Therapeutic potential of Toll-like receptor 9 activation (original) (raw)
Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nature Immunol.5, 987–995 (2004). ArticleCAS Google Scholar
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). This report demonstrates that the ability of TLR9 to detect specifically viral but not self DNA is a consequence of TLR9's unusual intracellular localization. ArticleCAS Google Scholar
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). ArticleCAS Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
Liu, Y. J. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol.23, 275–306 (2005). ArticleCASPubMed Google Scholar
Hayashi, F., Means, T. K. & Luster, A. D. Toll-like receptors stimulate human neutrophil function. Blood102, 2660–2669 (2003). ArticleCASPubMed Google Scholar
Li, J. et al. CpG DNA-mediated immune response in pulmonary endothelial cells. Am. J. Physiol. Lung Cell Mol. Physiol.287, L552–L558 (2004). ArticleCASPubMed Google Scholar
Platz, J. et al. Microbial DNA induces a host defense reaction of human respiratory epithelial cells. J. Immunol.173, 1219–1223 (2004). ArticleCASPubMed Google Scholar
Asselin-Paturel, C. et al. Type I interferon dependence of plasmacytoid dendritic cell activation and migration. J. Exp. Med.201, 1157–1167 (2005). ArticleCASPubMedPubMed Central Google Scholar
Krieg, A. M. CpG motifs in bacterial DNA and their immune effects. Annu. Rev. Immunol.20, 709–760 (2002). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Bernasconi, N. L., Traggiai, E. & Lanzavecchia, A. Maintenance of serological memory by polyclonal activation of human memory B cells. Science298, 2199–2202 (2002). ArticleCASPubMed Google Scholar
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. Blood101, 4500–4504 (2003). ArticleCASPubMed Google Scholar
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). Building on their earlier studies (references 12 and 13) into the ability of CpG ODN to activate B cells and cooperate with B cell antigen receptor signaling, this paper reports a remarkably efficient method for generating human monoclonal antibodies. ArticleCASPubMed Google Scholar
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. Blood103, 3058–3064 (2004). ArticleCASPubMed Google Scholar
Krieg, A. M. et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature374, 546–549 (1995). ArticleCASPubMed Google Scholar
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). CASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). CASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMed Google Scholar
Muzio, M., Ni, J., Feng, P. & Dixit, V. M. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science278, 1612–1615 (1997). ArticleCASPubMed Google Scholar
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 (TRAF6). J. Exp. Med.187, 2097–2101 (1998). ArticleCASPubMedPubMed Central Google Scholar
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). Direct binding of TLR9 to CpG ODN has been reported by several groups but is still poorly understood. These investigators report binding to be at least partly sequence-specific under the low-pH conditions present in the endosome. ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Yi, A. K. & Krieg, A. M. Rapid induction of mitogen-activated protein kinases by immune stimulatory CpG DNA. J. Immunol.161, 4493–4497 (1998). CASPubMed Google Scholar
Takeshita, F. & Klinman, D. M. CpG ODN-mediated regulation of IL-12 p40 transcription. Eur. J. Immunol.30, 1967–1976 (2000). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Choudhury, B. K. et al. In vivo role of p38 mitogen-activated protein kinase in mediating the anti-inflammatory effects of CpG oligodeoxynucleotide in murine asthma. J. Immunol.169, 5955–5961 (2002). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). CASPubMed Google Scholar
Bauer, S. et al. Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc. Natl Acad. Sci. USA98, 9237–9242 (2001). The first paper showing a direct and species-specific interaction between TLR9 and different CpG motifs. ArticleCASPubMedPubMed Central Google Scholar
Latz, E. et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nature Immunol.5, 190–198 (2004). A major advance in providing the clearest understanding yet into the intracellular trafficking of TLR9, and its response to CpG ODN. ArticleCAS Google Scholar
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). CASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Pisetsky, D. S. & Reich, C. F., III. The influence of base sequence on the immunological properties of defined oligonucleotides. Immunopharmacology40, 199–208 (1998). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Vollmer, J. et al. Oligodeoxynucleotides lacking CpG dinucleotides mediate Toll-like receptor 9 dependent T helper type 2 biased immune stimulation. Immunology113, 212–223 (2004). TLR9 can respond to more than CpG; this paper demonstrates that some CpG-free ODN can activate TLR9, but induce a distinct profile of cytokine production, revealing an unexpected plasticity in TLR9 biology. ArticleCASPubMedPubMed Central Google Scholar
Vollmer, J. et al. Characterization of three CpG oligodeoxynucleotide classes with distinct immunostimulatory activities. Eur. J. Immunol.34, 251–262 (2004). Together with references 196 and 197 these three papers define the third class of CpG ODN, based on unique structural characteristics. ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Honda, K. et al. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature434, 1035–1040 (2005). This paper provides intriguing evidence that ODN structures with different biological properties have distinct intracellular distribution. ArticleCASPubMed Google Scholar
Uhlmann, E. & Vollmer, J. Recent advances in the development of immunostimulatory oligonucleotides. Curr. Opin. Drug Discov. Devel.6, 204–217 (2003). CASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Krieg, A. M., Guga, P. & Stec, W. P-chirality-dependent immune activation by phosphorothioate CpG oligodeoxynucleotides. Oligonucleotides13, 491–499 (2003). ArticleCASPubMed Google Scholar
Krieg, A. M. et al. Sequence motifs in adenoviral DNA block immune activation by stimulatory CpG motifs. Proc. Natl Acad. Sci. USA95, 12631–12636 (1998). ArticleCASPubMedPubMed Central Google Scholar
Yamada, H. et al. Effect of suppressive DNA on CpG-induced immune activation. J. Immunol.169, 5590–5594 (2002). ArticleCASPubMed Google Scholar
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 oligodeoxyribonucleotides at a site proximal to NF-kB activation. Antisense Nucleic Acid Drug Dev.11, 247–256 (2001). ArticleCASPubMed Google Scholar
Jurk, M. Selective inhibition of Toll-like receptor-mediated signalling by inhibitory oligodeoxynucleotides. Clin. Invest. Med.27, 2333 (2005). Google Scholar
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). ArticleCAS Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
Shirota, H., Gursel, M. & Klinman, D. M. Suppressive oligodeoxynucleotides inhibit Th1 differentiation by blocking IFN-γ- and IL-12-mediated signaling. J. Immunol.173, 5002–5007 (2004). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). CASPubMed Google Scholar
Levin, A. A., Henry, S. & Monteith, D. Antisense Drug Technology (ed. Crooke, S. T.) 201–267 (Marcel Dekker, New York, 2001). Google Scholar
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). ArticleCASPubMed Google Scholar
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). CASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
Zimmermann, S. et al. CpG oligodeoxynucleotides trigger protective and curative Th1 responses in lethal murine leishmaniasis. J. Immunol.160, 3627–3630 (1998). CASPubMed Google Scholar
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). CASPubMed Google Scholar
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). CASPubMedPubMed Central Google Scholar
Klinman, D. M., Verthelyi, D., Takeshita, F. & Ishii, K. J. Immune recognition of foreign DNA: a cure for bioterrorism? Immunity11, 123–129 (1999). ArticleCASPubMed Google Scholar
Rees, D. G. et al. CpG-DNA protects against a lethal orthopoxvirus infection in a murine model. Antiviral Res.65, 87–95 (2005). ArticleCASPubMed Google Scholar
Deng, J. C. et al. CpG oligodeoxynucleotides stimulate protective innate immunity against pulmonary Klebsiella infection. J. Immunol.173, 5148–5155 (2004). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
Klinman, D. M. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nature Rev. Immunol.4, 249–259 (2004). ArticleCAS Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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. USA96, 6970–6975 (1999). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMed Google Scholar
Olbrich, A. R. et al. Effective postexposure treatment of retrovirus-induced disease with immunostimulatory DNA containing CpG motifs. J. Virol.76, 11397–11404 (2002). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMed Google Scholar
Ishii, K. J. et al. CpG-activated Thy1.2+ dendritic cells protect against lethal Listeria monocytogenes infection. Eur. J. Immunol.35, 2397–2405 (2005). ArticleCASPubMed Google Scholar
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. USA102, 13248–13253 (2005). ArticleCASPubMedPubMed Central Google Scholar
Sajic, D. et al. Parameters of CpG oligodeoxynucleotide-induced protection against intravaginal HSV-2 challenge. J Med. Virol.71, 561–568 (2003). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
Verthelyi, D. et al. CpG oligodeoxynucleotides protect normal and SIV-infected macaques from Leishmania infection. J. Immunol.170, 4717–4723 (2003). ArticleCASPubMed Google Scholar
Rehermann, B. & Nascimbeni, M. Immunology of hepatitis B virus and hepatitis C virus infection. Nature Rev. Immunol.5, 215–229 (2005). ArticleCAS Google Scholar
McHutchison, J. G. et al. Relationships of HCV RNA responses to CPG 10101, a TLR9 agonist: pharmacodynamics &patient characteristics. Hepatology42, 249A (2005). Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMed Google Scholar
Agrawal, S. and Martin, R. R. Was induction of HIV1 through TLR9? J. Immunol.171, 1621 (2003). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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. AIDS19, 1924–1925 (2005). ArticleCASPubMed Google Scholar
Cooper, C. L. et al. CPG 7909 adjuvant improves hepatitis B virus vaccine seroprotection in antiretroviral-treated HIV-infected adults. AIDS19, 1473–1479 (2005). In this clinical trial a TLR9 agonist was shown to have strong vaccine adjuvant activity even in immune-compromised (HIV-infected) humans, extending the results of vaccine trials in normal volunteers (references 129 and 130). ArticleCASPubMed Google Scholar
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). CASPubMed Google Scholar
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). ArticleCAS Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). This report shows that CpG responses are severely suppressed in dendritic cells isolated from primary human tumours, but less so in the draining lymph nodes. CASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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. Vaccine18, 597–603 (2000). Article Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMed Google Scholar
Roman, M. et al. Immunostimulatory DNA sequences function as T helper-1-promoting adjuvants [see comments]. Nature Med.3, 849–854 (1997). ArticleCASPubMed Google Scholar
Weeratna, R. D., McCluskie, M. J., Xu, Y. & Davis, H. L. CpG DNA induces stronger immune responses with less toxicity than other adjuvants. Vaccine18, 1755–1762 (2000). ArticleCASPubMed Google Scholar
Sugai, T. et al. A CpG-containing oligodeoxynucleotide as an efficient adjuvant counterbalancing the Th1/Th2 immune response in diphtheria-tetanus-pertussis vaccine. Vaccine23, 5450–5456 (2005). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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. USA95, 15553–15558 (1998). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Schirmbeck, R. & Reimann, J. Modulation of gene-gun-mediated Th2 immunity to hepatitis B surface antigen by bacterial CpG motifs or IL-12. Intervirology44, 115–123 (2001). ArticleCASPubMed Google Scholar
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 oligodeoxynucleotides. Scand. J. Immunol.58, 350–357 (2003). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). CASPubMed Google Scholar
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. ArticleCASPubMed Google Scholar
Krieg, A. M. & Davis, H. L. Enhancing vaccines with immune stimulatory CpG DNA. Curr. Opin. Mol. Ther.3, 15–24 (2001). CASPubMed Google Scholar
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. Vaccine16, 1216–1224 (1998). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). CASPubMed Google Scholar
McCluskie, M. J. & Davis, H. L. Oral, intrarectal and intranasal immunizations using CpG and non-CpG oligodeoxynucleotides as adjuvants. Vaccine19, 413–422 (2001). Article Google Scholar
Kwant, A. & Rosenthal, K. L. Intravaginal immunization with viral subunit protein plus CpG oligodeoxynucleotides induces protective immunity against HSV-2. Vaccine22, 3098–3104 (2004). ArticleCASPubMed Google Scholar
Eastcott, J. W. et al. Oligonucleotide containing CpG motifs enhances immune response to mucosally or systemically administered tetanus toxoid. Vaccine19, 1636–1642 (2001). ArticleCASPubMed Google Scholar
McCluskie, M. J., Weeratna, R. D., Krieg, A. M. & Davis, H. L. CpG DNA is an effective oral adjuvant to protein antigens in mice. Vaccine19, 950–957 (2001). Article Google Scholar
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. Virology339, 153–163 (2005). ArticleCASPubMed Google Scholar
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. Vaccine23, 873–883 (2005). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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. Vaccine21, 2461–2467 (2003). References 129 and 130 show dramatic adjuvant activity of two different B-Class CpG ODN added to the hepatitis B surface antigen both alone and in combination with alum. ArticleCASPubMed Google Scholar
Siegrist, C. A. et al. Co-administration of CpG oligonucleotides enhances the late affinity maturation process of human anti-hepatitis B vaccine response. Vaccine23, 615–622 (2004). ArticleCASPubMed Google Scholar
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).
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). ArticleCASPubMed Google Scholar
Cooper, C. L. et al. Safety and Immunogenicity of CpG 7909 Injection as an Adjuvant to Fluarix Influenza Vaccine. Vaccine22, 3136–3143 (2004). ArticleCASPubMed Google Scholar
Kline, J. N. et al. Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J. Immunol.160, 2555–2559 (1998). CASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). Google Scholar
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). This clinical trial report demonstrates that the anti-allergic effects of CpG ODN are not limited to mice, but are also seen in humans. ArticleCASPubMed Google Scholar
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). Google Scholar
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). This is the first human clinical trial report of a CpG ODN added to a cancer vaccine, and shows that patients receiving the vaccine made a strong CD8 T-cell response to the tumour antigen. ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMed Google Scholar
Fanucchi, M. V. et al. Immunostimulatory oligonucleotides attenuate airways remodelling in allergic monkeys. Am. J. Respir. Crit. Care Med.170, 1153–1157 (2004). ArticlePubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Hayashi, T. et al. Inhibition of experimental asthma by indoleamine 2, 3-dioxygenase. J. Clin. Invest.114, 270–279 (2004). This detailed investigation into the mechanism of action of a CpG ODN in treating experimental asthma in a mouse model revealed new insights into the surprising anti-inflammatory role of TLR9 activation in the lung. See also references 175 and 176. ArticleCASPubMedPubMed Central Google Scholar
Krieg, A. M. Antitumor applications of stimulating Toll-like receptor 9 with CpG oligodeoxynucleotides. Curr. Oncol. Rep.6, 88–95 (2004). ArticlePubMed Google Scholar
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).
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. Blood105, 489–495 (2005). ArticleCASPubMed Google Scholar
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 orthotopic murine model of rhabdomyosarcoma. Clin. Cancer Res.9, 3105–3114 (2003). CASPubMed Google Scholar
Balsari, A. et al. Combination of a CpG-oligodeoxynucleotide and a topoisomerase I inhibitor in the therapy of human tumour xenografts. Eur. J. Cancer40, 1275–1281 (2004). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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. Cancer3 (Suppl.), 326 A1131 (2005). Google Scholar
Levin, A. A. A review of the issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides. Biochim. Biophys. Acta1489, 69–84 (1999). ArticleCASPubMed Google Scholar
Monteith, D. K. & Levin, A. A. Synthetic oligonucleotides: the development of antisense therapeutics. Toxicol. Pathol.27, 8–13 (1999). ArticleCASPubMed Google Scholar
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). CASPubMed Google Scholar
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). CASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Heikenwalder, M. et al. Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nature Med.10, 187–192 (2004). ArticleCASPubMed Google Scholar
Jason, T. L., Koropatnick, J. & Berg, R. W. Toxicology of antisense therapeutics. Toxicol. Appl. Pharmacol.201, 66–83 (2004). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). CASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Sheehan, J. P. & Lan, H. C. Phosphorothioate oligonucleotides inhibit the intrinsic tenase complex. Blood92, 1617–1625 (1998). CASPubMed Google Scholar
Krieg, A. M. CpG DNA: a pathogenic factor in systemic lupus erythematosus? J. Clin. Immunol.15, 284–292 (1995). ArticleCASPubMed Google Scholar
Hasegawa, K. & Hayashi, T. Synthetic CpG oligodeoxynucleotides accelerate the development of lupus nephritis during preactive phase in NZB x NZWF1 mice. Lupus12, 838–845 (2003). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Obermeier, F. et al. CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice. Eur. J. Immunol.32, 2084–2092 (2002). ArticleCASPubMed Google Scholar
Ronaghy, A. et al. Immunostimulatory DNA sequences influence the course of adjuvant arthritis. J. Immunol.168, 51–56 (2002). ArticleCASPubMed Google Scholar
Katakura, K. et al. Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. J. Clin. Invest.115, 695–702 (2005). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Mellor, A. L. et al. Cutting edge: CpG oligonucleotides induce splenic CD19+ 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). Together with reference 175, these studies reveal what seems to be an important counter-regulatory pathway that is induced by TLR9 agonists given systemically (intravenously) but not when the agonists are given via local routes. Further studies will be required to determine whether this effect is direct (as described by one of the investigators) or indirect (as reported by the other). ArticleCASPubMed Google Scholar
Chen, Y. et al. CpG DNA induces cyclooxygenase-2 expression and prostaglandin production. Int. Immunol.13, 1013–1020 (2001). ArticleCASPubMed Google Scholar
Ioannou, Y. & Isenberg, D. A. Current evidence for the induction of autoimmune rheumatic manifestations by cytokine therapy. Arthritis Rheum.43, 1431–1442 (2000). ArticleCASPubMed Google Scholar
Leadbetter, E. A. et al. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature416, 603–607 (2002). This seminal paper provided the first evidence that chromatin can activate TLR9, potentially triggering autoimmunity, as explored in further experiments from these and other investigators (references 180–183). Together, these studies point to potential therapeutic applications for TLR antagonists, which have been confirmed in references 184 and 185. ArticleCASPubMed Google Scholar
Viglianti, G. A. et al. Activation of autoreactive B cells by CpG dsDNA. Immunity19, 837–847 (2003). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
Christensen, S. R. et al. Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J. Exp. Med.202, 321–331 (2005). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
Dong, L., Ito, S., Ishii, K. J. & Klinman, D. M. Suppressive oligodeoxynucleotides delay the onset of glomerulonephritis and prolong survival in lupus-prone NZB x NZW mice. Arthritis Rheum.52, 651–658 (2005). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCAS Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Honda, K. et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature434, 772–777 (2005). ArticleCASPubMed Google Scholar
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. Immunity23, 465–478 (2005). ArticleCASPubMedPubMed Central Google Scholar
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. Immunity22, 467–477 (2005). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Marshall, J. D. et al. Novel chimeric immunomodulatory compounds containing short CpG oligodeoxyribonucleotides have differential activities in human cells. Nucleic Acids Res.31, 5122–5133 (2003). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Klinman, D. M. Use of CpG oligodeoxynucleotides as immunoprotective agents. Exp. Opin. Biol. Ther.4, 937–946 (2004). ArticleCAS Google Scholar
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. Oligonucleotides15, 119–131 (2005). ArticleCASPubMed Google Scholar
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). Book Google Scholar
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. Vaccine24, 20–26 (2006). ArticleCASPubMed Google Scholar
Lin, L., Gerth, A. J. & Peng, S. L. CpG DNA redirects class-switching towards 'Th1-like' Ig isotype production via TLR9 and MyD88. Eur. J. Immunol.34, 1483–1487 (2004). ArticleCASPubMed Google Scholar