title: Hydroxypropyl-β-cyclodextrin spikes local inflammation that induces Th2 cell and T follicular helper cell responses to the coadministered antigen.
abstract: Cyclodextrins are commonly used as a safe excipient to enhance the solubility and bioavailability of hydrophobic pharmaceutical agents. Their efficacies and mechanisms as drug-delivery systems have been investigated for decades, but their immunological properties have not been examined. In this study, we reprofiled hydroxypropyl-β-cyclodextrin (HP-β-CD) as a vaccine adjuvant and found that it acts as a potent and unique adjuvant. HP-β-CD triggered the innate immune response at the injection site, was trapped by MARCO(+) macrophages, increased Ag uptake by dendritic cells, and facilitated the generation of T follicular helper cells in the draining lymph nodes. It significantly enhanced Ag-specific Th2 and IgG Ab responses as potently as did the conventional adjuvant, aluminum salt (alum), whereas its ability to induce Ag-specific IgE was less than that of alum. At the injection site, HP-β-CD induced the temporary release of host dsDNA, a damage-associated molecular pattern. DNase-treated mice, MyD88-deficient mice, and TBK1-deficient mice showed significantly reduced Ab responses after immunization with this adjuvant. Finally, we demonstrated that HP-β-CD-adjuvanted influenza hemagglutinin split vaccine protected against a lethal challenge with a clinically isolated pandemic H1N1 influenza virus, and the adjuvant effect of HP-β-CD was demonstrated in cynomolgus macaques. Our results suggest that HP-β-CD acts as a potent MyD88- and TBK1-dependent T follicular helper cell adjuvant and is readily applicable to various vaccines.
authors: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation, Osaka 567-0085, Japan; Laboratory of Vaccine Science, Immunology Frontier Research Center, World Premier Institute, Osaka University, Osaka 565-0871, Japan; Infectious Diseases, Medicinal Research Laboratories, Shionogi & Co., Ltd., Osaka 561-0825, Japan;
authors: Motoyasu
authors: M
authors: Onishi
authors: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation, Osaka 567-0085, Japan;
authors: Koji
authors: K
authors: Ozasa
authors: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation, Osaka 567-0085, Japan; Laboratory of Vaccine Science, Immunology Frontier Research Center, World Premier Institute, Osaka University, Osaka 565-0871, Japan;
authors: Kouji
authors: K
authors: Kobiyama
authors: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation, Osaka 567-0085, Japan; Laboratory of Vaccine Science, Immunology Frontier Research Center, World Premier Institute, Osaka University, Osaka 565-0871, Japan;
authors: Keiichi
authors: K
authors: Ohata
authors: Infectious Diseases, Medicinal Research Laboratories, Shionogi & Co., Ltd., Osaka 561-0825, Japan;
authors: Mitsutaka
authors: M
authors: Kitano
authors: Infectious Diseases, Medicinal Research Laboratories, Shionogi & Co., Ltd., Osaka 561-0825, Japan;
authors: Keiichi
authors: K
authors: Taniguchi
authors: Infectious Diseases, Medicinal Research Laboratories, Shionogi & Co., Ltd., Osaka 561-0825, Japan;
authors: Tomoyuki
authors: T
authors: Homma
authors: Infectious Diseases, Medicinal Research Laboratories, Shionogi & Co., Ltd., Osaka 561-0825, Japan;
authors: Masanori
authors: M
authors: Kobayashi
authors: Infectious Diseases, Medicinal Research Laboratories, Shionogi & Co., Ltd., Osaka 561-0825, Japan;
authors: Akihiko
authors: A
authors: Sato
authors: Corporation for the Production and Research of Laboratory Primates, Tsukuba, Ibaraki 305-0843, Japan;
authors: Yuko
authors: Y
authors: Katakai
authors: Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Tsukuba, Ibaraki 305-0843, Japan;
authors: Yasuhiro
authors: Y
authors: Yasutomi
authors: System Immunology Laboratory, Immunology Frontier Research Center, World Premier Institute, Osaka University, Osaka 565-0871, Japan;
authors: Edward
authors: E
authors: Wijaya
authors: Toxicogenomics Project, National Institute of Biomedical Innovation, Osaka 567-0085, Japan;
authors: Yoshinobu
authors: Y
authors: Igarashi
authors: Toxicogenomics Project, National Institute of Biomedical Innovation, Osaka 567-0085, Japan;
authors: Noriyuki
authors: N
authors: Nakatsu
authors: Laboratory of Lymphocyte Differentiation, Immunology Frontier Research Center, World Premier Institute, Osaka University, Osaka 565-0871, Japan;
authors: Wataru
authors: W
authors: Ise
authors: Laboratory of Lymphocyte Differentiation, Immunology Frontier Research Center, World Premier Institute, Osaka University, Osaka 565-0871, Japan;
authors: Takeshi
authors: T
authors: Inoue
authors: Toxicogenomics Project, National Institute of Biomedical Innovation, Osaka 567-0085, Japan;
authors: Hiroshi
authors: H
authors: Yamada
authors: System Immunology Laboratory, Immunology Frontier Research Center, World Premier Institute, Osaka University, Osaka 565-0871, Japan;
authors: Alexis
authors: A
authors: Vandenbon
authors: System Immunology Laboratory, Immunology Frontier Research Center, World Premier Institute, Osaka University, Osaka 565-0871, Japan;
authors: Daron M
authors: DM
authors: Standley
authors: Laboratory of Lymphocyte Differentiation, Immunology Frontier Research Center, World Premier Institute, Osaka University, Osaka 565-0871, Japan; Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; and.
authors: Tomohiro
authors: T
authors: Kurosaki
authors: Laboratory of Malaria Immunology, Immunology Frontier Research Center, World Premier Institute, Osaka University, Osaka 565-0871, Japan.
authors: Cevayir
authors: C
authors: Coban
authors: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation, Osaka 567-0085, Japan; Laboratory of Vaccine Science, Immunology Frontier Research Center, World Premier Institute, Osaka University, Osaka 565-0871, Japan;
authors: Taiki
authors: T
authors: Aoshi
authors: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation, Osaka 567-0085, Japan; Laboratory of Vaccine Science, Immunology Frontier Research Center, World Premier Institute, Osaka University, Osaka 565-0871, Japan;
authors: Etsushi
authors: E
authors: Kuroda
authors: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation, Osaka 567-0085, Japan; Laboratory of Vaccine Science, Immunology Frontier Research Center, World Premier Institute, Osaka University, Osaka 565-0871, Japan; kenishii@nibio.go.jp kenishii@biken.osaka-u.ac.jp.
authors: Ken J
authors: http://orcid.org/0000-0002-6728-3872
authors: KJ
authors: Ishii
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology / Q000502:physiology; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D036641:Microscopy, Fluorescence, Multiphoton; D020411:Oligonucleotide Array Sequence Analysis; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects / Q000276:immunology; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D007252:Influenza Vaccines; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin