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*
Loeb Research Institute, Ottawa Civic Hospital, Ottawa Canada;
Faculties of Health Sciences and Medicine, University of Ottawa, Canada;
Interdisciplinary Immunology Program and Department of Pathology, University of Iowa College of Medicine, Iowa City, IA 52242;
§
Qiagen GmbH, Hilden, Germany; and
¶
Interdisciplinary Immunology Program and Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA, 52242 and Veterans Affairs Medical Center, Iowa City, IA 52246.
Unmethylated CpG dinucleotides in bacterial DNA or synthetic
oligodeoxynucleotides (ODN) cause B cell proliferation and Ig
secretion, monocyte cytokine secretion, and activation of NK cell lytic
activity and IFN-
secretion in vivo and in vitro. The potent immune
activation by CpG ODN suggests possible utility for enhancing immune
responses to vaccines. Mice immunized with recombinant hepatitis B
virus surface Ag and a CpG ODN as an immune enhancer have titers of Abs
against HBsAg (anti-HBs) that are five times higher than those of
mice immunized with HBsAg and the standard adjuvant, aluminum hydroxide
(alum). Ab titers in mice immunized with HBsAg and both CpG ODN plus
alum were 35 times higher than the titers in mice immunized with alum
alone, indicating a strong synergistic interaction between the CpG ODN
and alum. ODN without CpG motifs had little or no immune-enhancing
activity at the doses used herein. Alum induces a Th2 humoral response
(mostly IgG1) and no CTL. In contrast, CpG ODN gives a strong Th1
response with predominantly IgG2a Abs and CTL, even when mixed with
alum. In vitro studies to determine possible mechanisms of CpG
immune-enhancing effects show that CpG ODN induce expression of
costimulatory molecules on Ag-presenting cells and drive B cell isotype
switching in the appropriate cytokine milieu. These studies demonstrate
that CpG ODN are promising new immune enhancers for vaccination
applications.
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G. J. Weiner The immunobiology and clinical potential of immunostimulatory CpG oligodeoxynucleotides J. Leukoc. Biol., October 1, 2000; 68(4): 455 - 463. [Abstract] [Full Text]
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S. W. Lee, M. K. Song, K. H. Baek, Y. Park, J. K. Kim, C. H. Lee, H.-K. Cheong, C. Cheong, and Y. C. Sung Effects of a Hexameric Deoxyriboguanosine Run Conjugation into CpG Oligodeoxynucleotides on Their Immunostimulatory Potentials J. Immunol., October 1, 2000; 165(7): 3631 - 3639. [Abstract] [Full Text] [PDF]
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W. Olszewska, C. D. Partidos, and M. W. Steward Antipeptide Antibody Responses following Intranasal Immunization: Effectiveness of Mucosal Adjuvants Infect. Immun., September 1, 2000; 68(9): 4923 - 4929. [Abstract] [Full Text] [PDF]
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T. Scharton-Kersten, J.-m. Yu, R. Vassell, D. O'Hagan, C. R. Alving, and G. M. Glenn Transcutaneous Immunization with Bacterial ADP-Ribosylating Exotoxins, Subunits, and Unrelated Adjuvants Infect. Immun., September 1, 2000; 68(9): 5306 - 5313. [Abstract] [Full Text] [PDF]
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P. A. Johnson, M. A. Conway, J. Daly, C. Nicolson, J. Robertson, and K. H. G. Mills Plasmid DNA encoding influenza virus haemagglutinin induces Th1 cells and protection against respiratory infection despite its limited ability to generate antibody responses J. Gen. Virol., July 1, 2000; 81(7): 1737 - 1745. [Abstract] [Full Text]
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E. Davila and E. Celis Repeated Administration of Cytosine-Phosphorothiolated Guanine-Containing Oligonucleotides Together with Peptide/Protein Immunization Results in Enhanced CTL Responses with Anti-Tumor Activity J. Immunol., July 1, 2000; 165(1): 539 - 547. [Abstract] [Full Text] [PDF]
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E. Ban, L. Dupre, E. Hermann, W. Rohn, C. Vendeville, B. Quatannens, P. Ricciardi-Castagnoli, A. Capron, and G. Riveau CpG motifs induce Langerhans cell migration in vivo Int. Immunol., June 1, 2000; 12(6): 737 - 745. [Abstract] [Full Text] [PDF]
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A. F. Carpentier, J. Xie, K. Mokhtari, and J.-Y. Delattre Successful Treatment of Intracranial Gliomas in Rat by Oligodeoxynucleotides Containing CpG Motifs Clin. Cancer Res., June 1, 2000; 6(6): 2469 - 2473. [Abstract] [Full Text]
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 J. He, S. Gurunathan, A. Iwasaki, B. Ash-Shaheed, and B. L. Kelsall Primary Role for GI Protein Signaling in the Regulation of Interleukin 12 Production and the Induction of T Helper Cell Type 1 Responses J. Exp. Med., May 1, 2000; 191(9): 1605 - 1610. [Abstract] [Full Text] [PDF]
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R. Schirmbeck, J. Wild, D. Stober, H. E. Blum, F. V. Chisari, M. Geissler, and J. Reimann Ongoing Murine T1 or T2 Immune Responses to the Hepatitis B Surface Antigen Are Excluded from the Liver that Expresses Transgene-Encoded Hepatitis B Surface Antigen J. Immunol., April 15, 2000; 164(8): 4235 - 4243. [Abstract] [Full Text] [PDF]
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R. S. Chu, T. McCool, N. S. Greenspan, J. R. Schreiber, and C. V. Harding CpG Oligodeoxynucleotides Act as Adjuvants for Pneumococcal Polysaccharide-Protein Conjugate Vaccines and Enhance Antipolysaccharide Immunoglobulin G2a (IgG2a) and IgG3 Antibodies Infect. Immun., March 1, 2000; 68(3): 1450 - 1456. [Abstract] [Full Text] [PDF]
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R. M. Vabulas, H. Pircher, G. B. Lipford, H. Hacker, and H. Wagner CpG-DNA Activates In Vivo T Cell Epitope Presenting Dendritic Cells to Trigger Protective Antiviral Cytotoxic T Cell Responses J. Immunol., March 1, 2000; 164(5): 2372 - 2378. [Abstract] [Full Text] [PDF]
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G. Hartmann, R. D. Weeratna, Z. K. Ballas, P. Payette, S. Blackwell, I. Suparto, W. L. Rasmussen, M. Waldschmidt, D. Sajuthi, R. H. Purcell, et al. Delineation of a CpG Phosphorothioate Oligodeoxynucleotide for Activating Primate Immune Responses In Vitro and In Vivo J. Immunol., February 1, 2000; 164(3): 1617 - 1624. [Abstract] [Full Text] [PDF]
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G. Hartmann and A. M. Krieg Mechanism and Function of a Newly Identified CpG DNA Motif in Human Primary B Cells J. Immunol., January 15, 2000; 164(2): 944 - 953. [Abstract] [Full Text] [PDF]
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M. G. Chiaramonte, M. Hesse, A. W. Cheever, and T. A. Wynn CpG Oligonucleotides Can Prophylactically Immunize Against Th2-Mediated Schistosome Egg-Induced Pathology by an IL-12-Independent Mechanism J. Immunol., January 15, 2000; 164(2): 973 - 985. [Abstract] [Full Text] [PDF]
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L.-Y. Huang, A. M. Krieg, N. Eller, and D. E. Scott Induction and Regulation of Th1-Inducing Cytokines by Bacterial DNA, Lipopolysaccharide, and Heat-Inactivated Bacteria Infect. Immun., December 1, 1999; 67(12): 6257 - 6263. [Abstract] [Full Text] [PDF]
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A.-K. Yi, D. W. Peckham, R. F. Ashman, and A. M. Krieg CpG DNA rescues B cells from apoptosis by activating NF{kappa}B and preventing mitochondrial membrane potential disruption via a chloroquine-sensitive pathway Int. Immunol., December 1, 1999; 11(12): 2015 - 2024. [Abstract] [Full Text] [PDF]
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A. F. Carpentier, L. Chen, F. Maltonti, and J.-Y. Delattre Oligodeoxynucleotides Containing CpG Motifs Can Induce Rejection of a Neuroblastoma in Mice Cancer Res., November 1, 1999; 59(21): 5429 - 5432. [Abstract] [Full Text] [PDF]
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A. Lobell, R. Weissert, S. Eltayeb, C. Svanholm, T. Olsson, and H. Wigzell Presence of CpG DNA and the Local Cytokine Milieu Determine the Efficacy of Suppressive DNA Vaccination in Experimental Autoimmune Encephalomyelitis J. Immunol., November 1, 1999; 163(9): 4754 - 4762. [Abstract] [Full Text] [PDF]
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R. J. Parks, J. L. Bramson, Y. Wan, C. L. Addison, and F. L. Graham Effects of Stuffer DNA on Transgene Expression from Helper-Dependent Adenovirus Vectors J. Virol., October 1, 1999; 73(10): 8027 - 8034. [Abstract] [Full Text] [PDF]
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S. Iho, T. Yamamoto, T. Takahashi, and S. Yamamoto Oligodeoxynucleotides Containing Palindrome Sequences with Internal 5'-CpG-3' Act Directly on Human NK and Activated T Cells to Induce IFN-{gamma} Production In Vitro J. Immunol., October 1, 1999; 163(7): 3642 - 3652. [Abstract] [Full Text] [PDF]
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J. Wild, M. J. Grusby, R. Schirmbeck, and J. Reimann Priming MHC-I-Restricted Cytotoxic T Lymphocyte Responses to Exogenous Hepatitis B Surface Antigen Is CD4+ T Cell Dependent J. Immunol., August 15, 1999; 163(4): 1880 - 1887. [Abstract] [Full Text] [PDF]
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S. A. Calarota, A.-C. Leandersson, G. Bratt, J. Hinkula, D. M. Klinman, K. J. Weinhold, E. Sandstrom, and B. Wahren Immune Responses in Asymptomatic HIV-1-Infected Patients After HIV-DNA Immunization Followed by Highly Active Antiretroviral Treatment J. Immunol., August 15, 1999; 163(4): 2330 - 2338. [Abstract] [Full Text] [PDF]
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G. Hartmann, G. J. Weiner, and A. M. Krieg CpG DNA: A potent signal for growth, activation, and maturation of human dendritic cells PNAS, August 3, 1999; 96(16): 9305 - 9310. [Abstract] [Full Text] [PDF]
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K. J. Stacey and J. M. Blackwell Immunostimulatory DNA as an Adjuvant in Vaccination against Leishmania major Infect. Immun., August 1, 1999; 67(8): 3719 - 3726. [Abstract] [Full Text] [PDF]
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M. M. Rodrigues, M. Ribeirao, V. Pereira-Chioccola, L. Renia, and F. Costa Predominance of CD4 Th1 and CD8 Tc1 Cells Revealed by Characterization of the Cellular Immune Response Generated by Immunization with a DNA Vaccine Containing a Trypanosoma cruzi Gene Infect. Immun., August 1, 1999; 67(8): 3855 - 3863. [Abstract] [Full Text] [PDF]
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R. S. Chu, D. Askew, E. H. Noss, A. Tobian, A. M. Krieg, and C. V. Harding CpG Oligodeoxynucleotides Down-Regulate Macrophage Class II MHC Antigen Processing J. Immunol., August 1, 1999; 163(3): 1188 - 1194. [Abstract] [Full Text] [PDF]
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R. Schirmbeck, K. Melber, and J. Reimann Adjuvants that enhance priming of cytotoxic T cells to a Kb-restricted epitope processed from exogenous but not endogenous hepatitis B surface antigen Int. Immunol., July 1, 1999; 11(7): 1093 - 1102. [Abstract] [Full Text] [PDF]
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D. A. Schwartz, C. L. Wohlford-Lenane, T. J. Quinn, and A. M. Krieg Bacterial DNA or Oligonucleotides Containing Unmethylated CpG Motifs Can Minimize Lipopolysaccharide-Induced Inflammation in the Lower Respiratory Tract Through an IL-12-Dependent Pathway J. Immunol., July 1, 1999; 163(1): 224 - 231. [Abstract] [Full Text] [PDF]
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 K. Bachmaier, N. Neu, L. M. de la Maza, S. Pal, A. Hessel, and J. M. Penninger Chlamydia Infections and Heart Disease Linked Through Antigenic Mimicry Science, February 26, 1999; 283(5406): 1335 - 1339. [Abstract] [Full Text]
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J. Kovarik, P. Bozzotti, L. Love-Homan, M. Pihlgren, H. L. Davis, P.-H. Lambert, A. M. Krieg, and C.-A. Siegrist CpG Oligodeoxynucleotides Can Circumvent the Th2 Polarization of Neonatal Responses to Vaccines But May Fail to Fully Redirect Th2 Responses Established by Neonatal Priming J. Immunol., February 1, 1999; 162(3): 1611 - 1617. [Abstract] [Full Text] [PDF]
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C. L. B. Millan, R. Weeratna, A. M. Krieg, C.-A. Siegrist, and H. L. Davis CpG DNA can induce strong Th1 humoral and cell-mediated immune responses against hepatitis B surface antigen in young mice PNAS, December 22, 1998; 95(26): 15553 - 15558. [Abstract] [Full Text] [PDF]
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S. Sun, X. Zhang, D. F. Tough, and J. Sprent Type I Interferon-mediated Stimulation of T Cells by CpG DNA J. Exp. Med., December 21, 1998; 188(12): 2335 - 2342. [Abstract] [Full Text] [PDF]
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H.-M. Liu, S. E. Newbrough, S. K. Bhatia, C. E. Dahle, A. M. Krieg, and G. J. Weiner Immunostimulatory CpG Oligodeoxynucleotides Enhance the Immune Response to Vaccine Strategies Involving Granulocyte-Macrophage Colony-Stimulating Factor Blood, November 15, 1998; 92(10): 3730 - 3736. [Abstract] [Full Text] [PDF]
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