CpG oligodeoxynucleotides as DNA adjuvants in vertebrates and their applications in immunotherapy

Chaung, Hso-Chi

doi:10.1016/j.intimp.2006.06.001

Cited by 30 publications

(33 citation statements)

References 64 publications

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“…Because of their potent immunostimulatory activities, CpGODNs are studied for their applications as antimicrobial agents and vaccine adjuvants in fish, in addition to their therapeutic applications in humans and domestic animals (4)(5)(6)(7)(18)(19)(20). We further investigated the molecular basis for the activity of CpG- -HC4040), despite the fact that these two CpGODNs showed better activity to zebTLR9.…”

Section: Discussionmentioning

confidence: 99%

“…Synthetic phosphorothioate-modified CpG-oligodeoxynucleotides (CpG-ODNs) mimic the functions of CpG-DNA and have been investigated as immune modulators for their adjuvant and antimicrobial activities in different species (4)(5)(6)(7). In general, a CpG-ODN contains one or more copies of CpG-deoxynucleotides containing hexamer motifs (CpG motifs).…”

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confidence: 99%

“…Similar to their actions in mammalian species, in chickens CpG-ODNs activate marked immune responses and provide protection from microbial infections (4,5,21). Nevertheless, analysis of the chicken and zebra finch genomes found that the TLR9 gene is not present in avian genomes.…”

mentioning

confidence: 99%

“…In addition, CpGODNs have been shown to protect fish against bacterial and viral infections. The molecular bases for CpG-ODN activation in fish remain unclear, however (5,6). The genomic DNA of zebrafish has been sequenced and annotated, leading to the discovery of at least 14 different types of TLR in fish, including TLR9 and TLR21 (25,26); however, whether these two TLRs are functional has not been investigated previously.…”

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confidence: 99%

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Toll-like receptor 9 and 21 have different ligand recognition profiles and cooperatively mediate activity of CpG-oligodeoxynucleotides in zebrafish

Yeh

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

113

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CpG-oligodeoxynucleotides (CpG-ODNs) are potent immune stimuli currently under investigation as antimicrobial agents for different species. Toll-like receptor (TLR) 9 and TLR21 are the cellular receptors of CpG-ODN in mammals and chickens, respectively. The avian genomes lack TLR9, whereas mammalian genomes lack TLR21. Although fish contain both of these genes, the biological functions of fish TLR9 and TLR21 have not been investigated previously. In this study, we comparatively investigated zebrafish TLR9 (zebTLR9) and TLR21 (zebTLR21). The two TLRs have similar expression profiles in zebrafish. They are expressed during early development stages and are preferentially expressed in innate immune function-related organs in adult fish. Results from cell-based activation assays indicate that these two zebrafish TLRs are functional, responding to CpG-ODN but not to other TLR ligands. zebTLR9 broadly recognized CpG-ODN with different CpG motifs, but CpG-ODN with GACGTT or AACGTT had better activity to this TLR. In contrast, zebTLR21 responded preferentially to CpG-ODN with GTCGTT motifs. The distinctive ligand recognition profiles of these two TLRs were determined by their ectodomains. Activation of these two TLRs by CpG-ODN occurred inside the cells and was modulated by UNC93B1. The biological functions of these two TLRs were further investigated. The CpGODNs that activate both zebTLR9 and zebTLR21 were more potent than others that activate only zebTLR9 in the activation of cytokine productions and were more bactericidal in zebrafish. These results suggest that zebTLR9 and zebTLR21 cooperatively mediate the antimicrobial activities of CpG-ODN. Overall, this study provides a molecular basis for the activities of CpG-ODN in fish.pattern recognition receptor | innate immunity | adjuvant B acterial and viral CpG-deoxynucleotides containing DNA (CpG-DNA) represent a type of pathogen-associated molecular pattern (PAMP) that activates immune cells and triggers host responses to microbial infections (1-3). Synthetic phosphorothioate-modified CpG-oligodeoxynucleotides (CpG-ODNs) mimic the functions of CpG-DNA and have been investigated as immune modulators for their adjuvant and antimicrobial activities in different species (4-7). In general, a CpG-ODN contains one or more copies of CpG-deoxynucleotides containing hexamer motifs (CpG motifs). A CpG-ODN's immunostimulatory activities are dependent on its length, the number of CpG motifs, and the position, spacing, and surrounding bases of these CpG motifs.A CpG-ODN can have varying immunostimulatory activity in different species. This species-specific property is determined by the nucleotide context of the CpG motifs within the CpG-ODN. For example, CpG-ODNs containing a purine-purine-CGpyrimidine-pyrimidine motif, such as a GACGTT motif, are more potent in activating murine cells compared with those containing a GTCGTT motif. In contrast, the GTCGTT motif containing CpG-ODN generates stronger immune responses in humans and various domestic animals (8, 9).Toll-like receptors (...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Toll-like receptor 9 and 21 have different ligand recognition profiles and cooperatively mediate activity of CpG-oligodeoxynucleotides in zebrafish

Yeh

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

113

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“…Thus, taken together, the data indicate that Btk negatively regulates IL-12 secretion via the autocrine induction of IL-10 production. (27)(28)(29). We had shown that CpG ODN treatment of Btk Ϫ/Ϫ B cells in vitro led to their higher secretion of IL-12 (Fig.…”

Section: Enhanced Il-12 and Reduced Il-10 Production In Tlr9-activatementioning

confidence: 99%

Bruton's Tyrosine Kinase Separately Regulates NFκB p65RelA Activation and Cytokine Interleukin (IL)-10/IL-12 Production in TLR9-stimulated B Cells

Lee

Wong

et al. 2008

Journal of Biological Chemistry

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Bruton's tyrosine kinase (Btk), 3 a member of the Tec family of protein-tyrosine kinases, has been shown to play important roles in B cell development, activation, and survival. Mutations in Btk are known to lead to X-linked agammaglobulinemia in humans and X-linked immunodeficiency in mice (1). These diseases are characterized by a block in B-lymphopoiesis and CD5ϩ B-1 cell generation, defects in B cell receptor (BCR) signaling, and impairment in humoral immune responses to certain types of T cell-independent antigens (2). Structurally, Btk contains multiple protein-protein interaction domains. It has a pleckstrin homology domain for membrane localization following its activation, as well as Src homology 2, Src homology 3, and proline-rich domains for binding other signaling molecules. In addition, it possesses multiple tyrosine phosphorylation sites. Hence, Btk is postulated to play a key role in signal transduction processes.

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Three types of humanCpG motifs differentially modulate and augment immunogenicity of nonviral and viral repliconDNA vaccines as built‐in adjuvants

Li²,

Ma³

et al. 2012

Eur J Immunol

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Naked DNA vaccines given by intramuscular injection are efficient in mouse models, but they require improvement for human use. As the immunogenicity of DNA vaccines depends, to a large extent, on the presence of CpG motifs as built-in adjuvants, we addressed this issue by inserting three types of human CpG motifs (A-type, B-type, and C-type) into the backbone of nonviral DNA and viral DNA replicon vectors with distinct immunostimulatory activities on human PBMCs. The adjuvant effects of CpG modifications in DNA vaccines expressing three types of antigens (β-Gal, AHc, or PA4) were then characterized in mice and found to significantly enhance antigen-specific humoral and cell-mediated immune responses. The three types of CpG motifs also differentially affected and modulated immune responses and protective potency against botulinum neurotoxin serotype A and Bacillus anthracis A16R challenge. Taken together, these results demonstrate that insertion of human CpG motifs can differentially modulate the immunogenicity of nonviral DNA vaccines as well as viral DNA replicon vaccines. Our study provides not only a better understanding of the in vivo activities of CpG motif adjuvants but implications for the rational design of such motifs as built-in adjuvants for DNA vectors targeting specific antigens.Keywords: adjuvant · CpG · DNA vaccine · Immunogenicity · Replicon vector Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPrevious studies have proved that DNA immunization can elicit antigen-specific humoral and cell-mediated immune responses and provide effective protective immunity against a variety of pathogens in various animal models [1,2]. However, the potency of naked DNA vaccines produced in nonhuman primates and humans is usually lower than that in the small animals used in these models [1]. Additionally, early DNA vaccines did not Correspondence: Dr. Zhi-Wei Sun e-mail: szwyhhh@yahoo.com.cn afford sufficient immunogenicity in human clinical studies. Therefore, the efficacy of DNA vaccines must be modulated and augmented to enable this technology to be successfully applied to human clinical trials. A number of strategies have been investigated to increase the immunogenicity of DNA vaccines over the last few years, including adjuvants, alterations in the codon bias, cytokines, chemokines, CpG, electroporation, liposomes, microparticles, and heterologous prime/boost immunization [2][3][4][5][6]. * These authors contributed equally to this work. The levels of IL-6 and IFN-γ in the culture supernatants of human PBMCs cultured with the indicated (C) CpG-modified nonviral DNA plasmids or (D) viral DNA replicon plasmids were determined by ELISA. Data are represented as mean + SD of n = 6 samples and are from one experiment representative of two experiments performed. Statistical significance over the control unmodified plasmids and media was determined by ANOVA test ( * P < 0.05; ** P < 0.01; *** P < 0.001).Previous studies have shown that the ef...

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CpG oligodeoxynucleotides as DNA adjuvants in vertebrates and their applications in immunotherapy

Cited by 30 publications

References 64 publications

Toll-like receptor 9 and 21 have different ligand recognition profiles and cooperatively mediate activity of CpG-oligodeoxynucleotides in zebrafish

Toll-like receptor 9 and 21 have different ligand recognition profiles and cooperatively mediate activity of CpG-oligodeoxynucleotides in zebrafish

Bruton's Tyrosine Kinase Separately Regulates NFκB p65RelA Activation and Cytokine Interleukin (IL)-10/IL-12 Production in TLR9-stimulated B Cells

Three types of humanCpG motifs differentially modulate and augment immunogenicity of nonviral and viral repliconDNA vaccines as built‐in adjuvants

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