A Palindromic CpG-Containing Phosphodiester Oligodeoxynucleotide as a Mucosal Adjuvant Stimulates Plasmacytoid Dendritic Cell-Mediated TH1 Immunity

Abstract

BackgroundCpG 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 TH1 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.MethodsTH1 and TH2 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.ResultsG9.1 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 TH1, but not TH2, -type Abs depended completely on pDCs, the first in vivo demonstration by CpG ODNs.ConclusionsG9.1 is a promising mucosal adjuvant for induction of pDC-mediated TH1 immunity.

Inhibitory/Suppressive Oligodeoxynucleotide Nanocapsules as Simple Oral Delivery Devices for Preventing Atopic Dermatitis in Mice

“…It has been reported that phosphodiester (PO)-bonded CpG-ODN, which does not require PS, exhibits strong immune activity due to the characteristics of its structure. 47 We therefore anticipate the development of PS-independent ODNs in the near future. The ability to compound capsules containing various ODN sequences opens the possibility of using ODNcaps in in vivo studies employing a variety of mouse disease models.…”

Induction of antibody responses in mice immunized intranasally with Type I interferon as adjuvant and synergistic effect of chitosan

“…G9.1 is a CpG‐ODN (oligodeoxynucleotides containing non‐methylated CpG motif) 48 . Nasally administered G9.1 and Dtd induced Dtd‐specific mucosal IgA and serum IgG responses with antitoxin activity in mice 48 . G9.1 also exhibited strong IFN‐α‐inducing activity 48 .…”

CpG oligodeoxynucleotides as mucosal adjuvants

“…As a result, GACGATCGTC with a 9-mer oligoG on the 5 0 side and a single G on the 3 0 side (GGGGGGGGG-GAC-GATCGTC-G) was found to be a potent inducer of IFN-a in human PBMCs. 26 We call this CpG ODN "G9.1. "…”

“…G9.1, even in its naked form, exhibits adjuvanticity during nasal vaccination in mice. 26 In those mice, an excess production of proinflammatory and immunosuppressive cytokines is not induced. Further, repetitive administration does not cause problems in the major organs, and IgE antibody (Ab) production is not induced but may be suppressed in a mouse model of ovalbumin-induced allergy.…”

“…26 In mice, a nasal administration of G9.1 with diphtheria toxoid (DT) induces the production of secretory IgA (sIgA) Ab specific to DT. This Ab was detected in the lungs, nasal lavage fluids, and feces, in conjunction with the increase of BAFF (B cell activating factor belonging to the tumor necrosis factor family) production by splenocytes.…”