Therapeutic potential of toll-like receptor 9 activation

Nature Reviews Drug Discovery

Volumn 5, Issue 6, 2006, Pages 471-484

  Krieg, Arthur M ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADJUVANT; AGENTS INTERACTING WITH TRANSMITTER, HORMONE OR DRUG RECEPTORS; ALPHA INTERFERON; ALUMINUM POTASSIUM SULFATE; ANTHRAX VACCINE; BACTERIAL DNA; CARBOPLATIN; CPG 10101; CPG 7909; CPG OLIGODEOXYNUCLEOTIDE; CYCLOPHOSPHAMIDE; FLUOROURACIL; GEMCITABINE; HYB 2055; INFLUENZA VACCINE; MELANOMA ANTIGEN; MELANOMA ANTIGEN 3; ODN 1018ISS; ODN 2216; ODN 2395; PEGINTERFERON; PF 3512676; POLYNUCLEOTIDE; RECOMBINANT HEPATITIS B VACCINE; RIBAVIRIN; TOLL LIKE RECEPTOR 9; TOLL LIKE RECEPTOR 9 AGONIST; TOPOTECAN; UNCLASSIFIED DRUG; UNINDEXED DRUG; VACCINE; CPG OLIGONUCLEOTIDE; CPG-OLIGONUCLEOTIDE; OLIGODEOXYRIBONUCLEOTIDE;

ALLERGY; ASTHMA; B LYMPHOCYTE; CANCER THERAPY; CLINICAL TRIAL; DRUG MEGADOSE; DRUG SCREENING; DRUG USE; FEBRILE NEUTROPENIA; FLU LIKE SYNDROME; HUMAN; IMMUNOTHERAPY; INFECTION; INJECTION SITE REACTION; NEUTROPENIA; NONHUMAN; PRIORITY JOURNAL; REVIEW; THROMBOCYTOPENIA; UNSPECIFIED SIDE EFFECT; ANIMAL; COMMUNICABLE DISEASE; CPG ISLAND; DRUG POTENTIATION; HYPERSENSITIVITY; NEOPLASM; STRUCTURE ACTIVITY RELATION;

ANIMALS; ASTHMA; CLINICAL TRIALS; COMMUNICABLE DISEASES; CPG ISLANDS; HUMANS; HYPERSENSITIVITY; NEOPLASMS; OLIGODEOXYRIBONUCLEOTIDES; STRUCTURE-ACTIVITY RELATIONSHIP; TOLL-LIKE RECEPTOR 9; VACCINES;

EID: 33745946911     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd2059     Document Type: Review

References (204)

1. Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nature Immunol. 5, 987-995 (2004).
2. Barton, G. M., Kagan, J. C. & Medzhitov, R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nature Immunol. 7, 49-56 (2006).
3. Ishii, K. J. et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nature Immunol. 7, 40-48 (2006).
4. Okabe, Y., Kawane, K., Akira, S., Taniguchi, T. & Nagata, S. Toll-like receptor-independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation. J. Exp. Med. 202, 1333-1339 (2005).
5. Liu, Y. J. IPC: Professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23, 275-306 (2005).
6. Hayashi, F., Means, T. K. & Luster, A. D. Toll-like receptors stimulate human neutrophil function. Blood 102, 2660-2669 (2003).
7. Li, J. et al. CpG DNA-mediated immune response in pulmonary endothelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. 287, L552-L558 (2004).
8. Platz, J. et al. Microbial DNA induces a host defense reaction of human respiratory epithelial cells. J. Immunol. 173, 1219-1223 (2004).
9. Asselin-Paturel, C. et al. Type I interferon dependence of plasmacytoid dendritic cell activation and migration. J. Exp. Med. 201, 1157-1167 (2005).
10. Krieg, A. M. CpG motifs in bacterial DNA and their immune effects. Annu. Rev. Immunol. 20, 709-760 (2002).
11. Jung, J. et al. Distinct response of human B cell subpopulations in recognition of an innate immune signal, CpG DNA. J. Immunol. 169, 2368-2373 (2002).
12. Bernasconi, N. L., Traggiai, E. & Lanzavecchia, A. Maintenance of serological memory by polyclonal activation of human memory B cells. Science 298, 2199-2202 (2002).
13. Bernasconi, N. L., Onai, N. & Lanzavecchia, A. A role for Toll-like receptors in acquired immunity: Up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells. Blood 101, 4500-4504 (2003).
14. Traggiai, E. et al. An efficient method to make human monoclonal antibodies from memory B cells: Potent neutralization of SARS coronavirus. Nature Med. 10, 871-875 (2004).
15. Poeck, H. et al. Plasmacytoid dendritic cells, antigen and CpG-C license human B cells for plasma cell differentiation and immunoglobulin production in the absence of T cell help. Blood 103, 3058-3064 (2004).
16. Krieg, A. M. et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374, 546-549 (1995).
17. Yi, A. K. et al. CpG motifs in bacterial DNA activate leukocytes through the pH-dependent generation of reactive oxygen species. J. Immunol. 160, 4755-4761 (1998).
18. Ahmad-Nejad, P. et al. Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments. Eur. J. Immunol. 32, 1958-1968 (2002).
19. Hacker, H. et al. CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. EMBO J. 17, 6230-6240 (1998).
20. Manzel, L., Strekowski, L., Ismail, F. M., Smith, J. C. & Macfarlane, D. E. Antagonism of immunostimulatory CpG-oligodeoxynucleotides by 4-aminoquinolines and other weak bases: Mechanistic studies. J Pharmacol. Exp. Ther. 291, 1337-1347 (1999).
21. Ishii, K. J. et al. Potential role of phosphatidylinositol 3 kinase, rather than DNA-dependent protein kinase, in CpG DNA-induced immune activation. J. Exp. Med. 196, 269-274 (2002).
22. Hacker, H. et al. Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6. J. Exp. Med. 192, 595-600 (2000).
23. Schnare, M., Holtdagger, A. C., Takeda, K., Akira, S. & Medzhitov, R. Recognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88. Curr. Biol. 10, 1139-1142 (2000).
24. Muzio, M., Ni, J., Feng, P. & Dixit, V. M. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278, 1612-1615 (1997).
25. Muzio, M., Natoli, G., Saccani, S., Levrero, M. & Mantovani, A. The human toll signaling pathway: Divergence of nuclear factor κB and JNK/ SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (FRAF6). J. Exp. Med. 187, 2097-2101 (1998).
26. Rutz, M. et al. Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. Eur. J. Immunol. 34, 2541-2550 (2004).
27. Hartmann, G. & Krieg, A. M. Mechanism and function of a newly identified CpG DNA motif in human primary B cells. J. Immunol. 164, 944-953 (2000).
28. Yi, A. K. & Krieg, A. M. Rapid induction of mitogen-activated protein kinases by immune stimulatory CpG DNA. J. Immunol. 161, 4493-4497 (1998).
29. Takeshita, F. & Klinman, D. M. CpG ODN-mediated regulation of IL-12 p40 transcription. Eur. J. Immunol. 30, 1967-1976 (2000).
30. Tsujimura, H. et al. Toll-like receptor 9 signaling activates NF-κB through IFN regulatory factor-8/IFN consensus sequence binding protein in dendritic cells. J. Immunol. 172, 6820-6827 (2004).
31. Choudhury, B. K. et al. In vivo role of p38 mitogen-activated protein kinase in mediating the antiinflammatory effects of CpG oligodeoxynucleotide in murine asthma. J. Immunol. 169, 5955-5961 (2002).
32. Yi, A. K., Yoon, J. G. & Krieg, A. M. Convergence of CpG DNA- and BCR-mediated signals at the c-Jun N- terminal kinase and NF-κB activation pathways: Regulation by mitogen-activated protein kinases. Int. Immunol. 15, 577-591 (2003).
33. Yi, A. K. et al. Role of mitogen-activated protein kinases in CpG DNA-mediated IL-10 and IL-12 production: Central role of extracellular signal-regulated kinase in the negative feedback loop of the CpG DNA-mediated Th1 response. J. Immunol. 168, 4711-4720 (2002).
34. Rankin, R. et al. CpG motif identification for veterinary and laboratory species demonstrates that sequence recognition is highly conserved. Antisense Nucleic Acid Drug Dev. 11, 333-340 (2001).
35. Yi, A. K., Chang, M., Peckham, D. W., Krieg, A. M. & Ashman, R. F. CpG oligodeoxyribonucleotides rescue mature spleen B cells from spontaneous apoptosis and promote cell cycle entry. J. Immunol. 160, 5898-5906 (1998).
36. Bauer, S. et al. Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc. Natl Acad. Sci. USA 98, 9237-9242 (2001).
37. Latz, E. et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nature Immunol. 5, 190-198 (2004).
38. Ballas, Z. K., Rasmussen, W. L. & Krieg, A. M. Induction of NK activity in murine and human cells by CpG motifs in oligodeoxynucleotides and bacterial DNA. J. Immunol. 157, 1840-1845 (1996).
39. Hartmann, G. et al. Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J. Immunol. 164, 1617-1624 (2000).
40. Pisetsky, D. S. & Reich, C. F., III. The influence of base sequence on the immunological properties of defined oligonucleotides. Immunopharmacology 40, 199-208 (1998).
41. Roberts, T. L., Sweet, M. J., Hume, D. A. & Stacey, K. J. Cutting edge: species-specific TLR9-mediated recognition of CpG and non-CpG phosphorothioate-modified oligonucleotides. J. Immunol. 174, 605-608 (2005).
42. Vollmer, J. et al. Oligodeoxynucleotides lacking CpG dinucleotides mediate Toll-like receptor 9 dependent T helper type 2 biased immune stimulation. Immunology 113, 212-223 (2004).
43. Vollmer, J. et al. Characterization of three CpG oligodeoxynucleotide classes with distinct immunostimulatory activities. Eur. J. Immunol. 34, 251-262 (2004).
44. Hemmi, H., Kaisho, T., Takeda, K. & Akira, S. The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J. Immunol. 170, 3059-3064 (2003).
45. Honda, K. et al. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434, 1035-1040 (2005).
46. Uhlmann, E. & Vollmer, J. Recent advances in the development of immunostimulatory oligonucleotides. Curr. Opin. Drug Discov. Devel. 6, 204-217 (2003).
47. Kandimalla, E. R., Zhu, F. G., Bhagat, L., Yu, D. & Agrawal, S. Toll-like receptor 9: Modulation of recognition and cytokine induction by novel synthetic CpG DNAs. Biochem. Soc. Trans. 31, 654-658 (2003).
48. Krieg, A. M., Guga, P. & Stec, W. P-chirality-dependent immune activation by phosphorothioate CpG oligodeoxynucleotides. Oligonucleotides 13, 491-499 (2003).
49. Krieg, A. M. et al. Sequence motifs in adenoviral DNA block immune activation by stimulatory CpG motifs. Proc. Natl Acad. Sci. USA 95, 12631-12636 (1998).
50. Yamada, H. et al. Effect of suppressive DNA on CpG-induced immune activation. J. Immunol. 169, 5590-5594 (2002).
51. Lenert, P., Stunz, L. L., Yi, A. K., Krieg, A. M. & Ashman, R. F. CpG stimulation of primary mouse B cells is blocked by inhibitory oligodeoxyribonucleotide s at a site proximal to NF-kB activation. Antisense Nucleic Acid Drug Dev. 11, 247-256 (2001).
52. Jurk, M. Selective inhibition of Toll-like receptor-mediated signalling by inhibitory oligodeoxynucleotides. Clin. Invest. Med. 27, 2333 (2005).
53. Beignon, A. S. et al. Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions. J. Clin. Invest. 15, 3265-3275 (2005).
54. Barrat, F. J. et al. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J. Exp. Med. 202, 1131-1139 (2005).
55. Shirota, H., Gursel, M. & Klinman, D. M. Suppressive oligodeoxynucleotides inhibit Th 1 differentiation by blocking IFN-γ- and IL-12-mediated signaling. J. Immunol. 173, 5002-5007 (2004).
56. Lenert, P., Rasmussen, W., Ashman, R. F. & Ballas, Z. K. Structural characterization of the inhibitory DNA motif for the type A (D)-CpG-induced cytokine secretion and NK-cell lytic activity in mouse spleen cells. DNA Cell Biol. 22, 621-631 (2003).
57. Geary R. S. et al. Pharmacokinetics and metabolism in mice of a phosphorothioate oligonucleotide antisense inhibitor of C-raf-1 kinase expression. Drug Metab. Dispos. 25, 1272-1281 (1997).
58. Levin, A. A., Henry, S. & Monteith, D. Antisense Drug Technology (ed. Crooke, S. T.) 201-267 (Marcel Dekker, New York, 2001).
59. Krieg, A. M., Efler, S. M., Wittpoth, M., Al Adhami, M. J. & Davis, H. L. Induction of systemic TH1-like innate immunity in normal volunteers following subcutaneous but not intravenous administration of CPG 7909, a synthetic B-class CpG oligodeoxynucleotide TLR9 agonist. J. Immunother. 27, 460-471 (2004).
60. Elkins, K. L., Rhinehart-Jones, T. R., Stibitz, S., Conover, J. S. & Klinman, D. M. Bacterial DNA containing CpG motifs stimulates lymphocyte-dependent protection of mice against lethal infection with intracellular bacteria. J. Immunol. 162, 2291-2298 (1999).
61. Gramzinski, R. A et al. Interleukin-12- and γ interferon-dependent protection against malaria conferred by CpG oligodeoxynucleotide in mice. Infect. Immun. 69, 1643-1649 (2001).
62. Zimmermann, S. et al. CpG oligodeoxynucleotides trigger protective and curative Th1 responses in lethal murine leishmaniasis. J. Immunol. 160, 3627-3630 (1998).
63. Krieg, A. M., Love-Homan, L., Yi, A. K. & Harty, J. T. CpG DNA induces sustained IL-12 expression in vivo and resistance to Listeria monocytogenes challenge. J. Immunol. 161, 2428-2434 (1998).
64. Klinman, D. M., Conover, J. & Coban, C. Repeated administration of synthetic oligodeoxynucleotides expressing CpG motifs provides long-term protection against bacterial infection. Infect. Immun. 67, 5658-5663 (1999).
65. Klinman, D. M., Verthelyi, D., Takeshita, F. & Ishii, K. J. Immune recognition of foreign DNA: A cure for bioterrorism? Immunity 11, 123-129 (1999).
66. Rees, D. G. et al. CpG-DNA protects against a lethal orthopoxvirus infection in a murine model. Antiviral Res. 65, 87-95 (2005).
67. Deng, J. C. et al. CpG oligodeoxynucleotides stimulate protective innate immunity against pulmonary Klebsiella infection. J. Immunol. 173, 5148-5155 (2004).
68. Ray, N. B. & Krieg, A. M. Oral pretreatment of mice with CpG DNA reduces susceptibility to oral or intraperitoneal challenge with virulent Listeria monocytogenes. Infect. Immun. 71, 4398-4404 (2003).
69. Klinman, D. M. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nature Rev. Immunol. 4, 249-259 (2004).
70. Weighardt, H. et al. Increased resistance against acute polymicrobial sepsis in mice challenged with immunostimulatory CpG oligodeoxynucleotides is related to an enhanced innate effector cell response. J. Immunol. 165, 4537-4543 (2000).
71. Pyles, R. B. et al. Use of immunostimulatory sequence-containing oligonucleotides as topical therapy for genital herpes simplex virus type 2 infection. J. Virol. 76, 11387-11396 (2002).
72. Ashkar, A. A., Bauer, S., Mitchell, W. J., Vieira, J. & Rosenthal, K. L. Local delivery of CpG oligodeoxynucleotides induces rapid changes in the genital mucosa and inhibits replication, but not entry, of herpes simplex virus type 2. J. Virol. 77, 8948-8956 (2003).
73. Walker, P. S. et al Immunostimulatory oligodeoxynucleotides promote protective immunity and provide systemic therapy for leishmaniasis via IL-12- and IFN-γ-dependent mechanisms. Proc. Natl Acad. Sci. USA 96, 6970-6975 (1999).
74. Cho, J. Y. et al. Immunostimulatory DNA sequences inhibit respiratory syncytial viral load, airway inflammation, and mucus secretion. J. Allergy Clin. Immunol. 108, 697-702 (2001).
75. Juffermans, N. P. et al. CpG oligodeoxynucleotides enhance host defense during murine tuberculosis. Infect. Immun. 70, 147-152 (2002).
76. Olbrich, A. R. et al. Effective postexposure treatment of retrovirus-induced disease with immunostimulatory DNA containing CpG motifs. J. Virol. 76, 11397-11404 (2002).
77. Freidag, B. L. et al. CpG oligodeoxynucleotides and interleukin-12 improve the efficacy of Mycobacterium bovis BCG vaccination in mice challenged with M. tuberculosis. Infect. Immun. 68, 2948-2953 (2000).
78. Ramirez-Pineda, J. R., Frohlich, A., Berberich, C. & Moll, H. Dendritic cells (DC) activated by CpG DNA ex vivo are potent inducers of host resistance to an intracellular pathogen that is independent of IL-12 derived from the immunizing DC. J. Immunol. 172, 6281-6289 (2004).
79. Ishii, K. J. et al. CpG-activated Thy1.2+ dendritic cells protect against lethal Listeria monocytogenes infection. Eur. J. Immunol. 35, 2397-2405 (2005).
80. Lugo-Villarino, G., Ito, S., Klinman, D. M. & Glimcher, L. H. The adjuvant activity of CpG DNA requires T-bet expression in dendritic cells. Proc. Natl Acad. Sci. USA 102, 13248-13253 (2005).
81. Sajic, D. et al. Parameters of CpG oligodeoxynucleotide-induced protection against intravaginal HSV-2 challenge. J Med. Virol. 71, 561-568 (2003).
82. Isogawa, M., Robek, M. D., Furuichi, Y. & Chisari, F. V. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J. Virol. 79, 7269-7272 (2005).
83. Verthelyi, D. et al. CpG oligodeoxynucleotides protect normal and SIV-infected macaques from Leishmania infection. J. Immunol. 170, 4717-4723 (2003).
84. Rehermann, B. & Nascimbeni, M. Immunology of hepatitis B virus and hepatitis C virus infection. Nature Rev. Immunol. 5, 215-229 (2005).
85. McHutchison, J. G. et al. Relationships of HCV RNA responses to CPG 10101, a TLR9 agonist: Pharmacodynamics & patient characteristics. Hepatology 42, 249A (2005).
86. Olbrich, A. R., Schimmer, S. & Dittmer, U. Preinfection treatment of resistant mice with CpG oligodeoxynucleotides renders them susceptible to friend retrovirus-induced leukemia. J. Virol. 77, 10658-10662 (2003).
87. Ito, S., Pedras-Vasconcelos, J. & Klinman, D. M. CpG oligodeoxynucleotides increase the susceptibility of normal mice to infection by Candida albicans. Infect. Immun. 73, 6154-6156 (2005).
88. Equils, O. et al. Toll-like receptor 2 (TLR2) and TLR9 signaling results in HIV-Long terminal repeat trans-activation and HIV replication in HIV-1 transgenic mouse spleen cells: Implications of simultaneous activation of TLRs on HIV replication. J. Immunol. 170, 5159-5164 (2003).
89. Agrawal, S. and Martin, R. R. Was induction of HIV1 through TLR9? J. Immunol. 171, 1621 (2003).
90. Gurney, K. B., Colantonio, A. D., Blom, B., Spits, H. & Uittenbogaart, C. H. Endogenous IFN-α production by plasmacytoid dendritic cells exerts an antiviral effect on thymic HIV-1 infection. J. Immunol. 173, 7269-7276 (2004).
91. Schlaepfer, E. et al. CpG oligodeoxynucleotides block human immunodeficiency virus type 1 replication in human lymphoid tissue infected ex vivo. J. Virol. 78, 12344-12354 (2004).
92. Saez, R., Echaniz, P., de Juan, M. D., Iribarren, J. A. & Cuadrado, E. HIV-infected progressors and long-term non-progressors differ in their capacity to respond to an A-class CpG oligodeoxynucleotide. AIDS 19, 1924-1925 (2005).
93. Cooper, C. L. et al. CPG 7909 adjuvant improves hepatitis B virus vaccine seroprotection in antiretroviral-treated HIV-infected adults. AIDS 19, 1473-1479 (2005).
94. Davis, H. L. et al. CpG DNA is a potent enhancer of specific immunity in mice immunized with recombinant hepatitis B surface antigen. J. Immunol. 160, 870-876 (1998).
95. Liu, N., Ohnishi, N., Ni, L., Akira, S. & Bacon, K. B. CpG directly induces T-bet expression and inhibits IgG1 and IgE switching in B cells. Nature Immunol. 4, 687-693 (2003).
96. He, B., Qiao, X. & Cerutti, A. CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10. J. Immunol. 173, 4479-4491 (2004).
97. Lipford, G. B., Sparwasser, T., Zimmermann, S., Heeg, K. & Wagner, H. CpG-DNA-mediated transient lymphadenopathy is associated with a state of Th1 predisposition to antigen-driven responses. J. Immunol. 165, 1228-1235 (2000).
98. Sparwasser, T., Vabulas, R. M., Villmow, B., Lipford, G. B. & Wagner, H. Bacterial CpG-DNA activates dendritic cells in vivo: T helper cell-independent cytotoxic T cell responses to soluble proteins. Eur. J. Immunol. 30, 3591-3597 (2000).
99. Tighe, H. et al. Conjugation of protein to immunostimulatory DNA results in a rapid, long-lasting and potent induction of cell-mediated and humoral immunity. Eur. J. Immunol. 30, 1939-1947 (2000).
100. Hartmann, E. et al. Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res. 63, 6478-6487 (2003).
101. Wettstein, P. J., Borson, N. D., Park, J. G., McNallan, K. T. & Reed, A. M. Cysteine-tailed class I-binding peptides bind to CpG adjuvant and enhance primary CTL responses. J. Immunol. 175, 3681-3689 (2005).
102. Kim, S. K. et al. Comparison of the effect of different immunological adjuvants on the antibody and T-cell response to immunization with MUC1-KLH and GD3-KLH conjugate cancer vaccines. Vaccine 18, 597-603 (2000).
103. Chu, R. S., Targoni, O. S., Krieg, A. M., Lehmann, P. V. & Harding, C. V. CpG oligodeoxynucleotides act as adjuvants that switch on T helper 1 (Th1) immunity. J. Exp. Med. 186, 1623-1631 (1997).
104. Lipford, G. B. et al. CpG-containing synthetic oligonucleotides promote B and cytotoxic T cell responses to protein antigen: A new class of vaccine adjuvants. Eur. J. Immunol. 27, 2340-2344 (1997).
105. Roman, M. et al. Immunostimulatory DNA sequences function as T helper-1-promoting adjuvants (see comments). Nature Med. 3, 849-854 (1997).
106. Weeratna, R. D., McCluskie, M. J., Xu, Y. & Davis, H. L. CpG DNA induces stronger immune responses with less toxicity than other adjuvants. Vaccine 18, 1755-1762 (2000).
107. Sugai, T. et al. A CpG-containing oligodeoxynucleotide as an efficient adjuvant counterbalancing the Th1/Th2 immune response in diphtheria-tetanus-pertussis vaccine. Vaccine 23, 5450-5456 (2005).
108. Oumouna, M., Mapletoft, J. W., Karvonen, B. C., Babiuk, L. A. & van Drunen Littel-van den Hurk. Formulation with CpG oligodeoxynucleotides prevents induction of pulmonary immunopathology following priming with formalin-inactivated or commercial killed bovine respiratory syncytial virus vaccine. J. Virol. 79, 2024-2032 (2005).
109. Brazolot Millan, C. L., Weeratna, R., Krieg, A. M., Siegrist, C. A. & Davis, H. L. CpG DNA can induce strong Th1 humoral and cell-mediated immune responses against hepatitis B surface antigen in young mice. Proc. Natl Acad. Sci. USA 95, 15553-15558 (1998).
110. Weeratna, R. D., Brazolot Millan, C. L., McCluskie, M. J., Siegrist, C. A. & Davis, H. L. Priming of immune responses to hepatitis B surface antigen in young mice immunized in the presence of maternally derived antibodies. FEMS Immunol. Med. Microbiol. 30, 241-247 (2001).
111. Schirmbeck, R. & Reimann, J. Modulation of gene-gun-mediated Th2 immunity to hepatitis B surface antigen by bacterial CpG motifs or IL-12. Intervirology 44, 115-123 (2001).
112. Zhou, X., Zheng, L., Liu, L., Xiang, L. & Yuan, Z. T helper 2 immunity to hepatitis B surface antigen primed by gene-gun-mediated DNA vaccination can be shifted towards T helper 1 immunity by codelivery of CpG motif-containing oligodeoxynudeotides. Scand. J. Immunol. 58, 350-357 (2003).
113. Weeratna, R. D., Brazolot Millan, C. L., McCluskie, M. J. & Davis, H. L. CpG ODN can re-direct the Th bias of established Th2 immune responses in adult and young mice. FEMS Immunol. Med. Microbiol. 32, 65-71 (2001).
114. Manning, B. M., Enioutina, E. Y., Visic, D. M., Knudson, A. D. & Daynes, R. A. CpG DNA functions as an effective adjuvant for the induction of immune responses in aged mice. Exp. Gerontol. 37, 107-126 (2001).
115. Maletto, B., Ropolo, A., Moron, V. & Pistoresi-Palencia, M. C. CpG-DNA stimulates cellular and humoral immunity and promotes Th1 differentiation in aged BALB/c mice. J. Leukoc. Biol. 72, 447-454 (2002).
116. Alignani, D. et al. Orally administered OVA/CpG-ODN induces specific mucosal and systemic immune response in young and aged mice. J. Leukoc. Biol. 77, 898-905 2005.
117. Krieg, A. M. & Davis, H. L. Enhancing vaccines with immune stimulatory CpG DNA. Curr. Opin. Mol. Ther. 3, 15-24 (2001).
118. Moldoveanu, Z., Love-Homan, L., Huang, W. Q. & Krieg, A. M. CpG DNA, a novel immune enhancer for systemic and mucosal immunization with influenza virus. Vaccine 16, 1216-1224 (1998).
119. Gallichan, W. S. et al. Intranasal immunization with CpG oligodeoxynucleotides as an adjuvant dramatically increases IgA and protection against herpes simplex virus- 2 in the genital tract. J. Immunol. 166, 3451-3457 (2001).
120. McCluskie, M. J. & Davis, H. L. CpG DNA is a potent enhancer of systemic and mucosal immune responses against hepatitis B surface antigen with intranasal administration to mice. J. Immunol. 161, 4463-4466 (1998).
121. McCluskie, M. J. & Davis, H. L. Oral, intrarectal and intranasal immunizations using CpG and non-CpG oligodeoxynucleotides as adjuvants. Vaccine 19, 413-422 (2001).
122. Kwant, A. & Rosenthal, K. L. Intravaginal immunization with viral subunit protein plus CpG oligodeoxynucleotides induces protective immunity against HSV-2. Vaccine 22, 3098-3104 (2004).
123. Eastcott, J. W. et al. Oligonucleotide containing CpG motifs enhances immune response to mucosally or systemically administered tetanus toxoid. Vaccine 19, 1636-1642 (2001).
124. McCluskie, M. J., Weeratna, R. D., Krieg, A. M. & Davis, H. L. CpG DNA is an effective oral adjuvant to protein antigens in mice. Vaccine 19, 950-957 (2001).
125. Dong, J. L., Liang, B. G., Jin, Y. S., Zhang, W. J. & Wang, T. Oral immunization with pBsVP6-transgenic alfalfa protects mice against rotavirus infection. Virology 339, 153-163 (2005).
126. Nesburn, A. B. et al. Local and systemic B cell and Th1 responses induced following ocular mucosal delivery of multiple epitopes of herpes simplex virus type 1 glycoprotein D together with cytosine-phosphate-guanine adjuvant. Vaccine 23, 873-883 (2005).
127. Berry, L. J. et al. Transcutaneous immunization with combined cholera toxin and CpG adjuvant protects against Chlamydia muridarum genital tract infection. Infect. Immun. 72, 1019-1028 (2004).
128. Dumais, N., Patrick, A., Moss, R. B., Davis, H. L. & Rosenthal, K. L. Mucosal immunization with inactivated human immunodeficiency virus plus CpG oligodeoxynucleotides induces genital immune responses and protection against intravaginal challenge. J. Infect. Dis. 186, 1098-1105 (2002).
129. Cooper, C. L. et al. CpG 7909, an immunostimulatory TLR9 agonist oligodeoxynucleotide, as adjuvant to Engerix-B HBV vaccine in healthy adults: A double-blind Phase I/II study. J. Clin. Immunol. 24, 693-702 (2004).
130. Halperin, S. A. et al. A phase I study of the safety and immunogenicity of recombinant hepatitis B surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide adjuvant. Vaccine 21, 2461-2467 (2003).
131. Siegrist, C. A. et al. Co-administration of CpG oligonucleotides enhances the late affinity maturation process of human anti-hepatitis B vaccine response. Vaccine 23, 615-622 (2004).
132. Rynkiewicz, D. et al. Marked enhancement of antibody response to anthrax vaccine adsorbed with CPG 7909 in healthy volunteers. Intersci. Conf. Antimicrob. Agents Chemother. Poster (2005).
133. Weeratna, R., Comanita, L. & Davis, H. L. CPG ODN allows lower dose of antigen against hepatitis B surface antigen in BALB/c mice. Immunol. Cell Biol. 81, 59-62 (2003).
134. Cooper, C. L. et al. Safety and Immunogenicity of CpG 7909 Injection as an Adjuvant to Fluarix Influenza Vaccine. Vaccine 22, 3136-3143 (2004).
135. Kline, J. N. et al. Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J. Immunol. 160, 2555-2559 (1998).
136. Jain, V. V. et al. CpG-oligodeoxynucleotides inhibit airway remodeling in a murine model of chronic asthma. J. Allergy Clin. Immunol. 110, 867-872 (2002).
137. Creticos, P. S., Eiden, J. J. & et al. Immunotherapy with immunostimulatory oligonucleotides linked to purified ragweed Amb a 1 allergen: Effects on antibody production, nasal allergen provocation, and ragweed seasonal rhinitis J. Allergy Clin. Immunol. 109, 742-743 (2002).
138. Simons, F. E., Shikishima, Y., Van Nest, G., Eiden, J. J. & HayGlass, K. T. Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA. J. Allergy Clin. Immunol. 113, 1144-1151 (2004).
139. van Ojik, H. et al. Phase I/II study with CpG 7909 as adjuvant to vaccination with MAGA-3 protein in patients with MAGE-3 positive tumors. Ann. Oncol. 13, 157 (2002).
140. Speiser, D. E. et al. Rapid and strong human CD8(+) T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J. Clin. Invest. 115, 739-746 (2005).
141. Jain, V. V. et al. Mucosal immunotherapy with CpG oligodeoxynucleotides reverses a murine model of chronic asthma induced by repeated antigen exposure. Am. J. Physiol. Lung Cell Mol. Physiol. 285, L1137-L1146 (2003).
142. Fanucchi, M. V. et al. Immunostimulatory oligonucleotides attenuate airways remodelling in allergic monkeys. Am. J. Respir. Crit. Care Med. 170, 1153-1157 (2004).
143. Racila, D. M. & Kline, J. N. Perspectives in asthma: Molecular use of microbial products in asthma prevention and treatment. J. Allergy Clin. Immunol. 116, 1202-1205 (2005).
144. Hayashi, T. et al. Inhibition of experimental asthma by indoleamine 2, 3-dioxygenase. J. Clin. Invest. 114, 270-279 (2004).
145. Krieg, A. M. Antitumor applications of stimulating Toll-like receptor 9 with CpG oligodeoxynucleotides. Curr. Oncol. Rep. 6, 88-95 (2004).
146. Link, B. et al. Oligodeoxynucleotide CPG 7909 Delivered as intravenous infusion demonstrates immunologic modulation in patients with previously treated non-Hodgkin's lymphoma. J. Immunother. (in the press).
147. Friedberg, J. W. et al. Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and rituximab in patients with non-Hodgkin lymphoma: Increased interferon-α/β-inducible gene expression, without significant toxicity. Blood 105, 489-495 (2005).
148. Weigel, B. J., Rodeberg, D. A., Krieg, A. M. & Blazar, B. R. CpG oligodeoxynucleotides potentiate the antitumor effects of chemotherapy or tumor resection in an orthatopic murine model of rhabdomyosarcoma. Clin. Cancer Res. 9, 3105-3114 (2003).
149. Balsari, A. et al. Combination of a CpG-oligodeoxynucleotide and a topoisomerase I inhibitor in the therapy of human tumour xenografts. Eur. J. Cancer 40, 1275-1281 (2004).
150. Wang, X. S., Sheng, Z., Ruan, Y. B., Guang, Y. & Yang, M. L. CpG oligodeoxynucleotides inhibit tumor growth and reverse the immunosuppression caused by the therapy with 5-fluorouracil in murine hepatoma. World J. Gastroenterol. 11, 1220-1224 (2005).
151. Carson, W. E., III, Shapiro, C. L., Crespin, T. R., Thornton, L. M. & Andersen, B. L. Cellular immunity in breast cancer patients completing taxane treatment. Clin. Cancer Res. 10, 3401-3409 (2004).
152. Emens, L. A., Reilly, R. T. & Jaffee, E. M. Augmenting the potency of breast cancer vaccines: Combined modality immunotherapy. Breast Dis 20, 13-24 (2004).
153. Manegold, C., Leichman, G., Gravenor, D. & et al. Addition of PF-3512676 (CpG 7909) to a Taxane/Platinum regimen for first-line treatment of unresectable non-small cell lung cancer (NSCLC) improves objective response - Phase II clinical trial. Eur. J. Cancer 3 (Suppl.), 326 A1131 (2005).
154. Levin, A. A. A review of the issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides. Biochim. Biophys. Acta 1489, 69-84 (1999).
155. Monteith, D. K. & Levin, A. A. Synthetic oligonucleotides: The development of antisense therapeutics. Toxicol. Pathol. 27, 8-13 (1999).
156. Geary R. S., Leeds, J. M., Henry, S. P., Monteith, D. K. & Levin, A. A. Antisense oligonucleotide inhibitors for the treatment of cancer: 1. Pharmacokinetic properties of phosphorothioate oligodeoxynucleotides. Anticancer Drug Des. 12, 383-393 (1997).
157. Cossum, P. A. et al. Disposition of the 14C-labeled phosphorothioate oligonucleotide ISIS 2105 after intravenous administration to rats. J. Pharmacol. Exp. Ther. 267, 1181-1190 (1993).
158. Henry, S. P., Taylor, J., Midgley, L., Levin, A. A. & Kornbrust, D. J. Evaluation of the toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a 4-week study in CD-1 mice. Antisense Nucleic Acid Drug Dev. 7, 473-481 (1997).
159. Heikenwalder, M. et al. Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nature Med. 10, 187-192 (2004).
160. Jason, T. L., Koropatnick, J. & Berg, R. W. Toxicology of antisense therapeutics. Toxicol. Appl. Pharmacol. 201, 66-83 (2004).
161. Sparwasser, T. et al. Bacterial DNA causes septic shock. Nature 386, 336-337 (1997).
162. Henry, S. P. et al. Complement activation is responsible for acute toxicities in rhesus monkeys treated with a phosphorothioate oligodeoxynucleotide. Int. Immunopharmacol. 2, 1657-1666 (2002).
163. Galbraith, W. M., Hobson, W. C., Giclas, P. C., Schechter, P. J. & Agrawal, S. Complement activation and hemodynamic changes following intravenous administration of phosphorothioate oligonucleotides in the monkey. Antisense Res. Dev. 4, 201-206 (1994).
164. Monteith, D. K. et al. Preclinical evaluation of the effects of a novel antisense compound targeting C-raf kinase in mice and monkeys. Toxicol. Sci. 46, 365-375 (1998).
165. Henry, S. P., Novotny, W., Leeds, J., Auletta, C. & Kornbrust, D. J. Inhibition of coagulation by a phosphorothioate oligonucleotide. Antisense Nucleic Acid Drug Dev. 7, 503-510 (1997).
166. Sheehan, J. P. & Lan, H. C. Phosphorothioate oligonucleotides inhibit the intrinsic tenase complex. Blood 92, 1617-1625 (1998).
167. Krieg, A. M. CpG DNA: A pathogenic factor in systemic lupus erythematosus? J. Clin. Immunol. 15, 284-292 (1995).
168. Hasegawa, K. & Hayashi, T. Synthetic CpG oligodeoxynucleotides accelerate the development of lupus nephritis during preactive phase in NZB × NZWF1 mice. Lupus 12, 838-845 (2003).
169. Ichikawa, H. T., Williams, L. P. & Segal, B. M. Activation of APCs through CD40 or Toll-like receptor 9 overcomes tolerance and precipitates autoimmune disease. J. Immunol. 169, 2781-2787 (2002).
170. Obermeier, F. et al. CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice. Eur. J. Immunol. 32, 2084-2092 (2002).
171. Ronaghy, A. et al. Immunostimulatory DNA sequences influence the course of adjuvant arthritis. J. Immunol. 168, 51-56 (2002).
172. Katakura, K. et al. Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. J. Clin. Invest. 115, 695-702 (2005).
173. Boccaccio, G. L., Mor, F. & Steinman, L. Non-coding plasmid DNA induces IFN-γ in vivo and suppresses autoimmune encephalomyelitis. Int. Immunol. 11, 289-296 (1999).
174. Quintana, F. J., Rotem, A., Carmi, P. & Cohen, I. R. Vaccination with empty plasmid DNA or CpG oligonucleotide inhibits diabetes in nonobese diabetic mice: Modulation of spontaneous 60-kDa heat shock protein autoimmunity. J. Immunol. 165, 6148-6155 (2000).
175. Wingender, G. et al. Systemic application of CpG-rich DNA suppresses adaptive T cell immunity via induction of IDO. Eur. J. Immunol. 36, 12-20 (2006).
176. Mellor, A. L. et al. Cutting edge: CpG oligonucleotides induce splenic CD 19 + dendritic cells to acquire potent indoleamine 2, 3-dioxygenase-dependent T cell regulatory functions via IFN Type 1 signaling. J. Immunol. 175, 5601-5605 (2005).
177. Chen, Y. et al. CpG DNA induces cyclooxygenase-2 expression and prostaglandin production. Int. Immunol. 13, 1013-1020 (2001).
178. Ioannou, Y. & Isenberg, D. A. Current evidence for the induction of autoimmune rheumatic manifestations by cytokine therapy. Arthritis Rheum. 43, 1431-1442 (2000).
179. Leadbetter, E. A. et al. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603-607 (2002).
180. Viglianti, G. A. et al. Activation of autoreactive B cells by CpG dsDNA. Immunity 19, 837-847 (2003).
181. Boule, M. W. et al. Toll-like receptor 9-dependent and-independent dendritic cell activation by chromatin-immunoglobulin G complexes. J. Exp. Med. 199, 1631-1640 (2004).
182. Christensen, S. R. et al. Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J. Exp. Med. 202, 321-331 (2005).
183. Means, T. K. et al. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J. Clin. Invest. 115, 407-417 (2005).
184. Dong, L., Ito, S., Ishii, K. J. & Klinman, D. M. Suppressive oligodeoxynucleotides delay the onset of glomerulonephritis and prolong survival in lupus-prone NZB × NZW mice. Arthritis Rheum. 52, 651-658 (2005).
185. Dong, L., Ito, S., Ishii, K. J. & Klinman, D. M. Suppressive oligonucleotides protect against collagen-induced arthritis in mice. Arthritis Rheum. 50, 1686-1689 (2004).
186. Kawai, T. et al. Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nature Immunol. 5, 1061-1068 (2004).
187. Uematsu, S. et al. Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-α induction. J. Exp. Med. 201, 915-923 (2005).
188. Yeo, S. J., Yoon, J. G. & Yi, A. K. Myeloid differentiation factor 88-dependent post-transcriptional regulation of cyclooxygenase-2 expression by CpG DNA: Tumor necrosis factor-α receptor-associated factor 6, a diverging point in the Toll-like receptor 9-signaling. J. Biol. Chem. 278, 40590-40600 (2003).
189. Yeo, S. J., Gravis, D., Yoon, J. G. & Yi, A. K. Myeloid differentiation factor 88-dependent transcriptional regulation of cyclooxygenase-2 expression by CpG DNA: Role of NF-κB and p38. J. Biol. Chem. 278, 22563-22573 (2003).
190. Honda, K. et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772-777 (2005).
191. Yang, K. et al. Human TLR-7-, -8-, and-9-mediated induction of IFN-α/β and-λ Is IRAK-4 dependent and redundant for protective immunity to viruses. Immunity 23, 465-478 (2005).
192. Sun, C. M., Deriaud, E., Leclerc, C. & Lo-Man, R. Upon TLR9 signaling, CD5 + B cells control the IL-12-dependent Th1-priming capacity of neonatal DCs. Immunity 22, 467-477 (2005).
193. Kerkmann, M. et al. Spontaneous formation of nucleic acid-based nanoparticles is responsible for high interferon-α induction by CpG-A in plasmacytoid dendritic cells. J. Biol. Chem. 280, 8086-8093 (2005).
194. Marshall, J. D. et al. Novel chimeric immunomodulatory compounds containing short CpG oligodeoxyribonucleo tides have differential activities in human cells. Nucleic Acids Res. 31, 5122-5133 (2003).
195. Fearon, K. et al. A minimal human immunostimulatory CpG motif that potently induces IFN-γ and IFN-α production. Eur. J. Immunol. 33, 2114-2122 (2003).
196. Hartmann, G. et al. Rational design of new CpG oligonucleotides that combine B cell activation with high IFN-α induction in plasmacytoid dendritic cells. Eur. J. Immunol. 33, 1633-1641 (2003).
197. Marshall, J. D. et al. Identification of a novel CpG DNA class and motif that optimally stimulate B cell and plasmacytoid dendritic cell functions. J. Leukoc. Biol. 73, 781-792 (2003).
198. Kemp, T. J., Elzey, B. D. & Griffith, T. S. Plasmacytoid dendritic cell-derived IFN-α induces TNF-related apoptosis-inducing ligand/ Apo-2L-mediated antitumor activity by human monocytes following CpG oligodeoxynucleotide stimulation. J. Immunol. 171, 212-218 (2003).
199. Utaisincharoen, P. et al. CpG ODN enhances uptake of bacteria by mouse macrophages. Clin. Exp. Immunol. 132, 70-75 (2003).
200. Klinman, D. M. Use of CpG oligodeoxynucleotides as immunoprotective agents. Exp. Opin. Biol. Ther. 4, 937-946 (2004).
201. Efler, S. M., Zhang, L., Noll, B. O., Uhlmann, E. & Davis, H. L. Quantification of oligodeoxynucleotides in human plasma with a novel hybridization assay offers greatly enhanced sensitivity over capillary gel electrophoresis. Oligonucleotides 15, 119-131 (2005).
202. Krieg, A. M. & Davis, H. L. Vaccine Adjuvants: Immunological and Clinical Principles (eds Hackett, C. J. & Harn, Jr. D. A.) 87-110 (Humana, Totowa, 2006).
203. Halperin, S. A. et al. Comparison of the safety and immunogenicity of hepatitis B virus surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide and a licensed hepatitis B vaccine in healthy young adults. Vaccine 24, 20-26 (2006).
204. Lin, L., Gerth, A. J. & Peng, S. L. CpG DNA redirects class-switching towards 'Th 1-like' Ig isotype production via TLR9 and MyD88. Eur. J. Immunol. 34, 1483-1487 (2004).