Double-stranded Phosphodiester Cytosine-guanine Oligodeoxynucleotide Complexed with Calcium Phosphate As a Potent Vaccine Adjuvant for Activating Cellular and Th1-type Humoral Immunities

Overview

Journal Int J Nanomedicine

Publisher Dove Medical Press

Specialty Biotechnology

Date 2018 Jan 11

PMID 29317815

Citations 4

Authors

Nobutaka Hanagata

Xianglan Li

Min-Hua Chen

Jie Li

Shinya Hattori

Affiliations

Soon will be listed here.

Abstract

Conventional class B cytosine-guanine (CpG) (CpG-B) oligodeoxynucleotide (ODNs) consisting of a single-stranded (ss) phosphorothioate (PT) backbone (ss CpG-B-PT) is converted from a proinflammatory cytokine inducer to a type-I interferon (IFN) inducer when complexed with cationic materials. In this study, we designed ss CpG-B and double-stranded (ds) CpG-B ODNs with a phosphodiester (PD) backbone (ss CpG-B-PD and ds CpG-B-PD, respectively) that became type-I IFN inducers upon complexation with Lipofectamine 2000 (Lipo), a cationic liposome. The ds CpG-B-PD complex induced higher IFN-β expression in mouse macrophage-like RAW264 cells than ss CpG-B-PD and ss CpG-B-PT complexes. The fold induction of IFN-β increased with the number of CpG motifs in ds CpG-B-PD, and a complex of ds CpG-B-PD consisting of 72 base pairs with nine CpG motifs (ds CpG-B72-PD) and Lipo showed the highest capacity to induce IFN-β. The materials and method used for complexation influenced the degree of IFN-β induction: ds CpG-B72-PD entrapped by calcium phosphate (CaP) (ds CpG-B72-PD/CaP) showed a higher induction capacity than ds CpG-B72-PD adsorbed onto the CaP surface. Entrapment of ds CpG-B72-PD by CaP also enhanced the induction of the proinflammatory cytokine interleukin-12. Vaccinating mice with ds CpG-B72-PD/CaP in conjunction with ovalbumin (OVA) increased the ratios of OVA-specific CD8 T cells to total CD8 T cells in peripheral blood and of OVA-specific IgG2a associated with helper T (Th)1 cells to OVA-specific IgG1 associated with Th2 cells. These results indicate that ds CpG-B72-PD/CaP is an effective vaccine adjuvant that can activate both cellular and Th1-type humoral immune responses.

Citing Articles

Non-Modified CpG Oligodeoxynucleotide Forming Guanine-Quadruplex Structure Complexes with ε-Poly--Lysine Induce Antibody Production as Vaccine Adjuvants.

Zhao D, Tu A, Shobo M, Le N, Yoshikawa C, Sugai K Biomolecules. 2022; 12(12).

PMID: 36551297 PMC: 9775190. DOI: 10.3390/biom12121868.

Chitosan/Calcium-Coated Ginsenoside Rb1 Phosphate Flower-like Microparticles as an Adjuvant to Enhance Immune Responses.

Song X, Li H, Zhang L, Zhang X, Zhao L, Zhang G Vet Sci. 2022; 9(7).

PMID: 35878372 PMC: 9316975. DOI: 10.3390/vetsci9070355.

Enhancement of the Immunostimulatory Effect of Phosphodiester CpG Oligodeoxynucleotides by an Antiparallel Guanine-Quadruplex Structural Scaffold.

Safitri F, Tu A, Hoshi K, Shobo M, Zhao D, Witarto A Biomolecules. 2021; 11(11).

PMID: 34827615 PMC: 8615816. DOI: 10.3390/biom11111617.

Design and application of nanoparticles as vaccine adjuvants against human corona virus infection.

Mao L, Chen Z, Wang Y, Chen C J Inorg Biochem. 2021; 219:111454.

PMID: 33878530 PMC: 8007196. DOI: 10.1016/j.jinorgbio.2021.111454.

References

Hartmann G, Weiner G, Krieg A . CpG DNA: a potent signal for growth, activation, and maturation of human dendritic cells. Proc Natl Acad Sci U S A. 1999; 96(16):9305-10. PMC: 17777. DOI: 10.1073/pnas.96.16.9305. View

Hartmann G, Krieg A . Mechanism and function of a newly identified CpG DNA motif in human primary B cells. J Immunol. 2000; 164(2):944-53. DOI: 10.4049/jimmunol.164.2.944. View

Hartmann G, Weeratna R, Ballas Z, Payette P, Blackwell S, Suparto I . Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J Immunol. 2000; 164(3):1617-24. DOI: 10.4049/jimmunol.164.3.1617. View

Levin A . A review of the issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides. Biochim Biophys Acta. 2000; 1489(1):69-84. DOI: 10.1016/s0167-4781(99)00140-2. View

Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H . A Toll-like receptor recognizes bacterial DNA. Nature. 2000; 408(6813):740-5. DOI: 10.1038/35047123. View

Verthelyi D, Ishii K, Gursel M, Takeshita F, Klinman D . Human peripheral blood cells differentially recognize and respond to two distinct CPG motifs. J Immunol. 2001; 166(4):2372-7. DOI: 10.4049/jimmunol.166.4.2372. View

Bauer M, Redecke V, Ellwart J, Scherer B, Kremer J, Wagner H . Bacterial CpG-DNA triggers activation and maturation of human CD11c-, CD123+ dendritic cells. J Immunol. 2001; 166(8):5000-7. DOI: 10.4049/jimmunol.166.8.5000. View

Krug A, Rothenfusser S, Hornung V, Jahrsdorfer B, Blackwell S, Ballas Z . Identification of CpG oligonucleotide sequences with high induction of IFN-alpha/beta in plasmacytoid dendritic cells. Eur J Immunol. 2001; 31(7):2154-63. DOI: 10.1002/1521-4141(200107)31:7<2154::aid-immu2154>3.0.co;2-u. View

Kadowaki N, Ho S, Antonenko S, Malefyt R, Kastelein R, Bazan F . Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med. 2001; 194(6):863-9. PMC: 2195968. DOI: 10.1084/jem.194.6.863. View

10.

Takeshita F, Leifer C, Gursel I, Ishii K, Takeshita S, Gursel M . Cutting edge: Role of Toll-like receptor 9 in CpG DNA-induced activation of human cells. J Immunol. 2001; 167(7):3555-8. DOI: 10.4049/jimmunol.167.7.3555. View

11.

Krug A, Towarowski A, Britsch S, Rothenfusser S, Hornung V, Bals R . Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. Eur J Immunol. 2001; 31(10):3026-37. DOI: 10.1002/1521-4141(2001010)31:10<3026::aid-immu3026>3.0.co;2-h. View

12.

Krieg A . CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol. 2002; 20:709-60. DOI: 10.1146/annurev.immunol.20.100301.064842. View

13.

Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T . Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol. 2002; 168(9):4531-7. DOI: 10.4049/jimmunol.168.9.4531. View

14.

Cho H, Hayashi T, Datta S, Takabayashi K, Van Uden J, Horner A . IFN-alpha beta promote priming of antigen-specific CD8+ and CD4+ T lymphocytes by immunostimulatory DNA-based vaccines. J Immunol. 2002; 168(10):4907-13. DOI: 10.4049/jimmunol.168.10.4907. View

15.

Gursel M, Verthelyi D, Gursel I, Ishii K, Klinman D . Differential and competitive activation of human immune cells by distinct classes of CpG oligodeoxynucleotide. J Leukoc Biol. 2002; 71(5):813-20. View

16.

Marshall J, Fearon K, Abbate C, Subramanian S, Yee P, Gregorio J . Identification of a novel CpG DNA class and motif that optimally stimulate B cell and plasmacytoid dendritic cell functions. J Leukoc Biol. 2003; 73(6):781-92. DOI: 10.1189/jlb.1202630. View

17.

Hartmann G, Battiany J, Poeck H, Wagner M, Kerkmann M, Lubenow N . Rational design of new CpG oligonucleotides that combine B cell activation with high IFN-alpha induction in plasmacytoid dendritic cells. Eur J Immunol. 2003; 33(6):1633-41. DOI: 10.1002/eji.200323813. View

18.

Heikenwalder M, Polymenidou M, Junt T, Sigurdson C, Wagner H, Akira S . Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nat Med. 2004; 10(2):187-92. DOI: 10.1038/nm987. View

19.

Ahonen C, Doxsee C, McGurran S, Riter T, Wade W, Barth R . Combined TLR and CD40 triggering induces potent CD8+ T cell expansion with variable dependence on type I IFN. J Exp Med. 2004; 199(6):775-84. PMC: 2212721. DOI: 10.1084/jem.20031591. View

20.

Bjersing J, Eriksson K, Tarkowski A, Collins L . The arthritogenic and immunostimulatory properties of phosphorothioate oligodeoxynucleotides rely on synergy between the activities of the nuclease-resistant backbone and CpG motifs. Inflammation. 2004; 28(1):39-51. DOI: 10.1023/b:ifla.0000014710.44475.94. View