007369:Interferon Inducers; D037181:Lectins, C-Type; D009838:Oligodeoxyribonucleotides; D012566:Sizofiran; D051217:Toll-Like Receptor 9; C546929:CLEC7A protein, human; D000099181:Dectin-1; C495371:TLR9 protein, human
keywords: MARCO; Siglec-1; innate immunity; two-photon microscopy; β-glucan