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Therapeutic Applications of Synthetic CpG Oligodeoxynucleotides as TLR9 Agonists for Immune Modulation

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Abstract

Vertebrate toll-like receptors (TLRs) sense invading pathogens by recognizing bacterial and viral structures and, as a result, activate innate and adaptive immune responses. Ten human functional TLRs have been reported so far; three of these (TLR7, 8, and 9) are expressed in intracellular compartments and respond to single-stranded nucleic acids as natural ligands. The pathogen structure selectively recognized by TLR9 in bacterial or viral DNA was identified to be CpG dinucleotides in specific sequence contexts (CpG motifs). Short phosphorothioate-stabilized oligodeoxynucleotides (ODNs) containing such motifs are used as synthetic TLR9 agonists, and different classes of ODN TLR9 agonists have been identified with distinct immune modulatory profiles. The TLR9-mediated activation of the vertebrate immune system suggests using such TLR9 agonists as effective vaccine adjuvants for infectious disease, and for the treatment of cancer and asthma/allergy. Immune activation by CpG ODNs has been demonstrated to be beneficial in animal models as a vaccine adjuvant and for the treatment of a variety of viral, bacterial, and parasitic diseases. Antitumor activity of CpG ODNs has also been established in numerous mouse models. In clinical vaccine trials in healthy human volunteers or in immunocompromised HIV-infected patients, CpG ODNs strongly enhanced vaccination efficiency. Most encouraging results in the treatment of cancers have come from human phase I and II clinical trials using CpG ODNs as a tumor vaccine adjuvant, monotherapy, or in combination with chemotherapy. Therefore, CpG ODNs represent targeted immune modulatory drugs with a broad range of potential applications.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Tokunaga T, Yamamoto H, Shimada S, et al. Antitumor activity of deoxyribonucleic acid fraction from Mycobacterium bovis BCG: I. Isolation, physicochemical characterization, and antitumor activity. J Natl Cancer Inst 1984; 72 (4): 955–62

    PubMed  CAS  Google Scholar 

  2. Tokunaga T, Yano O, Kuramoto E, et al. Synthetic oligonucleotides with particular base sequences from the cDNA encoding proteins of Mycobacterium bovis BCG induce interferons and activate natural killer cells. Microbiol Immunol 1992; 36 (1): 55–66

    PubMed  CAS  Google Scholar 

  3. Tokunaga T, Yamamoto T, Yamamoto S. How BCG led to the discovery of immunostimulatory DNA. Jpn J Infect Dis 1999; 52 (1): 1–11

    PubMed  CAS  Google Scholar 

  4. Krieg AM, Yi AK, Matson S, et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 1995; 374 (6522): 546–9

    PubMed  CAS  Google Scholar 

  5. Akira S. TLR signaling. Curr Top Microbiol Immunol 2006; 311: 1–16

    PubMed  CAS  Google Scholar 

  6. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004; 4 (7): 499–511

    PubMed  CAS  Google Scholar 

  7. Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA. Nature 2000; 408 (6813): 740–5

    PubMed  CAS  Google Scholar 

  8. Dalpke A, Frank J, Peter M, et al. Activation of toll-like receptor 9 by DNA from different bacterial species. Infect Immun 2006; 74 (2): 940–6

    PubMed  CAS  Google Scholar 

  9. Lund J, Sato A, Akira S, et al. Toll-like receptor 9-mediated recognition of herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med 2003; 198 (3): 513–20

    PubMed  CAS  Google Scholar 

  10. Ueta M, Hamuro J, Kiyono H, et al. Triggering of TLR3 by polyI:C in human corneal epithelial cells to induce inflammatory cytokines. Biochem Biophys Res Commun 2005; 331 (1): 285–94

    PubMed  CAS  Google Scholar 

  11. Matsumoto M, Funami K, Tanabe M, et al. Subcellular localization of toll-like receptor 3 in human dendritic cells. J Immunol 2003; 171 (6): 3154–62

    PubMed  CAS  Google Scholar 

  12. Hewson CA, Jardine A, Edwards MR, et al. Toll-like receptor 3 is induced by and mediates antiviral activity against rhinovirus infection of human bronchial epithelial cells. J Virol 2005; 79 (19): 12273–9

    PubMed  CAS  Google Scholar 

  13. Honda K, Yanai H, Takaoka A, et al. Regulation of the type I IFN induction: a current view. Int Immunol 2005; 17 (11): 1367–78

    PubMed  CAS  Google Scholar 

  14. Hornung V, Rothenfusser S, Britsch S, et al. 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

    PubMed  CAS  Google Scholar 

  15. Cottalorda A, Verscheide C, Marcais A, et al. TLR2 engagement on CD8 T cells lowers the threshold for optimal antigen-induced T cell activation. Eur J Immunol 2006; 36 (7): 1684–93

    PubMed  CAS  Google Scholar 

  16. Mansson A, Adner M, Cardeil LO. Toll-like receptors in cellular subsets of human tonsil T cells: altered expression during recurrent tonsillitis. Respir Res 2006; 7: 36

    PubMed  Google Scholar 

  17. Caron G, Duluc D, Fremaux I, et al. Direct stimulation of human T cells via TLR5 and TLR7/8: flagellin and R-848 up-regulate proliferation and IFN-gamma production by memory CD4+ T cells. J Immunol 2005; 175 (3): 1551–7

    PubMed  CAS  Google Scholar 

  18. Gelman AE, LaRosa DF, Zhang J, et al. The adaptor molecule MyD88 activates PI-3 kinase signaling in CD4+ T cells and enables CpG oligodeoxynucleotidemediated costimulation. Immunity 2006; 25 (5): 783–93

    PubMed  CAS  Google Scholar 

  19. Bowman CC, Rasley A, Tranguch SL, et al. Cultured astrocytes express toll-like receptors for bacterial products. Glia 2003; 43 (3): 281–91

    PubMed  Google Scholar 

  20. Takeshita S, Takeshita F, Haddad DE, et al. Activation of microglia and astrocytes by CpG oligodeoxynucleotides. Neuroreport 2001; 12 (14): 3029–32

    PubMed  CAS  Google Scholar 

  21. Andersen JM, Al Khairy D, Ingalls RR. Innate immunity at the mucosal surface: role of toll-like receptor 3 and toll-like receptor 9 in cervical epithelial cell responses to microbial pathogens. Biol Reprod 2006; 74 (5): 824–31

    PubMed  CAS  Google Scholar 

  22. Vollmer J, Weeratna R, Payette P, et al. Characterization of three CpG oligodeoxynucleotide classes with distinct immunostimulatory activities. Eur J Immunol 2004; 34 (1): 251–62

    PubMed  CAS  Google Scholar 

  23. Vollmer J. Progress in drug development of immunostimulatory CpG oligodeoxynucleotide ligands for TLR9. Expert Opin Biol Ther 2005; 5 (5): 673–82

    PubMed  CAS  Google Scholar 

  24. Krieg AM. Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov 2006; 5 (6): 471–84

    PubMed  CAS  Google Scholar 

  25. Hartmann G, Krieg AM. Mechanism and function of a newly identified CpG DNA motif in human primary B cells. J Immunol 2000; 164 (2): 944–53

    PubMed  CAS  Google Scholar 

  26. Rankin R, Pontarollo R, Ioannou X, et al. CpG motif identification for veterinary and laboratory species demonstrates that sequence recognition is highly conserved. Antisense Nucleic Acid Drug Dev 2001; 11 (5): 333–40

    PubMed  CAS  Google Scholar 

  27. Yi AK, Chang M, Peckham DW, et al. CpG oligodeoxyribonucleotides rescue mature spleen B cells from spontaneous apoptosis and promote cell cycle entry. J Immunol 1998; 160 (12): 5898–906

    PubMed  CAS  Google Scholar 

  28. Jurk M, Kritzler A, Debelak H, et al. Structure-activity relationship studies on the immune stimulatory effects of base-modified CpG toll-like receptor 9 agonists. ChemMedChem 2006; 1 (9): 1007–14

    PubMed  CAS  Google Scholar 

  29. Verthelyi D, Ishii KJ, Gursel M, et al. Human peripheral blood cells differentially recognize and respond to two distinct CPG motifs. J Immunol 2001; 166 (4): 2372–7

    PubMed  CAS  Google Scholar 

  30. Fonteneau JF, Larsson M, Beignon AS, et al. Human immunodeficiency virus type 1 activates plasmacytoid dendritic cells and concomitantly induces the bystander maturation of myeloid dendritic cells. J Virol 2004; 78 (10): 5223–32

    PubMed  CAS  Google Scholar 

  31. Krug A, Rothenfusser S, Hornung V, et al. Identification of CpG oligonucleotide sequences with high induction of IFN-alpha/beta in plasmacytoid dendritic cells. Eur J Immunol 2001; 31 (7): 2154–63

    PubMed  CAS  Google Scholar 

  32. Puig M, Grajkowski A, Boczkowska M, et al. Use of thermolytic protective groups to prevent G-tetrad formation in CpG ODN type D: structural studies and immunomodulatory activity in primates. Nucleic Acids Res 2006; 34 (22): 6488–95

    PubMed  CAS  Google Scholar 

  33. Guiducci C, Ott G, Chan JH, et al. Properties regulating the nature of the plasmacytoid dendritic cell response to Toll-like receptor 9 activation. J Exp Med 2006; 203 (8): 1999–2008

    PubMed  CAS  Google Scholar 

  34. Wu CC, Lee J, Raz E, et al. Necessity of oligonucleotide aggregation for Toll-like receptor 9 activation. J Biol Chem 2004; 279 (32): 33071–8

    PubMed  CAS  Google Scholar 

  35. Kerkmann M, Rothenfusser S, Hornung V, et al. Activation with CpG-A and CpGB oligonucleotides reveals two distinct regulatory pathways of type I IFN synthesis in human plasmacytoid dendritic cells. J Immunol 2003; 170 (9): 4465–74

    PubMed  CAS  Google Scholar 

  36. Gursel M, Gursel I, Mostowski HS, et al. CXCL16 influences the nature and specificity of CpG-induced immune activation. J Immunol 2006; 177 (3): 1575–80

    PubMed  CAS  Google Scholar 

  37. Lang R, Hultner L, Lipford GB, et al. Guanosine-rich oligodeoxynucleotides induce proliferation of macrophage progenitors in cultures of murine bone marrow cells. Eur J Immunol 1999; 29 (11): 3496–506

    PubMed  CAS  Google Scholar 

  38. Lipford GB, Bendigs S, Heeg K, et al. Poly-guanosine motifs costimulate antigenreactive CD8 T cells while bacterial CpG-DNA affect T-cell activation via antigen-presenting cell-derived cytokines. Immunology 2000; 101 (1): 46–52

    PubMed  CAS  Google Scholar 

  39. Jurk M, Schulte B, Kritzler A, et al. C-Class CpG ODN: sequence requirements and characterization of immunostimulatory activities on mRNA level. Immunobiology 2004; 209: 141–54

    PubMed  CAS  Google Scholar 

  40. Hartmann G, Battiany J, Poeck H, et al. Rational design of new CpG oligonucleotides that combine B cell activation with high IFN-A induction in plasmacytoid dendritic cells. Eur J Immunol 2003; 33 (6): 1633–41

    PubMed  CAS  Google Scholar 

  41. Lenert P, Rasmussen W, Ashman RF, et al. 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 2003; 22 (10): 621–31

    PubMed  CAS  Google Scholar 

  42. Jurk M, Kritzler A, Schulte B, et al. Selective inhibition of Toll-like receptor mediated signalling by inhibitory oligodeoxyribonucleotides. Clin Invest Med 2005; 27: 2333

    Google Scholar 

  43. Duramad O, Fearon KL, Chang B, et al. Inhibitors of TLR-9 act on multiple cell subsets in mouse and man in vitro and prevent death in vivo from systemic inflammation. J Immunol 2005; 174 (9): 5193–200

    PubMed  CAS  Google Scholar 

  44. Gursel I, Gursel M, Yamada H, et al. Repetitive elements in mammalian telomeres suppress bacterial DNA-induced immune activation. J Immunol 2003; 171 (3): 1393–400

    PubMed  CAS  Google Scholar 

  45. Rutz M, Metzger J, Geliert T, et al. Toll-like receptor 9 binds single-stranded CpGDNA in a sequence- and pH-dependent manner. Eur J Immunol 2004; 34 (9): 2541–50

    PubMed  CAS  Google Scholar 

  46. Jurk M, Kritzler A, Schulte B, et al. Modulating responsiveness of human TLR7 and 8 to small molecule ligands with T-rich phosphorothiate oligodeoxynucleotides. Eur J Immunol 2006; 36 (7): 1815–26

    PubMed  CAS  Google Scholar 

  47. Gorden KK, Qiu X, Battiste JJ, et al. Oligodeoxynucleotides differentially modulate activation of TLR7 and TLR8 by imidazoquinolines. J Immunol 2006; 177 (11): 8164–70

    PubMed  CAS  Google Scholar 

  48. Klinman DM, Gursel I, Klaschik S, et al. Therapeutic potential of oligonucleotides expressing immunosuppressive TTAGGG motifs. Ann N Y Acad Sci 2005; 1058: 87–95

    PubMed  CAS  Google Scholar 

  49. Lenert P. Inhibitory oligodeoxynucleotides: therapeutic promise for systemic autoimmune diseases? Clin Exp Immunol 2005; 140 (1): 1–10

    PubMed  CAS  Google Scholar 

  50. Lenert P, Yi AK, Krieg AM, et al. Inhibitory oligonucleotides block the induction of AP-1 transcription factor by stimulatory CpG oligonucleotides in B cells. Antisense Nucleic Acid Drug Dev 2003; 13 (3): 143–50

    PubMed  CAS  Google Scholar 

  51. Shirota H, Gursel M, Klinman DM. Suppressive oligodeoxynucleotides inhibit Th1 differentiation by blocking IFN-γ- and IL-12-mediated signaling. J Immunol 2004; 173 (8): 5002–7

    PubMed  CAS  Google Scholar 

  52. Shirota H, Gursel I, Gursel M, et al. Suppressive oligodeoxynucleotides protect mice from lethal endotoxic shock. J Immunol 2005; 174 (8): 4579–83

    PubMed  CAS  Google Scholar 

  53. Vollmer J, Weeratna RD, Jurk M, et al. Oligodeoxynucleotides lacking CpG dinucleotides mediate Toll-like receptor 9 dependent T helper type 2 biased immune stimulation. Immunology 2004; 113 (2): 212–23

    PubMed  CAS  Google Scholar 

  54. Roberts TL, Sweet MJ, Hume DA, et al. Cutting edge: species-specific TLR9-mediated recognition of CpG and non-CpG phosphorothioate-modified oligonucleotides. J Immunol 2005; 174 (2): 605–8

    PubMed  CAS  Google Scholar 

  55. Wagner H, Bauer S. All is not Toll: new pathways in DNA recognition. J Exp Med 2006; 203 (2): 265–8

    PubMed  Google Scholar 

  56. Sano K, Shirota H, Terui T, et al. Oligodeoxynucleotides without CpG motifs work as adjuvant for the induction of Th2 differentiation in a sequence-independent manner. J Immunol 2003; 170 (5): 2367–73

    PubMed  CAS  Google Scholar 

  57. Yasuda K, Rutz M, Schlatter B, et al. CpG motif-independent activation of TLR9 upon endosomal translocation of ‘natural’ phosphodiester DNA. Eur J Immunol 2006; 36 (2): 431–6

    PubMed  CAS  Google Scholar 

  58. Ishii KJ, Coban C, Kato H, et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat Immunol 2006 Jan; 7 (1): 40–8

    PubMed  CAS  Google Scholar 

  59. Takaoka A, Wang Z, Choi MK, et al. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 2007; 448 (7152): 423–4

    Google Scholar 

  60. Latz E, Schoenemeyer A, Visintin A, et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol 2004 Feb; 5 (2): 190–8

    PubMed  CAS  Google Scholar 

  61. Latz E, Visintin A, Espevik T, et al. Mechanisms of TLR9 activation. J Endotoxin Res 2004; 10 (6): 406–12

    PubMed  CAS  Google Scholar 

  62. Zhao Q, Matson S, Herrera CJ, et al. Comparison of cellular binding and uptake of antisense phosphodiester, phosphorothioate, and mixed phosphorothioate and methylphosphonate oligonucleotides. Antisense Res Dev 1993; 3 (1): 53–66

    PubMed  CAS  Google Scholar 

  63. Temsamani J, Kubert M, Tang J, et al. Cellular uptake of oligodeoxynucleotide phosphorothioates and their analogs. Antisense Res Dev 1994; 4 (1): 35–42

    PubMed  CAS  Google Scholar 

  64. Dalpke AH, Zimmermann S, Albrecht I, et al. Phosphodiester CpG oligonucleotides as adjuvants: polyguanosine runs enhance cellular uptake and improve immunostimulative activity of phosphodiester CpG oligonucleotides in vitro and in vivo. Immunology 2002; 106 (1): 102–12

    PubMed  CAS  Google Scholar 

  65. Bartz H, Mendoza Y, Gebker M, et al. Poly-guanosine strings improve cellular uptake and stimulatory activity of phosphodiester CpG oligonucleotides in human leukocytes. Vaccine 2004; 23 (2): 148–55

    PubMed  CAS  Google Scholar 

  66. Vollmer J. TLR9 in health and disease. Int Rev Immunol 2006; 25 (3): 155–81

    PubMed  CAS  Google Scholar 

  67. Honda K, Yanai H, Negishi H, et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 2005 Apr 7; 434 (7034): 772–7

    PubMed  CAS  Google Scholar 

  68. Honda K, Yanai H, Mizutani T, et al. Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc Natl Acad Sci U S A 2004; 101 (43): 15416–21

    PubMed  CAS  Google Scholar 

  69. Honda K, Ohba Y, Yanai H, et al. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 2005 Apr 21; 434 (7036): 1035–40

    PubMed  CAS  Google Scholar 

  70. Brinkmann MM, Spooner E, Hoebe K, et al. The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling. J Cell Biol 2007; 177 (2): 265–75

    PubMed  CAS  Google Scholar 

  71. McCluskie MJ, Krieg AM. Enhancement of infectious disease vaccines through TLR9-dependent recognition of CpG DNA. Curr Top Microbiol Immunol 2006; 311: 155–78

    PubMed  CAS  Google Scholar 

  72. Wang H, Rayburn E, Zhang R. Synthetic oligodeoxynucleotides containing deoxycytidyl-deoxyguanosine dinucleotides (CpG ODNs) and modified analogs as novel anticancer therapeutics. Curr Pharm Des 2005; 11 (22): 2889–907

    PubMed  CAS  Google Scholar 

  73. Wilson HL, Dar A, Napper SK, et al. Immune mechanisms and therapeutic potential of CpG oligodeoxynucleotides. Int Rev Immunol 2006; 25 (3-4): 183–213

    PubMed  CAS  Google Scholar 

  74. Deng JC, Moore TA, Newstead MW, et al. CpG oligodeoxynucleotides stimulate protective innate immunity against pulmonary klebsiella infection. J Immunol 2004; 173 (8): 5148–55

    PubMed  CAS  Google Scholar 

  75. Gramzinski RA, Doolan DL, Sedegah M, et al. Interleukin-12- and gamma interferon-dependent protection against malaria conferred by CpG oligodeoxynucleotide in mice. Infect Immun 2001; 69 (3): 1643–9

    PubMed  CAS  Google Scholar 

  76. Ashkar AA, Bauer S, Mitchell WJ, et al. 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 2003; 77 (16): 8948–56

    PubMed  CAS  Google Scholar 

  77. Meng Y, Carpentier AF, Chen L, et al. Successful combination of local CpG-ODN and radiotherapy in malignant glioma. Int J Cancer 2005; 116 (6): 992–7

    PubMed  CAS  Google Scholar 

  78. Sharma S, Karakousis CP, Takita H, et al. Cytokines and chemokines are expressed at different levels in small and large murine colon-26 tumors following intratumoral injections of CpG ODN. Neoplasia 2004; 6 (5): 523–8

    PubMed  CAS  Google Scholar 

  79. Furumoto K, Soares L, Engleman EG, et al. Induction of potent antitumor immunity by in situ targeting of intratumoral DCs. J Clin Invest 2004; 113 (5): 774–83

    PubMed  CAS  Google Scholar 

  80. Carpentier AF, Xie J, Mokhtari K, et al. Successful treatment of intracranial gliomas in rat by oligodeoxynucleotides containing CpG motifs. Clin Cancer Res 2000; 6 (6): 2469–73

    PubMed  CAS  Google Scholar 

  81. Lonsdorf AS, Kuekrek H, Stern BV, et al. Intratumor CpG-oligodeoxynucleotide injection induces protective antitumor T cell immunity. J Immunol 2003; 171 (8): 3941–6

    PubMed  CAS  Google Scholar 

  82. Wang XS, Sheng Z, Ruan YB, et al. CpG oligodeoxynucleotides inhibit tumor growth and reverse the immunosuppression caused by the therapy with 5-fluorouracil in murine hepatoma. World J Gastroenterol 2005; 11 (8): 1220–4

    PubMed  CAS  Google Scholar 

  83. Krepier C, Wacheck V, Strommer S, et al. CpG oligonucleotides elicit antitumor responses in a human melanoma NOD/SCID xenotransplantation model. J Invest Dermatol 2004; 122 (2): 387–91

    Google Scholar 

  84. Kunikata N, Sano K, Honda M, et al. Peritumoral CpG oligodeoxynucleotide treatment inhibits tumor growth and metastasis of B16F10 melanoma cells. J Invest Dermatol 2004; 123 (2): 395–402

    PubMed  CAS  Google Scholar 

  85. Heckelsmiller K, Rall K, Beck S, et al. Peritumoral CpG DNA elicits a coordinated response of CD8 T cells and innate effectors to cure established tumors in a murine colon carcinoma model. J Immunol 2002; 169 (7): 3892–9

    PubMed  CAS  Google Scholar 

  86. Kawarada Y, Ganss R, Garbi N, et al. NK- and CD8 (+) T cell-mediated eradication of established tumors by peritumoral injection of CpG-containing oligodeoxynucleotides. J Immunol 2001; 167 (9): 5247–53

    PubMed  CAS  Google Scholar 

  87. Sfondrini L, Besusso D, Zoia MT, et al. Absence of the CD1 molecule up-regulates antitumor activity induced by CpG oligodeoxynucleotides in mice. J Immunol 2002; 169 (1): 151–8

    PubMed  CAS  Google Scholar 

  88. Krieg AM. Antitumor applications of stimulating toll-like receptor 9 with CpG oligodeoxynucleotides. Curr Oncol Rep 2004; 6 (2): 88–95

    PubMed  Google Scholar 

  89. Carpentier AF, Chen L, Maltonti F, et al. Oligodeoxynucleotides containing CpG motifs can induce rejection of a neuroblastoma in mice. Cancer Res 1999; 59 (21): 5429–32

    PubMed  CAS  Google Scholar 

  90. Baines J, Celis E. Immune-mediated tumor regression induced by CpG-containing oligodeoxynucleotides. Clin Cancer Res 2003; 9 (7): 2693–700

    PubMed  CAS  Google Scholar 

  91. Krieg AM, Efler SM, Wittpoth M, et al. 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 2004; 27 (6): 460–71

    PubMed  CAS  Google Scholar 

  92. Wingender G, Garbi N, Schumak B, et al. Systemic application of CpG-rich DNA suppresses adaptive T cell immunity via induction of IDO. Eur J Immunol 2006 Jan; 36 (1): 12–20

    PubMed  CAS  Google Scholar 

  93. Hayashi T, Beck L, Rossetto C, et al. Inhibition of experimental asthma by indoleamine 2,3-dioxygenase. J Clin Invest 2004; 114 (2): 270–9

    PubMed  CAS  Google Scholar 

  94. Dvorchik BH. The disposition (ADME) of antisense oligonucleotides. Curr Opin Mol Ther 2000; 2 (3): 253–7

    PubMed  CAS  Google Scholar 

  95. Noll BO, McCluskie MJ, Sniatala T, et al. Biodistribution and metabolism of immunostimulatory oligodeoxynucleotide CPG 7909 in mouse and rat tissues following subcutaneous administration. Biochem Pharmacol 2005; 69 (6): 981–91

    PubMed  CAS  Google Scholar 

  96. Levin AA. A review of the issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides. Biochim Biophys Acta 1999; 1489 (1): 69–84

    PubMed  CAS  Google Scholar 

  97. Geary RS, Leeds JM, Henry SP, et al. Antisense oligonucleotide inhibitors for the treatment of cancer: I. Pharmacokinetic properties of phosphorothioate oligodeoxynucleotides. Anticancer Drug Des 1997; 12 (5): 383–93

    PubMed  CAS  Google Scholar 

  98. Henry SP, Taylor J, Midgley L, et al. Evaluation of the toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a 4-week study in CD-I mice. Antisense Nucleic Acid Drug Dev 1997; 7 (5): 473–81

    PubMed  CAS  Google Scholar 

  99. Sparwasser T, Miethke T, Lipford G, et al. Bacterial DNA causes septic shock. Nature 1997; 386 (6623): 336–7

    PubMed  CAS  Google Scholar 

  100. Heikenwalder M, Polymenidou M, Junt T, et al. Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nat Med 2004

  101. Uhlmann E, Vollmer J. Recent advances in the development of immunostimulatory oligonucleotides. Curr Opin Drug Discov Devel 2003; 6 (2): 204–17

    PubMed  CAS  Google Scholar 

  102. Leadbetter EA, Rifkin IR, Hohlbaum AM, et al. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 2002; 416 (dy6881): 603–7

    PubMed  CAS  Google Scholar 

  103. Hasegawa K, Hayashi T. Synthetic CpG oligodeoxynucleotides accelerate the development of lupus nephritis during preactive phase in NZB × NZWF1 mice. Lupus 2003; 12 (11): 838–45

    PubMed  CAS  Google Scholar 

  104. Obermeier F, Dunger N, Deml L, et al. CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice. Eur J Immunol 2002; 32 (7): 2084–92

    PubMed  CAS  Google Scholar 

  105. Ichikawa HT, Williams LP, Segal BM. Activation of APCs through CD40 or Tolllike receptor 9 overcomes tolerance and precipitates autoimmune disease. J Immunol 2002; 169 (5): 2781–7

    PubMed  CAS  Google Scholar 

  106. Ronaghy A, Prakken BJ, Takabayashi K, et al. Immunostimulatory DNA sequences influence the course of adjuvant arthritis. J Immunol 2002; 168 (1): 51–6

    PubMed  CAS  Google Scholar 

  107. Katakura K, Lee J, Rachmilewitz D, et al. Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. J Clin Invest 2005; 115 (3): 695–702

    PubMed  CAS  Google Scholar 

  108. Boule MW, Broughton C, Mackay F, et al. Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin-immunoglobulin G complexes. J Exp Med 2004; 199 (12): 1631–40

    PubMed  CAS  Google Scholar 

  109. Christensen SR, Kashgarian M, Alexopoulou L, et al. Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J Exp Med 2005; 202 (2): 321–31

    PubMed  CAS  Google Scholar 

  110. Klinman DM. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nature Reviews 2004; 4: 1–10

    Google Scholar 

  111. Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 2002; 20: 709–60

    PubMed  CAS  Google Scholar 

  112. Dittmer U, Olbrich AR. Treatment of infectious diseases with immunostimulatory oligodeoxynucleotides containing CpG motifs. Curr Opin Microbiol 2003; 6 (5): 472–7

    PubMed  CAS  Google Scholar 

  113. Slotta JE, Scheuer C, Menger MD, et al. Immunostimulatory CpG-oligodeoxynucleotides (CpG-ODN) induce early hepatic injury, but provide a late window for protection against endotoxin-mediated liver damage. J Hepatol 2006 Mar; 44 (3): 576–85

    PubMed  CAS  Google Scholar 

  114. Rice L, Orlow D, Ceonzo K, et al. CpG oligodeoxynucleotide protection in polymicrobial sepsis is dependent on interleukin-17. J Infect Dis 2005; 191 (8): 1367–75

    Google Scholar 

  115. He H, Lowry VK, Swaggerty CL, et al. In vitro activation of chicken leukocytes and in vivo protection against Salmonella enteritidis organ invasion and peritoneal S. enteritidis infection-induced mortality in neonatal chickens by immunostimulatory CpG oligodeoxynucleotide. FEMS Immunol Med Microbiol 2005; 43 (1): 81–9

    PubMed  CAS  Google Scholar 

  116. Gomis S, Babiuk L, Allan B, et al. Protection of neonatal chicks against a lethal challenge of Escherichia coli using DNA containing cytosine-phosphodiesterguanine motifs. Avian Dis 2004; 48 (4): 813–22

    PubMed  Google Scholar 

  117. Nichani AK, Mena A, Kaushik RS, et al. Stimulation of innate immune responses by CpG oligodeoxynucleotide in newborn lambs can reduce bovine herpesvirus-1 shedding. Oligonucleotides 2006; 16 (1): 58–67

    PubMed  CAS  Google Scholar 

  118. Nichani AK, Kaushik RS, Mena A, et al. CpG oligodeoxynucleotide induction of antiviral effector molecules in sheep. Cell Immunol 2004; 227 (1): 24–37

    PubMed  CAS  Google Scholar 

  119. Flynn B, Wang V, Sacks DL, et al. Prevention and treatment of cutaneous leishmaniasis in primates by using synthetic type D/A oligodeoxynucleotides expressing CpG motifs. Infect Immun 2005; 73 (8): 4948–54

    PubMed  CAS  Google Scholar 

  120. Teleshova N, Kenney J, Jones J, et al. CpG-C immunostimulatory oligodeoxyribonucleotide activation of plasmacytoid dendritic cells in rhesus macaques to augment the activation of IFN-gamma-secreting simian immunodeficiency virus-specific T cells. J Immunol 2004; 173 (3): 1647–57

    PubMed  CAS  Google Scholar 

  121. Wang Y, Abel K, Lantz K, et al. The Toll-like receptor 7 (TLR7) agonist, imiquimod, and the TLR9 agonist, CpG ODN, induce antiviral cytokines and chemokines but do not prevent vaginal transmission of simian immunodeficiency virus when applied intravaginally to rhesus macaques. J Virol 2005; 79 (22): 14355–70

    PubMed  CAS  Google Scholar 

  122. Jorgensen JB, Johansen LH, Steiro K, et al. CpG DNA induces protective antiviral immune responses in Atlantic salmon (Salmo salar L.). J Virol 2003; 77 (21): 11471–9

    PubMed  CAS  Google Scholar 

  123. Strandskog G, Ellingsen T, Jorgensen JB. Characterization of three distinct CpG oligonucleotide classes which differ in ability to induce IFN alpha/beta activity and cell proliferation in Atlantic salmon (Salmo salar L.) leukocytes. Dev Comp Immunol 2007; 31 (1): 39–51

    PubMed  Google Scholar 

  124. Krieg AM, Love-Homan L, Yi AK, et al. CpG DNA induces sustained IL-12 expression in vivo and resistance to Listeria monocytogenes challenge. J Immunol 1998; 161 (5): 2428–34

    PubMed  CAS  Google Scholar 

  125. Elkins KL, Rhinehart-Jones TR, Stibitz S, et al. Bacterial DNA containing CpG motifs stimulates lymphocyte-dependent protection of mice against lethal infection with intracellular bacteria. J Immunol 1999; 162 (4): 2291–8

    PubMed  CAS  Google Scholar 

  126. Ishii KJ, Ito S, Tamura T, et al. CpG-activated Thyl.2+ dendritic cells protect against lethal Listeria monocytogenes infection. Eur J Immunol 2005; 35 (8): 2397–405

    PubMed  CAS  Google Scholar 

  127. Lugo-Villarino G, Ito S, Klinman DM, et al. The adjuvant activity of CpG DNA requires T-bet expression in dendritic cells. Proc Natl Acad Sci U S A 2005; 102 (37): 13248–53

    PubMed  CAS  Google Scholar 

  128. Juffermans NP, Leemans JC, Florquin S, et al. CpG oligodeoxynucleotides enhance host defense during murine tuberculosis. Infect Immun 2002; 70 (1): 147–52

    PubMed  CAS  Google Scholar 

  129. Waag DM, McCluskie MJ, Zhang N, et al. A CpG oligonucleotide can protect mice from a low aerosol challenge dose of Burkholderia mallei. Infect Immun 2006; 74 (3): 1944–8

    PubMed  CAS  Google Scholar 

  130. Zimmermann S, Egeter O, Hausmann S, et al. CpG oligodeoxynucleotides trigger protective and curative Thl responses in lethal murine leishmaniasis. J Immunol 1998; 160 (8): 3627–30

    PubMed  CAS  Google Scholar 

  131. Verthelyi D, Gursel M, Kenney RT, et al. CpG oligodeoxynucleotides protect normal and SIV-infected macaques from Leishmania infection. J Immunol 2003; 170 (9): 4717–23

    PubMed  CAS  Google Scholar 

  132. Klinman DM, Conover J, Coban C. Repeated administration of synthetic oligodeoxynucleotides expressing CpG motifs provides long-term protection against bacterial infection. Infect Immun 1999; 67 (11): 5658–63

    PubMed  CAS  Google Scholar 

  133. Rees DG, Gates AJ, Green M, et al. CpG-DNA protects against a lethal orthopoxvirus infection in a murine model. Antiviral Res 2005; 65 (2): 87–95

    PubMed  CAS  Google Scholar 

  134. Kamstrup S, Frimann TH, Barfoed AM. Protection of Balb/c mice against infection with FMDV by immunostimulation with CpG oligonucleotides. Antiviral Res 2006; 72 (1): 42–8

    PubMed  CAS  Google Scholar 

  135. Olbrich AR, Schimmer S, Heeg K, et al. Effective postexposure treatment of retrovirus-induced disease with immunostimulatory DNA containing CpG motifs. J Virol 2002; 76 (22): 11397–404

    PubMed  CAS  Google Scholar 

  136. Kraft AR, Arndt T, Hasenkrug KJ, et al. Effective treatment of retrovirus-induced suppression of antibody responses with CpG oligodeoxynucleotides. J Gen Virol 2005; 86 (Pt 12): 3365–8

    PubMed  CAS  Google Scholar 

  137. Olbrich AR, Schimmer S, Dittmer U. Preinfection treatment of resistant mice with CpG oligodeoxynucleotides renders them susceptible to friend retrovirus-induced leukemia. J Virol 2003; 77 (19): 10658–62

    PubMed  CAS  Google Scholar 

  138. Dong L, Mori I, Hossain MJ, et al. An immunostimulatory oligodeoxynucleotide containing a cytidine-guanosine motif protects senescence-accelerated mice from lethal influenza virus by augmenting the T helper type 1 response. J Gen Virol 2003; 84 (Pt 6): 1623–8

    PubMed  CAS  Google Scholar 

  139. Abe T, Takahashi H, Hamazaki H, et al. Baculovirus induces an innate immune response and confers protection from lethal influenza virus infection in mice. J Immunol 2003; 171 (3): 1133–9

    PubMed  CAS  Google Scholar 

  140. Abe T, Hemmi H, Miyamoto H, et al. Involvement of the Toll-like receptor 9 signaling pathway in the induction of innate immunity by baculovirus. J Virol 2005; 79 (5): 2847–58

    PubMed  CAS  Google Scholar 

  141. Pedras-Vasconcelos JA, Goucher D, Puig M, et al. CpG oligodeoxynucleotides protect newborn mice from a lethal challenge with the neurotropic Tacaribe arenavirus. J Immunol 2006; 176 (8): 4940–9

    PubMed  CAS  Google Scholar 

  142. Harandi AM. The potential of immunostimulatory CpG DNA for inducing immunity against genital herpes: opportunities and challenges. J Clin Virol 2004; 30 (3): 207–10

    PubMed  CAS  Google Scholar 

  143. Pyles RB, Higgins D, Chalk C, et al. Use of immunostimulatory sequencecontaining oligonucleotides as topical therapy for genital herpes simplex virus type 2 infection. J Virol 2002; 76 (22): 11387–96

    PubMed  CAS  Google Scholar 

  144. McCluskie MJ, Cartier JL, Patrick AJ, et al. Treatment of intravaginal HSV-2 infection in mice: a comparison of CpG oligodeoxynucleotides and resiquimod (R-848). Antiviral Res 2006; 69 (2): 77–85

    PubMed  CAS  Google Scholar 

  145. Harandi AM, Eriksson K, Holmgren J. A protective role of locally administered immunostimulatory CpG oligodeoxynucleotide in a mouse model of genital herpes infection. J Virol 2003; 77 (2): 953–62

    PubMed  CAS  Google Scholar 

  146. Shen H, Iwasaki A. A crucial role for plasmacytoid dendritic cells in antiviral protection by CpG ODN-based vaginal microbicide. J Clin Invest 2006; 116 (8): 2237–43

    PubMed  CAS  Google Scholar 

  147. Li N, Fan XG, Chen ZH, et al. Inhibition of the hepatitis B virus replication in vitro by an oligodeoxynucleotide containing cytidine-guanosine motifs. Immunol Lett 2006; 102 (1): 60–6

    PubMed  CAS  Google Scholar 

  148. Li N, Fan XG, Chen ZH, et al. Anti-HBV effects of CpG oligodeoxynucleotideactivated peripheral blood mononuclear cells from patients with chronic hepatitis B. APMIS 2005; 113 (10): 647–54

    PubMed  CAS  Google Scholar 

  149. Isogawa M, Robek MD, Furuichi Y, et al. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J Virol 2005; 79 (11): 7269–72

    PubMed  CAS  Google Scholar 

  150. Schlaepfer E, Audige A, von Beust B, et al. CpG oligodeoxynucleotides block human immunodeficiency virus type 1 replication in human lymphoid tissue infected ex vivo. J Virol 2004; 78 (22): 12344–54

    PubMed  CAS  Google Scholar 

  151. Saez R, Echaniz P, de Juan MD, et al. HIV-infected progressors and long-term nonprogressors differ in their capacity to respond to an A-class CpG oligodeoxynucleotide. AIDS 2005; 19 (16): 1924–5

    PubMed  CAS  Google Scholar 

  152. Gurney KB, Colantonio AD, Blom B, et al. Endogenous IFN-alpha production by plasmacytoid dendritic cells exerts an antiviral effect on thymic HIV-1 infection. J Immunol 2004; 173 (12): 7269–76

    PubMed  CAS  Google Scholar 

  153. Equils O, Schito ML, Karahashi H, 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 2003; 170 (10): 5159–64

    PubMed  CAS  Google Scholar 

  154. McHutchison JG, Bacon BR. Chronic hepatitis C: an age wave of disease burden. Am J Manag Care 2005; 11 (10 Suppl.): S286–95

    PubMed  Google Scholar 

  155. McHutchison JG. Understanding hepatitis C. Am J Manag Care 2004; 10 (2 Suppl.): S21–9

    PubMed  Google Scholar 

  156. Link BK, Ballas ZK, Weisdorf D, et al. Oligodeoxynucleotide CpG 7909 delivered as intravenous infusion demonstrates immunologic modulation in patients with previously treated non-hodgkin lymphoma. J Immunother 2006; 29 (5): 558–68

    PubMed  CAS  Google Scholar 

  157. Leichman G, Gravenor D, Woytowitz D, et al. CPG 7909, a TLR9 agonist, added to first line taxane/platinum for advanced non-small cell lung cancer, a randomized, controlled phase II study [abstract]. J Clin Oncol 2005; 23 (16 Suppl.): 7039

    Google Scholar 

  158. van den Eertwegh AJ, Lensen RJ, Scheper RJ, et al. Autologous tumor cell vaccination with PF-3512676 (CPG 7909) and GM-CSF followed by subcutaneous PF-3512676 and IFN-alpha for patients with metastatic renal cell carcinoma [abstract]. J Clin Oncol 2006; 24 (18 Suppl.): 2530

    Google Scholar 

  159. Thompson JA, Kuzel T, Bukowski R, et al. Phase Ib trial of a targeted TLR9 CpG immunomodulator (CPG 7909) in advanced renal cell carcinoma (RCC) [abstract]. J Clin Oncol 2004; 22 (14 Suppl.): 4644

    Google Scholar 

  160. Kim Y, Girardi M, McAuley S, et al. Cutaneous T-cell lymphoma (CTCL) responses to a TLR9 agonist CPG immunomodulator (CPG 7909), a phase I study [abstract]. J Clin Oncol 2004; 22 (14 Suppl.): 6600

    Google Scholar 

  161. Wagner S, Weber J, Redman B, et al. CPG 7909, a TLR9 agonist immunomodulator in metastatic melanoma: a randomized phase II trial comparing two doses and in combination with DTIC [abstract]. J Clin Oncol 2005; 23 (16 Suppl.): 7526

    Google Scholar 

  162. Friedberg JW, Freedman AS. Antibody and immunomodulatory agents in treatment of indolent non-Hodgkin’s lymphoma. Curr Treat Options Oncol 2006; 7 (4): 276–84

    PubMed  Google Scholar 

  163. Carpentier A, Laigle-Donadey F, Zohar S, et al. Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma. Neuro Oncol 2006; 8 (1): 60–6

    PubMed  CAS  Google Scholar 

  164. Switaj T, Lasek W. Technology evaluation: HYB-2055, Hybridon. Curr Opin Mol Ther 2005; 7 (4): 376–83

    PubMed  CAS  Google Scholar 

  165. vanOjik HH, Kruit W, Portielje J, et al. Phase I/II study with CpG 7909 as adjuvant to vaccination with MAGE-3 protein in patients with MAGE-3 positive tumors. Ann Oncol 2002; 13: 157

    Google Scholar 

  166. Cooper CL, Davis HL, Angel JB, et al. CPG 7909 adjuvant improves hepatitis B virus vaccine seroprotection in antiretroviral-treated HIV-infected adults. AIDS 2005; 19 (14): 1473–9

    PubMed  CAS  Google Scholar 

  167. Cooper CL, Davis HL, Morris ML, 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 2004 Nov; 24 (6): 693–701

    PubMed  CAS  Google Scholar 

  168. Cooper CL, Davis HL, Morris ML, et al. CPG 7909, an immunostimulatory TLR9 agonist oligodeoxynucleotide, as adjuvant to Engerix-B ( (R)) HBV vaccine in healthy adults: a double-blind phase I/II study. J Clin Immunol 2004; 24 (6): 693–701

    PubMed  CAS  Google Scholar 

  169. Halperin SA, Dobson S, McNeil S, 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 2006; 24 (1): 20–6

    PubMed  CAS  Google Scholar 

  170. Halperin SA, Van Nest G, Smith B, 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 2003; 21 (19-20): 2461–7

    PubMed  CAS  Google Scholar 

  171. Mason KA, Neal R, Hunter N, et al. CpG oligodeoxynucleotides are potent enhancers of radio- and chemoresponses of murine tumors. Radiother Oncol 2006; 80 (2): 192–8

    PubMed  CAS  Google Scholar 

  172. van der Most RG, Himbeck R, Aarons S, et al. Antitumor efficacy of the novel chemotherapeutic agent coramsine is potentiated by cotreatment with CpGcontaining oligodeoxynucleotides. J Immunother 2006; 29 (2): 134–42

    PubMed  Google Scholar 

  173. Weigel BJ, Rodeberg DA, Krieg AM, et al. CpG oligodeoxynucleotides potentiate the antitumor effects of chemotherapy or tumor resection in an orthotopic murine model of rhabdomyosarcoma. Clin Cancer Res 2003; 9 (8): 3105–14

    PubMed  CAS  Google Scholar 

  174. Balsari A, Tortoreto M, Besusso D, et al. Combination of a CpG-oligodeoxynucle-otide and a topoisomerase I inhibitor in the therapy of human tumour xenografts. Eur J Cancer 2004; 40 (8): 1275–81

    PubMed  CAS  Google Scholar 

  175. Mason KA, Ariga H, Neal R, et al. Targeting toll-like receptor 9 with CpG oligodeoxynucleotides enhances tumor response to fractionated radiotherapy. Clin Cancer Res 2005; 11 (1): 361–9

    PubMed  CAS  Google Scholar 

  176. Milas L, Mason KA, Ariga H, et al. CpG oligodeoxynucleotide enhances tumor response to radiation. Cancer Res 2004; 64 (15): 5074–7

    PubMed  CAS  Google Scholar 

  177. Koski GK, Czerniecki BJ. Combining innate immunity with radiation therapy for cancer treatment. Clin Cancer Res 2005; 11 (1): 7–11

    PubMed  CAS  Google Scholar 

  178. Gekeler V, Gimmnich P, Hofmann HP, et al. G3139 and other CpG-containing immunostimulatory phosphorothioate oligodeoxynucleotides are potent suppressors of the growth of human tumor xenografts in nude mice. Oligonucleotides 2006; 16 (1): 83–93

    PubMed  CAS  Google Scholar 

  179. Ballas ZK, Rasmussen WL, Krieg AM. Induction of NK activity in murine and human cells by CpG motifs in oligodeoxynucleotides and bacterial DNA. J Immunol 1996; 157 (5): 1840–5

    PubMed  CAS  Google Scholar 

  180. Auf G, Carpentier AF, Chen L, et al. Implication of macrophages in tumor rejection induced by CpG-oligodeoxynucleotides without antigen. Clin Cancer Res 2001; 7 (11): 3540–3

    PubMed  CAS  Google Scholar 

  181. Buhtoiarov IN, Lum H, Berke G, et al. CD40 ligation activates murine macrophages via an IFN-gamma-dependent mechanism resulting in tumor cell destruction in vitro. J Immunol 2005; 174 (10): 6013–22

    PubMed  CAS  Google Scholar 

  182. Buhtoiarov IN, Lum HD, Berke G, et al. Synergistic activation of macrophages via CD40 and TLR9 results in T cell independent antitumor effects. J Immunol 2006; 176 (1): 309–18

    PubMed  CAS  Google Scholar 

  183. Lum HD, Buhtoiarov IN, Schmidt BE, et al. In vivo CD40 ligation can induce T-cell-independent antitumor effects that involve macrophages. J Leukoc Biol 2006; 79 (6): 1181–92

    PubMed  CAS  Google Scholar 

  184. Lum HD, Buhtoiarov IN, Schmidt BE, et al. Tumoristatic effects of anti-CD40 mAb-activated macrophages involve nitric oxide and tumour necrosis factor-alpha. Immunology 2006; 118 (2): 261–70

    PubMed  CAS  Google Scholar 

  185. Jahrsdorfer B, Wooldridge JE, Blackwell SE, et al. Immunostimulatory oligodeoxynucleotides induce apoptosis of B cell chronic lymphocytic leukemia cells. J Leukoc Biol 2005; 77 (3): 378–87

    PubMed  Google Scholar 

  186. Jahrsdorfer B, Muhlenhoff L, Blackwell SE, et al. B-cell lymphomas differ in their responsiveness to CpG oligodeoxynucleotides. Clin Cancer Res 2005; 11 (4): 1490–9

    PubMed  CAS  Google Scholar 

  187. Pashenkov M, Goess G, Wagner C, et al. Phase II trial of a toll-like receptor 9-activating oligonucleotide in patients with metastatic melanoma. J Clin Oncol 2006; 24 (36): 5716–24

    PubMed  CAS  Google Scholar 

  188. Kim SK, Ragupathi G, Musselli C, 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 1999; 18 (7-8): 597–603

    PubMed  CAS  Google Scholar 

  189. Weeratna RD, Makinen SR, McCluskie MJ, et al. TLR agonists as vaccine adjuvants: comparison of CpG ODN and Resiquimod (R-848). Vaccine 2005; 23 (45): 5263–70

    PubMed  CAS  Google Scholar 

  190. Yasuda K, Yu P, Kirschning CJ, et al. Endosomal translocation of vertebrate DNA activates dendritic cells via TLR9-dependent and -independent pathways. J Immunol 2005; 174 (10): 6129–36

    PubMed  CAS  Google Scholar 

  191. Siegrist CA, Pihlgren M, Tougne C, et al. Co-administration of CpG oligonucleotides enhances the late affinity maturation process of human anti-hepatitis B vaccine response. Vaccine 2004; 23 (5): 615–22

    PubMed  CAS  Google Scholar 

  192. Davis HL, Suparto II, Weeratna RR, et al. CpG DNA overcomes hyporesponsiveness to hepatitis B vaccine in orangutans. Vaccine 2000; 18 (18): 1920–4

    PubMed  CAS  Google Scholar 

  193. Belardelli F, Ferrantini M, Parmiani G, et al. International meeting on cancer vaccines: how can we enhance efficacy of therapeutic vaccines? Cancer Res 2004; 64 (18): 6827–30

    PubMed  CAS  Google Scholar 

  194. Gendron KB, Rodriguez A, Sewell DA. Vaccination with human papillomavirus type 16 E7 peptide with CpG oligonucleotides for prevention of tumor growth in mice. Arch Otolaryngol Head Neck Surg 2006; 132 (3): 327–32

    PubMed  Google Scholar 

  195. Cornet S, Menez-Jamet J, Lemonnier F, et al. CpG oligodeoxynucleotides activate dendritic cells in vivo and induce a functional and protective vaccine immunity against a TERT derived modified cryptic MHC class I-restricted epitope. Vaccine 2006; 24 (11): 1880–8

    PubMed  CAS  Google Scholar 

  196. Miconnet I, Koenig S, Speiser D, et al. CpG are efficient adjuvants for specific CTL induction against tumor antigen-derived peptide. J Immunol 2002; 168 (3): 1212–8

    PubMed  CAS  Google Scholar 

  197. Wakita D, Chamoto K, Zhang Y, et al. An indispensable role of type-1 IFNs for inducing CTL-mediated complete eradication of established tumor tissue by CpG-liposome co-encapsulated with model tumor antigen. Int Immunol 2006; 18 (3): 425–34

    PubMed  CAS  Google Scholar 

  198. Speiser DE, Lienard D, Rufer N, et al. Rapid and strong human CD8 (+) T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J Clin Invest 2005 Mar; 115 (3): 739–46

    PubMed  CAS  Google Scholar 

  199. Appay V, Jandus C, Voelter V, et al. New generation vaccine induces effective melanoma-specific CD8+ T cells in the circulation but not in the tumor site. J Immunol 2006; 177 (3): 1670–8

    PubMed  CAS  Google Scholar 

  200. Daftarian P, Mansour M, Benoit AC, et al. Eradication of established HPV 16-expressing tumors by a single administration of a vaccine composed of a liposome-encapsulated CTL-T helper fusion peptide in a water-in-oil emulsion. Vaccine 2006; 24 (24): 5235–44

    PubMed  CAS  Google Scholar 

  201. Schneeberger A, Wagner C, Zemann A, et al. CpG motifs are efficient adjuvants for DNA cancer vaccines. J Invest Dermatol 2004; 123 (2): 371–9

    PubMed  CAS  Google Scholar 

  202. Prud’homme GJ. DNA vaccination against tumors. J Gene Med 2005; 7 (1): 3–17

    PubMed  Google Scholar 

  203. Lazarus R, Klimecki WT, Raby BA, et al. Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): frequencies, pairwise linkage disequilibrium, and haplotypes in three U.S. ethnic groups and exploratory case-control disease association studies (small star, filled). Genomics 2003; 81 (1): 85–91

    PubMed  CAS  Google Scholar 

  204. Noguchi E, Nishimura F, Fukai H, et al. An association study of asthma and total serum immunoglobin E levels for Toll-like receptor polymorphisms in a Japanese population. Clin Exp Allergy 2004; 34 (2): 177–83

    PubMed  CAS  Google Scholar 

  205. Berghofer B, Frommer T, Konig IR, et al. Common human Toll-like receptor 9 polymorphisms and haplotypes: association with atopy and functional relevance. Clin Exp Allergy 2005; 35 (9): 1147–54

    PubMed  CAS  Google Scholar 

  206. Erb KJ, Holloway JW, Sobeck A, et al. Infection of mice with Mycobacterium bovis-Bacillus Calmette-Guerin (BCG) suppresses allergen-induced airway eosinophilia. J Exp Med 1998; 187 (4): 561–9

    PubMed  CAS  Google Scholar 

  207. Koh YI, Choi IS, Kim WY. BCG infection in allergen-presensitized rats suppresses Th2 immune response and prevents the development of allergic asthmatic reaction. J Clin Immunol 2001; 21 (1): 51–9

    PubMed  CAS  Google Scholar 

  208. Kline JN. Effects of CpG DNA on Thl/Th2 balance in asthma. Curr Top Microbiol Immunol 2000; 247: 211–25

    PubMed  CAS  Google Scholar 

  209. Kline JN, Waldschmidt TJ, Businga TR, et al. Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J Immunol 1998; 160 (6): 2555–9

    PubMed  CAS  Google Scholar 

  210. Jain VV, Kitagaki K, Businga T, et al. CpG-oligodeoxynucleotides inhibit airway remodeling in a murine model of chronic asthma. J Allergy Clin Immunol 2002; 110 (6): 867–72

    PubMed  CAS  Google Scholar 

  211. Tighe H, Takabayashi K, Schwartz D, et al. Conjugation of immunostimulatory DNA to the short ragweed allergen amb a 1 enhances its immunogenicity and reduces its allergenicity. J Allergy Clin Immunol 2000; 106 (1 Pt 1): 124–34

    PubMed  CAS  Google Scholar 

  212. Hussain I, Kline JN. CpG oligodeoxynucleotides: a novel therapeutic approach for atopic disorders. Curr Drug Targets Inflamm Allergy 2003; 2 (3): 199–205

    PubMed  CAS  Google Scholar 

  213. Hessel EM, Chu M, Lizcano JO, et al. Immunostimulatory oligonucleotides block allergic airway inflammation by inhibiting Th2 cell activation and IgE-mediated cytokine induction. J Exp Med 2005; 202 (11): 1563–73

    PubMed  CAS  Google Scholar 

  214. Kulka M, Alexopoulou L, Flavell RA, et al. Activation of mast cells by doublestranded RNA: evidence for activation through Toll-like receptor 3. J Allergy Clin Immunol 2004; 114 (1): 174–82

    PubMed  CAS  Google Scholar 

  215. Fanucchi MV, Schelegle ES, Baker GL, et al. Immunostimulatory oligonucleotides attenuate airways remodeling in allergic monkeys. Am J Respir Crit Care Med 2004; 170 (11): 1153–7

    PubMed  Google Scholar 

  216. Gauvreau GM, Hessel EM, Boulet LP, et al. Immunostimulatory sequences regulate interferon-inducible genes but not allergic airway responses. Am J Respir Crit Care Med 2006; 174 (1): 15–20

    PubMed  CAS  Google Scholar 

  217. Simons FE, Shikishima Y, Van Nest G, et al. Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA. J Allergy Clin Immunol 2004; 113 (6): 1144–51

    PubMed  CAS  Google Scholar 

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The authors are employees of Coley Pharmaceutical GmbH and hold company stock options. No external sources of funding were used to assist in the preparation of this review.

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    Marion Jurk &  Jörg Vollmer

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Jurk, M., Vollmer, J. Therapeutic Applications of Synthetic CpG Oligodeoxynucleotides as TLR9 Agonists for Immune Modulation. BioDrugs 21, 387–401 (2007). https://doi.org/10.2165/00063030-200721060-00006

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