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: Motoyasu Onishi, Koji Ozasa, Kouji Kobiyama, Keiichi Ohata, Mitsutaka Kitano, Keiichi Taniguchi, Tomoyuki Homma, Masanori Kobayashi, Akihiko Sato, Yuko Katakai, Yasuhiro Yasutomi, Edward Wijaya, Yoshinobu Igarashi, Noriyuki Nakatsu, Wataru Ise, Takeshi Inoue, Hiroshi Yamada, Alexis Vandenbon, Daron M Standley, Tomohiro Kurosaki, Cevayir Coban, Taiki Aoshi, Etsushi Kuroda, Ken J Ishii
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 194 Issue 6 Pg. 2673-82 (Mar 15 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 25681338 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• Adjuvants, Immunologic
• Antigens
• Influenza Vaccines
• beta-Cyclodextrins
• 2-Hydroxypropyl-beta-cyclodextrin

Topics

• 2-Hydroxypropyl-beta-cyclodextrin
• Adjuvants, Immunologic (administration & dosage)
• Animals
• Antibody Formation (drug effects, genetics, immunology)
• Antigens (administration & dosage, immunology)
• Host-Pathogen Interactions (drug effects, immunology)
• Inflammation (genetics, immunology)
• Influenza A Virus, H1N1 Subtype (immunology, physiology)
• Influenza Vaccines (administration & dosage, immunology)
• Lymph Nodes (drug effects, immunology, metabolism)
• Macaca fascicularis
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Microscopy, Fluorescence, Multiphoton
• Oligonucleotide Array Sequence Analysis
• Orthomyxoviridae Infections (immunology, prevention & control, virology)
• Spleen (drug effects, immunology, metabolism)
• T-Lymphocytes, Helper-Inducer (drug effects, immunology, metabolism)
• Th2 Cells (drug effects, immunology, metabolism)
• Transcriptome (drug effects, immunology)
• beta-Cyclodextrins (administration & dosage, immunology)