Skip to main content
SpringerLink
Log in

Oligodeoxyribonucleotides with 5′-ACGT-3′ or 5′-TCGA-3′ Sequence Induce Production of Interferons

  • Chapter
Immunobiology of Bacterial CpG-DNA

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 247))

Abstract

More than 1 billion children in 182 countries throughout the world have been vaccinated with the Bacillus of Calmette and Guerin (BCG) against tuberculosis. BCG appears to be able to elicit protective cell-mediated immune responses in the absence of progressive disease. In addition, experimental uses of BCG and related mycobacteria have greatly contributed to the progress of modern immunology. Trials of cancer immunotherapy with BCG were carried out on a worldwide scale in the 1970s and contributed much information to the fields of basic and clinical immunology (Bast 1974). Evidence foreshadowing our finding of senseless immunostimulatory DNA was also obtained by the experimental use of BCG.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Anitescu M, Chase JH, Tueken B, Yi A-M, Berg DJ, Krieg AM, Cowdery JS (1997) Interleukin-10 functions in vitro and in vivo to inhibit bacterial DNA-induced secretion of interleukin-12. J Interferon Cytokine Res 17: 781–788

    Article  PubMed  CAS  Google Scholar 

  • Ballas ZK, Rasmussen WL, Krieg AM (1996) Induction of NK activity in murine and human cells by CpG motifs in oligodeoxynucleotides and bacterial DNA. J Immunol 157: 1840–1845

    PubMed  CAS  Google Scholar 

  • Bast RC, Zbar B, Borsos T, Rapp HJ (1974) BCG and cancer. New Engl J Med 290: 1413–1458

    Article  PubMed  Google Scholar 

  • Benimetskaya L, Loike JD, Khaled Z, Loike G, Silverman SC, Cao L, Khoury JE, Cai T-Q, Stein CA (1997) Mac-1 (CDI lb/CD18) is an oligonucleotide-binding protein. Nature Medicine 3: 414–420

    Article  PubMed  CAS  Google Scholar 

  • Bird AP (1986) CpG-rich islands and the function of DNA methylation. Nature 321: 209–213

    Article  PubMed  CAS  Google Scholar 

  • Boggs RL, McGraw K, Condon T, Flournoy S, Villiet P, Bennett CF, Monia BP (1997) Characterization and modulation of immune stimulation by modified oligonucleotides. Antisense Nucleic Acid Drug Develop 7: 461–471

    Article  CAS  Google Scholar 

  • Broide D, Schwarze J, Tighe H, Gifford T, Nguyen M-D, Malek S, Van Uden U, Martin-Orozco E, Gelfand EW, Raz E (1998) Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation, and airway hyperresponsiveness in mice. J Immunol 161: 7054–7062

    PubMed  CAS  Google Scholar 

  • Carson DA, Raz E (1997) Oligonucleotide adjuvants for Thelperl The-specific vaccination. J Exp Med 186: 1621–1622

    Article  PubMed  CAS  Google Scholar 

  • Chase JH, Hooker NA, Mildenstein KL, Krieg AM, Cowdery JS (1997) Bacterial DNA-induces NK cell IFN-y production is dependent on macrophage secretion of IL-12. Clin Immunol Immunother 84: 185–193

    Article  Google Scholar 

  • Chu RA, Targori O, Krieg AM, Lehmann PV, Harding CV (1997) CpG oligodeoxynucleotides act as adjuvants that switch on T helper 1 ( ThI) immunity. J Exp Med 186: 1623–1631

    Article  PubMed  CAS  Google Scholar 

  • Cowdery JS, Chase JH, Yi A-K, Krieg AM (1996) Bacterial DNA induces NK cells to produce IFN-y in vivo and increases the toxicity of lipopolysaccharides. J Immunol 156: 4570–4575

    PubMed  CAS  Google Scholar 

  • Dennis MK (1998) Therapeutic applications of CpG-containing oligodeoxynucleotides. Antisense Nucleic Acid Drug Develop 8: 181–184

    Article  Google Scholar 

  • Gregoriadis G (1998) Genetic vaccines: Strategies for optimization. Pharmaceut Res 15: 661–670

    Article  CAS  Google Scholar 

  • Halpern MD, Kurlander RJ, Pisetsky DS (1996) Bacterial DNA induces murine interferon-y production by stimulation of interleukin-12 and tumor necrosis factor-a. Cell Immunol 167: 72–78

    Article  PubMed  CAS  Google Scholar 

  • Ishihara K, Ikeda S, Arao T, Matsunaka M (1988) Pilot study on local administration of a new BRM, MY-1, for the treatment of malignant skin tumors. Skin Cancer 3: 273–281

    Article  Google Scholar 

  • Ishihara K, Ikeda S, Furue H (1990) Late phase-II clinical study on MY-I in the treatment of malignant skin tumors. Skin Cancer 5: 192–202

    Google Scholar 

  • Johno M, Arao T, Ishihara K (1991) Adult T-cell leukemia/lymphoma and mycosis fungoides responding well to MY-l. West Jpn Dermatol. 53: 1297–1306

    Google Scholar 

  • Krieg AM (1995) CpG DNA: A pathogenic factor in systemic lupus erythematosus? J Clin Immunol 15: 284–292

    Article  PubMed  CAS  Google Scholar 

  • Krieg AM (1996a) An innate immune defense mechanism based on the recognition of CpG motifs in microbial DNA. J Lab Clin Med 128: 128–133

    Article  PubMed  CAS  Google Scholar 

  • Krieg AM (1996b) Lymphocyte activation by CpG dinucleotide motifs in prokaryotic DNA. Trends Microbiol 4: 73–77

    Article  PubMed  CAS  Google Scholar 

  • Krieg AM, Love-Homan L, Yi A-M, Harty JT (1998) CpG DNA induces sustained IL-12 expression in vivo and resistance to Listeria monocytogenes challenge. J Immunol 161: 2428–2434

    PubMed  CAS  Google Scholar 

  • Krieg AM, Yi A-K, Matson S, Waldscmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 373: 546–549

    Article  Google Scholar 

  • Krieg AM, Yi A-M, Schorr J, Davis HL (1998) The role of CpG dinucleotides in DNA vaccines. Trends Microbiol 6: 23–27

    Article  PubMed  CAS  Google Scholar 

  • Kataoka T, Yamamoto S, Yamamoto T, Kuramoto E, Kimura Y, Tokunaga T (1992) Antitumor activity of synthetic oligonucleotides with sequences from cDNA encoding proteins of Mycobacterium bovis BCG. Jpn J Cancer Res 83: 244–247

    PubMed  CAS  Google Scholar 

  • Kimura Y, Sonehara K, Kuramoto E, Makino T, Yamamoto S, Yamamoto T, Kataoka T, Tokunaga T (1994) Binding of oligoguanylate to scavenger receptors is required for oligonucleotides to augment NK cell activity and induce IFN. J Biochem 116: 991–994

    PubMed  CAS  Google Scholar 

  • Kline JN, Waldschmidt TJ, Businga TR, Lemish JE, Weinstock JV, Thorne PS, Krieg AM (1998) Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J Immunol 160: 2555–2559

    PubMed  CAS  Google Scholar 

  • Klinman DM (1998) Therapeutic application of CpG-containing oligodeoxynucleotides. Antisense Nucleic Acid Drug Develop 8: 181–184

    Article  CAS  Google Scholar 

  • Klinman DM, Yamshchikov G, Ishigatsubo Y (1997) Contribution of CpG motifs to the immunogenicity of DNA vaccines. J Immunol 158: 3635–3639

    PubMed  CAS  Google Scholar 

  • Klinman DM, Yi A-K, Beaucaga SL, Conover J, Krieg AM (1996) CpG motifs present in bacterial DNA rapidly induce lymphocytes to secret interleukin 6, interleukin 12, and interferon y. Proc Natl Acad Sci USA. 93: 2879–2833

    Article  PubMed  CAS  Google Scholar 

  • Kuramoto E, Toizumi S, Shimada S, Tokunaga T (1989) In situ infiltration of natural killer-like cells induced by intradermal injection of the nucleic acid fraction from BCG. Microbiol Immunol 33: 929–940

    PubMed  CAS  Google Scholar 

  • Kuramoto E, Watanabe N, Iwata D, Yano O, Shimada S, Tokunaga T (1992) Changes of host cell infiltration into Meth A fibrosarcoma tumor during the course of regression induced by infections of a BCG nucleic acid fraction. Int J Immunopharmac 14: 773–782

    Article  CAS  Google Scholar 

  • Leclerc C, Deriaud E, Rojas M, Whalen RG (1997) The preferential induction of a Th 1 immune response by DNA-based immunization is mediated by the immunostimulatory effect of plasmid DNA. Cell Itmnunol 179: 97–106

    Article  CAS  Google Scholar 

  • Lipford GB, Beaure M, Blank C, Reiter R, Wagner H, Heeg K (1997) 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

    Article  PubMed  CAS  Google Scholar 

  • Lipford GB, Sparwasser T, Bauer M, Zimmermann S, Koch ES, Heeg KK, Wagner H (1997) Immunostimulatory DNA: sequence-dependent production of potentially harmful or useful cytokines. Eur J Immunol 27: 3420–3426

    Article  PubMed  CAS  Google Scholar 

  • Macfarlane DE, Manzel L, Krieg AM (1997) Unmethylated CpG-containing oligodeoxynucleotides inhibit apoptosis in WEHI 231 B lymphocytes induced by several agents: evidence for blockade of apoptosis at a distal signalling step. Immunology 91: 586–593

    Article  PubMed  CAS  Google Scholar 

  • Majima H, Nomura K (1986) Phase I clinical study of MY-1, A new biological response modifier. Jpn J Cancer Chemother 13: 109–115

    CAS  Google Scholar 

  • Mashiba H, Matsunaga K, Tomoda H, Furusawa M, Jimi S, Tokunaga T (1988) In vitro augmentation of natural killer activity of peripheral blood cells from cancer patients by a DNA fraction from Mycobacterium bovis BCG. Jpn J Med Sci Biol 41: 197–202

    PubMed  CAS  Google Scholar 

  • Miyata M, Kanno T, Ishida T, Kobayashi H, Sato Y, Sato Y, Nishimaki T, Kasukawa R (1996) CpG motif in DNA from immune complexes of SLE patients augments expression on intercellular adhesion molecule-1 on endothelial cells. Clin Path 44: 1125–1131

    CAS  Google Scholar 

  • Moldoveanu Z, Love-Homan L, Huang WQ, Krieg AM (1998) CpG DNA, a novel immune enhancer for systemic and mucosal immunization with influenza virus. Vaccine 16: 1216–1224

    Article  PubMed  CAS  Google Scholar 

  • Monteith DK, Henry SP, Howard RB, Flounoy S, Levin AA, Benett CF, Crooke ST (1997) Immune stimulation — a class effect of phosphorothioate oligonucleotides in rodents. Anticancer Drug Design 12: 421–432

    CAS  Google Scholar 

  • Ochiai T. Suzuki T, Nakajima K, Asano T, Mukai M, Kouzu T, Okayama K, Isono K, Nishijima H, Ohkawa M (1986) Studies on lymphocyte subsets of regional lymph nodes after endoscopie injection of biological response modifiers in gastric cancer patients. Int J Immunother 4: 259–265

    Google Scholar 

  • Pisetsky DA, Drayton DM (1997) Deficient expression of antibodies specific for bacterial DNA by patients with systemic lupus erythematosis. Proc Assoc Am Physicians 109: 237–244

    PubMed  CAS  Google Scholar 

  • Pisetsky DS (1996) Immune activation by bacterial DNA: A new genetic code. Immunity 5: 303–310

    Article  PubMed  CAS  Google Scholar 

  • Pisetsky DS (1997) Immunostimulatory DNA: A clear and present danger? Nature Medicine 3: 829–831

    Article  PubMed  CAS  Google Scholar 

  • Raz E, Tighe H, Sato Y, Corr M, Dudler JA, Roman M, Swain SL, Spiegelberg HL, Carson DA (1996) Preferential induction of a ThI immune response and inhibition of specific IgE antibody formation by plasmid DNA immunization. Proc Natl Acad Sci USA. 93: 5141–5145

    Article  PubMed  CAS  Google Scholar 

  • Roman M, Orozco EM, Goodman JS, Nguyen MD, Sato Y, Ronaghy A, Kornbluth RS, Richman D, Carson DA, Raz E (1997) Immunostimulatory DNA sequences function as T helper-1 promoting adjuvants. Nature Medicine 3: 849–854

    Article  PubMed  CAS  Google Scholar 

  • Sato Y, Roman M. Tighe H, Lee D, Corr M, Nguyen M-D, Silverman GJ, Lotz M, Carson DA, Raz E (1996) Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 273: 352–354

    Article  PubMed  CAS  Google Scholar 

  • Schwartz DA, Quinn TJ, Thorne PS, Sayeed S, Yi A-M, Krieg AM (1997) CpG motifs in bacterial DNA cause inflammation in the lower respiratory tract. J Clin Invest 100: 68–73

    Article  PubMed  CAS  Google Scholar 

  • Segal BM, Klinman DM, Shevach EM (1997) Microbial products induce autoimmune disease by an IL-12 dependent pathway. J Immunol 158: 5087–5090

    PubMed  CAS  Google Scholar 

  • Shimada S, Yano O, Inoue H, Kuramoto E, Fukuda T, Yamamoto H, Kataoka T, Tokunaga T (1985) Antitumor activity of the DNA fraction from Mycobacterium bovis BCG. II. Effects on various syngeneic mouse tumors. J Natl Cancer Inst 74: 681–688

    PubMed  CAS  Google Scholar 

  • Shimada S, Yano O, Tokunaga T (1986) In vivo augmentation of natural killer cell activity with a deoxyribonucleic acid fraction of BCG. Jpn J Cancer Res (Gann) 77: 808–816

    CAS  Google Scholar 

  • Sonehara K, Saito H, Kuramoto E, Yamamoto S, Yamamoto T, Tokunaga T (1996) Hexamer palindromic oligonucleotides with 5’-CG-3’ motif(s) induce production of interferon. J Interferon Cytokine Res 16: 799–803

    Article  PubMed  CAS  Google Scholar 

  • Sparwasser T, Koch E-S, Vabulas RM, Heeg K, Lipford GB, Ellwart JW, Wagner H (1998) Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur J Immunol 28: 2045–2054

    Article  PubMed  CAS  Google Scholar 

  • Sparwasser T, Miethke T, Lipford G, Borschert K, Hacker H, Heeg K, Wagner H (1997) Bacterial DNA causes septic shock. Nature 386: 336–337

    Article  PubMed  CAS  Google Scholar 

  • Sparwasser T, Miethke T, Lipford G, Erdmann A, Hacker H, Heeg K, Wagner H (1997) Macrophages sense pathogens via DNA motifs: Induction of tumor necrosis factor-a mediated shock. Eur J Immunol 27: 1671–1679

    Article  PubMed  CAS  Google Scholar 

  • Stein CA (1995) Does antisense exist? It may, but only under very special circumstances. Nature Medicine 1: 1119–1121

    Article  PubMed  CAS  Google Scholar 

  • Sweet MJ, Stacey KJ, Kakuda DK, Markovich D, Hume DA (1998) IFN-y primes macrophage response to bacterial DNA. J Interferon Cytokine Res 18: 263–271

    Article  PubMed  CAS  Google Scholar 

  • Tighe H, Corr M, Roman M, Rax E (1998) Gene vaccination: plasmid DNA is more than just a blueprint. Immunol Today 19: 89–97

    Article  PubMed  CAS  Google Scholar 

  • Tokunaga T, Yamamoto H, Shimada S, Abe H, Fukuda T, Fujisawa Y, Furutani Y, Yano O, Kataoka T, Sudo T, Makiguchi N, Suganuma T (1984) Antitumor activity of deoxyribonucleic acid fraction from Mycobacterium bovis BCG. I. Isolation, physicochemical characterization and antitumor activity. J Natl Cancer Inst 72: 955–962

    PubMed  CAS  Google Scholar 

  • Tokunaga T, Yamamoto S, Namba K (1988) A synthetic single-stranded DNA, poly(dG,dC), induces interferon-a/ß and y, augments natural killer activity and suppresses tumor growth. Jpn J Cancer Res (Gann) 79: 682–686

    CAS  Google Scholar 

  • Tokunaga T, Yano O, Kuramoto E, Kimura Y, Yamamoto T, Kataoka T, Yamamoto S (1992) Synthetic oligonucleotides with particular base sequences from cDNA encoding proteins of Mycobacterium bovis BCG induce interferons and activate natural killer cells. Microbiol Immunnol 36: 55–66

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  • Weiner GJ, Liu HM, Wooldrodge EJ, Dahle CE, Krieg AM (1997) Immunostimulatory oligonucleotides containing the CpG motif are effective as immune adjuvants in tumor antigen immunization. Proc Natl Acd Sci U.S.A. 94: 10833–10837

    Article  CAS  Google Scholar 

  • Wloch MK, Alexander AL, Pippen AMM, Pisetsky DS, Gilkeson GS (1997) Molecular properties of anti-DNA induced in pre-autoimmune NZB/W mice by immunization with bacterial DNA. J Immunol 158: 4500–4506

    PubMed  CAS  Google Scholar 

  • Wooldridge JE, Ballas Z, Krieg AM, Weiner GJ (1997) Immunostimulatory oligodeoxynucleotides containing CpG motifs enhance the efficacy of monoclonal antibody therapy of lymphoma. Blood 89: 2994–2998

    PubMed  CAS  Google Scholar 

  • Yamamoto S, Kuramoto E, Shimada S, Tokunaga T (1988) In vitro augmentation of natural killer cell activity with a deoxyribonucleic acid fraction from Mycobacterium bovis BCG. Jpn J Cancer Res (Gann) 79: 866–873

    CAS  Google Scholar 

  • Yamamoto S, Yamamoto T, Kataoka T, Kuramoto E, Yano O, Tokunaga T (1992) Unique palindromic sequences in synthetic oligonucleotides are required to induce IFN and augment IFN-mediated natural killer activity. J Immunol 148: 4072–4076

    PubMed  CAS  Google Scholar 

  • Yamamoto S, Yamamoto T, Shimada S, Kuramoto E, Yano O, Kataoka T, Tokunaga T (1992) DNA from bacteria, but not from vertebrates, induces interferons, activates natural killer cells and inhibits tumor growth. Microbiol Immunol 36: 983–997

    PubMed  CAS  Google Scholar 

  • Yamamoto T, Yamamoto S, Kataoka T, Komuro K, Kohase M, Tokunaga T (1994) Synthetic oligonucleotides with certain palindromes stimulate interferon production of human peripheral blood lymphocytes in vitro. Jpn J Cancer Res 85: 775–779

    PubMed  CAS  Google Scholar 

  • Yamamoto T, Yamamoto S, Kataoka T, Tokunaga T (1994a) Ability of oligonucleotides with certain palindromes to induce interferon production and augment natural killer cell activity is associated with their base length. Antisense Res Develop 4: 119–122

    CAS  Google Scholar 

  • Yamamoto T, Yamamoto S, Kataoka T, Tokunaga T (1994b) Lipofection of synthetic oligodeoxyribonucleotide having a palindromic sequence of AACGTT to murine splenocytes enhances interferon production and natural killer activity. Microbiol Immunol 38: 831–836

    PubMed  CAS  Google Scholar 

  • Yi A-K, Chang M, Peckham DW, Krieg AM, Ashman RF (1998) CpG oligodeoxyribonucleotides rescue mature spleen B cells from spontaneous apoptosis and promote cell cycle entry. J Immunol 160: 5895–5906

    Google Scholar 

  • Yi A-K, Chase JH, Cowdery JS, Krieg AM (1996) IFN-y promotes IL-6 and IgM secretion in response to CpG motifs in bacterial DNA and oligodeoxynucleotides. J Immunol 157: 558–564

    Google Scholar 

  • Yi A-K, Klinman DM, Martin TL, Matson S, Krieg AM (1996) Rapid immune activation by CpG motifs in bacterial DNA. J Immunol 157: 5394–5402

    PubMed  CAS  Google Scholar 

  • Yi A-K, Krieg AM (1998) CpG DNA rescue from anti-IgM induced WEHI-231 B lymphoma apoptosis via modulation of IkBa and IkBß and sustained activation of nuclear factor-k B/cRel. J Immunol 160: 1240–1245

    PubMed  CAS  Google Scholar 

  • Yi A-K, Tuetken R, Redford T, Waldschmidt M, Kirsch J, Krieg AM (1998) CpG motifs in bacterial DNA activate leukocytes through the pH-dependent generation of reactive oxygen species. J Immunol 160: 4755–4761

    PubMed  CAS  Google Scholar 

  • Zimmermann S, Egeter O, Hausmann S, Lipford GB, Rocken M, Wagner H, Heeg K (1998) CpG oligodeoxynucleotides trigger protective and curative Thl response in lethal murine leishmaniasis. J Immunol 160: 3627–3630

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Bacterial and Blood Products, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan

    S. Yamamoto & T. Yamamoto

  2. National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo, 162-8640, Japan

    T. Tokunaga

Authors
  1. S. Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. Tokunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institut für Medizinische Mikrobiologie, Immunologie und Hygiene der Technischen Universität München, Trogerstr. 9, D-81675, München, Germany

    Hermann Wagner Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 2000 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Yamamoto, S., Yamamoto, T., Tokunaga, T. (2000). Oligodeoxyribonucleotides with 5′-ACGT-3′ or 5′-TCGA-3′ Sequence Induce Production of Interferons. In: Wagner, H. (eds) Immunobiology of Bacterial CpG-DNA. Current Topics in Microbiology and Immunology, vol 247. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59672-8_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-59672-8_2

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-64077-3

  • Online ISBN: 978-3-642-59672-8

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation