A palindromic CpG-containing phosphodiester oligodeoxynucleotide as a mucosal adjuvant stimulates plasmacytoid dendritic cell-mediated T(H)1 immunity

Jun-ichi Maeyama; Hisakazu Takatsuka; Fumiko Suzuki; Ayumi Kubota; Satomi Horiguchi; Takako Komiya; Ichiroh Shimada; Eri Murata; Youko Osawa; Harukazu Kitagawa; Takasumi Matsuki; Masanori Isaka; Saburo Yamamoto; Sumiko Iho

doi:10.1371/journal.pone.0088846

A palindromic CpG-containing phosphodiester oligodeoxynucleotide as a mucosal adjuvant stimulates plasmacytoid dendritic cell-mediated T(H)1 immunity

PLoS One. 2014 Feb 24;9(2):e88846. doi: 10.1371/journal.pone.0088846. eCollection 2014.

Authors

Affiliations

¹ Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama-shi, Tokyo, Japan.
² Division of Legal Medicine, Niigata University Graduate School of Medicine and Dental Sciences, Niigata-shi, Niigata, Japan.
³ Department of Ophthalmology, Faculty of Medical Science, University of Fukui, Yoshida-gun, Fukui, Japan.
⁴ Laboratory of Host Defense, Faculty of Medical Sciences, University of Fukui, Yoshida-gun, Fukui, Japan.
⁵ Department of Anatomy and Neuroscience, Faculty of Medical Sciences, University of Fukui, Yoshida-gun, Fukui, Japan.
⁶ Department of Bacterial Pathogenesis and Infection, National Institute of Infectious Diseases, Musashimurayama-shi, Tokyo, Japan.
⁷ Forensic Medicine and Human Genetics, Faculty of Medical Sciences, University of Fukui, Yoshida-gun, Fukui, Japan ; Research and Education Program for Life Science and Translational Research Program, University of Fukui, Fukui-shi, Fukui, Japan.
⁸ Anesthesiology and Reanimatology, Faculty of Medical Sciences, University of Fukui, Yoshida-gun, Fukui, Japan.
⁹ Otorhinolaryngology-Head and Neck Surgery, Faculty of Medical Sciences, University of Fukui, Yoshida-gun, Fukui, Japan.
¹⁰ Chemical Substances Management, Administration Control Office, Emori & Co., Ltd., Fukui-shi, Fukui, Japan.
¹¹ Department of Microbiology, Nagoya City University Medical School, Nagoya-shi, Aichi, Japan.
¹² Central Laboratory, Japan BCG Laboratory, Kiyose-shi, Tokyo, Japan.
¹³ Laboratory of Host Defense, Faculty of Medical Sciences, University of Fukui, Yoshida-gun, Fukui, Japan ; Research and Education Program for Life Science and Translational Research Program, University of Fukui, Fukui-shi, Fukui, Japan.

Abstract

Background: CpG oligodeoxynucleotides (ODNs), resembling bacterial DNA, are currently tested in clinical trials as vaccine adjuvants. They have the nuclease-resistant phosphorothioate bond; the immune responses elicited differ according to the CpG ODN sequence and vaccination method. To develop a CpG ODN that can induce plasmacytoid dendritic cell (pDC)-mediated T(H)1 immunity through the mucosa, we constructed phosphodiester G9.1 comprising one palindromic CpG motif with unique polyguanosine-runs that allows degradation similar to naturally occurring bacterial DNA.

Methods: T(H)1 and T(H)2 immunity activation was evaluated by cytokine production pattern and T-bet/GATA-3 ratio in human peripheral blood mononuclear cells and mouse bone marrow cells. Adjuvanticity was evaluated in mice administered G9.1 with diphtheria toxoid (DT) through nasal vaccination.

Results: G9.1 exhibited stronger IFN-α-inducing activity than A-class CpG ODN2216 and increased T-bet/GATA-3 ratio by enhancing T-bet expression. Nasally administered G9.1 plus DT induced DT-specific mucosal IgA and serum IgG, but not IgE, responses with antitoxin activity in C57BL/6 and BALB/c mice, possibly due to IFN/BAFF production. Induction of T(H)1, but not T(H)2-type Abs depended completely on pDCs, the first in vivo demonstration by CpG ODNs.

Conclusions: G9.1 is a promising mucosal adjuvant for induction of pDC-mediated T(H)1 immunity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adjuvants, Immunologic / pharmacology*
Adjuvants, Pharmaceutic / pharmacology*
Animals
Bone Marrow Cells / drug effects
Bone Marrow Cells / immunology
DNA, Bacterial / immunology
Dendritic Cells / drug effects
Dendritic Cells / immunology*
Diphtheria Toxoid / immunology
Female
Humans
Interferon-alpha / immunology
Leukocytes, Mononuclear / drug effects
Leukocytes, Mononuclear / immunology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mucous Membrane / drug effects
Mucous Membrane / immunology*
Oligodeoxyribonucleotides / immunology*
Th1 Cells / drug effects
Th1 Cells / immunology*

Substances

Adjuvants, Immunologic
Adjuvants, Pharmaceutic
CPG-oligonucleotide
DNA, Bacterial
Diphtheria Toxoid
Interferon-alpha
Oligodeoxyribonucleotides

Grants and funding

This work was supported in part by a Grant-in-Aid for Scientific Research [22591105 to SI, JIM, 19591962 to SI] from the Japan Society for the Promotion of Science; A-STEP [AS231Z03382G to SI, AS2314067G and AS2121188G to SY, SI, 09-08 and 06-057 to SI] from the Japan Science and Technology Agency; a grant for Research on Publicly Essential Drugs and Medical Devices [KHC1021 to JIM, MI, SY, SI, SH54411 to SY, SI] from The Japan Health Sciences Foundation; and Smoking Research Foundation [to SI, JIM]; and Fukui University [SI]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.