Skip to main content

Use of CpG DNA for Enhancing Specific Immune Responses

  • Chapter
Immunobiology of Bacterial CpG-DNA

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

Abstract

Bacterial DNA, in contrast to vertebrate DNA, has the capacity to act as a potent immune stimulator (Tokunaga et al. 1984; Messina et al. 1991; Yamamoto et al. 1992b). This is now known to be due to unmethylated CpG dinucleotides that are immunostimulatory when present within the context of certain flanking bases (CpG-S motifs) (Krieg et al. 1995). CpG dinucleotides are present at the expected frequency of 1/16 bases in bacterial DNA but are under-represented (1/50–1/60 bases) in vertebrate DNA, where they are almost always methylated (Bird et al. 1987). CpG-S motifs are virtually absent from vertebrate DNA, and the rapid immune activation in response to CpG DNA appears to be an evolutionary adaptation whereby CpG-S motifs act as a “danger” signal that the vertebrate innate immune defense mechanisms can recognize and respond to (Krieg et al. 1996).

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

Access this chapter

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.

Similar content being viewed by others

References

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

    PubMed  CAS  Google Scholar 

  • Barrios C, Brawand P, Berney M, Brandt C, Lambert PH, Siegrist CA (1996) Neonatal and early life immune responses to various forms of vaccine antigens qualitatively differ from adult responses: predominance of a Th2-biased pattern which persists after adult boosting. Eur J Immunol 26: 1489–1496

    Article  PubMed  CAS  Google Scholar 

  • Bird AP (1987) CpG islands as gene markers in the vertebrate nucleus. Trends in Genetics 3: 342

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Brazolot Milian CL, Weeratna R, Krieg AM, Siegrist CA, Davis HL (1998) CpG DNA can induce strong Thl humoral and cell-mediated immune responses against hepatitis B surface antigen in young mice. Proc Natl Acad Sci USA (In press)

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Chisari FV (1997) Cytotoxic T cells and viral hepatitis. J Clin Invest 99: 1472–1477

    Article  PubMed  CAS  Google Scholar 

  • Chong C, Friberg M, Clements JD (1998) LT(R192G), a non-toxic mutant of the heat-labile enterotoxin of Escherichia coif, elicits enhanced humoral and cellular immune responses associated with protection against lethal oral challenge with Salmonella spp. Vaccine 16: 732–740

    Article  PubMed  CAS  Google Scholar 

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

    Google Scholar 

  • Cookson OCM, Moffatt MF (1997) Asthma: An epidemic in the absence of infection? Science 275: 41–42

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Davis HL, Weeratna R, Waldschmidt TJ, Schorr J, Krieg AM (1998) CpG DNA is a potent enhancer of specific Immunity in mice immunized with recombinant hepatitis B surface antigen. J Immunol 160: 870–876

    PubMed  CAS  Google Scholar 

  • Di Tommaso A, Saletti G, Pizza M, Rappuoli R, Dougan G, Abrignani S, Douce G, De Magistris MT (1996) Induction of antigen-specific antibodies in vaginal secretions by using a nontoxic mutant of heat-labile enterotoxin as a mucosal adjuvant. Infect Immun 64: 974–979

    PubMed  Google Scholar 

  • Donnelly JJ, Ulmer JB, Liu MA (1997) DNA vaccines. Life Sciences 60: 163–172

    CAS  Google Scholar 

  • Douce G, Giuliani MM, Giannelli V, Pizza MG, Rappuoli R, Dougan G (1998) Mucosal immunogenicity of genetically detoxified derivatives of heat labile toxin from Escherichia coll. Vaccine 16: 1065–1073

    Article  PubMed  CAS  Google Scholar 

  • Fontana MR, Manetti R, Giannelli V, Magagnoli C, Marchini A, Olivieri R, Domenighini M, Rappuoli R, Pizza M (1995) Construction of nontoxic derivatives of cholera toxin and characterization of the immunological response against the A subunit. Infect Immun 63: 2356–2360

    PubMed  CAS  Google Scholar 

  • Gallichan WS, Rosenthal KL (1995) Specific secretory immune responses in the female genital tract following intranasal immunization with a recombinant adenovirus expressing glycoprotein B of herpes simplex virus. Vaccine 13: 1589–1595

    Article  PubMed  CAS  Google Scholar 

  • Giuliani MM, Del Giudice G, Giannelli V, Dougan G, Douce G, Rappuoli R, Pizza M (1998) Mucosal adjuvanticity and immunogenicity of LTR72, a novel mutant of Escherichia coli heat-labile enterotoxin with partial knockout of ADP-ribosyltransferase activity. J Exp Med 187: 1123–1132

    Article  PubMed  CAS  Google Scholar 

  • Haddad EE, Whitfill CE, Avakian AP, Ricks CA, Andrews PD, Thoma JA, Wakenell PS (1997) Efficacy of a novel infectious bursal disease virus immune complex vaccine in broiler chickens. Avian Dis 41: 882–889

    Article  PubMed  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 

  • Haneberg B, Kendall D, Amerongen HM, Apter FM, Kraehenbuhl JP, Neutra MR (1994) Induction of specific immunoglobulin A in the small intestine, colon-rectum, and vagina measured by a new method of collection of secretions from local mucosal surfaces. Infection and Immunity 62: 15–23

    PubMed  CAS  Google Scholar 

  • Hanke T, Boning, C, Green EA, Szawlowski PW, Rud E, Randall RE (1994) Expression and purification of nonglycosylated SIV proteins, and their use in induction and detection of SIV-specific immune responses. AIDS Res Hum Retroviruses 10: 665–674

    Article  PubMed  CAS  Google Scholar 

  • Hogg JC (1997) The pathology of asthma. APM1S 105: 735–745

    CAS  Google Scholar 

  • Holmgren J, Lycke N, Czerkinsky C (1993) Cholera toxin and cholera B subunit as oral-mucosal adjuvant and antigen vector systems. Vaccine 11: 1179–1184

    Article  PubMed  CAS  Google Scholar 

  • Homer AA, Ronaghy A, Cheng PM, Nguyen MD, Cho HJ, Broide D, Raz E (1998) Immunostimulatory DNA is a potent mucosal adjuvant. Cell Immunol 190: 77–82

    Article  Google Scholar 

  • Hughes JA, Awrutskaya AV, Juliano RL (1994) Influence of base composition cellular uptake of 10-mer phosphorothioate oligonucleotides in Chinese hamster ovary ( CHRCS) cells. Antisense Res Develop 4: 211–215

    Google Scholar 

  • Hunt DW, Huppertz HI, Jiang FIJ, Petty RE (1994) Studies of human cord blood dendritic cells: evidence for functional immaturity. Blood 84: 4333–4343

    PubMed  CAS  Google Scholar 

  • Jertborn M, Svennerholm AM, Holmgren J (1992) Safety and immunogenicity of an oral recombinant cholera B subunit-whole cell vaccine in Swedish volunteers. Vaccine 10: 130–132

    Article  PubMed  CAS  Google Scholar 

  • Kay AB (1996) TH2-type cytokines in asthma. Ann NY Acad Sci 796: 1–8

    Article  PubMed  CAS  Google Scholar 

  • Kline JN, Businga TR, Waldschmidt TJ, Weinstock JV, 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, Yi A, Beaucage SL, Conover J, Krieg AM (1996) CpG motifs present in bacterial DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12 and interferon y. Proc Natl Acad Sci USA 93: 2879–2883

    Article  PubMed  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 

  • Komase K, Tamura S, Matsuo K, Watanabe K, Hattori N, Odaka A, Suzuki Y, Kurata T, Aizawa C (1998) Mutants of Escherichia coli heat-labile enterotoxin as an adjuvant for nasal influenza vaccine. Vaccine 16: 248–254

    Article  PubMed  CAS  Google Scholar 

  • Kovarik J, Siegrist CA (1998) Immunity in early life. Immunol Today 19: 150–152

    Article  PubMed  CAS  Google Scholar 

  • Kovarik J, Siegrist CA (1998) Immunity in early life. Immunol Today 19: 150–152

    Article  PubMed  CAS  Google Scholar 

  • Krieg AM, Yi A-K, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374: 546–549

    Article  PubMed  CAS  Google Scholar 

  • Krieg AM, Matson S, Fisher E (1996) Oligodeoxynucleotide modifications determine the magnitude of immune stimulation by CpG motifs. Antisense Res Dev 6: 133–139

    Article  CAS  Google Scholar 

  • Krieg AM, Wu T, Weeratna R, Efler SM, Love-Homan L, Yang L, Yi AK, Short D, Davis HL (1998) Sequence motifs in adenoviral DNA block immune activation by stimulatory CpG motifs. Proc Natl Acad Sci USA 95: 12631–12636

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Lipford GB, Bauer M, Blank C, Reiter R, Wagner H, Heeg K (1997a) 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 E-S, Heeg K, Wagner H (1997b) Immunostimulatory DNA: sequence-dependent production of potentially harmful or useful cytokines. Eur J Immunol 27: 3420–3426

    Article  PubMed  CAS  Google Scholar 

  • Liu SJ, Sher YP, Ting CC, Liao KW, Yu CP, Tao MH (1998) Treatment of B-cell lymphoma with chimeric IgG and single-chain Fv antibody-interleukin-2 fusion proteins. Blood 92: 2103–2112

    PubMed  CAS  Google Scholar 

  • Lycke N, Tsuji T, Holmgren J (1992) The adjuvant effect of Vibrio cholerae and Escherichia colt heat-labile enterotoxins is linked to their ADP-ribosyltransferase activity. European Journal of Immunology 22: 2277–2281

    Article  PubMed  CAS  Google Scholar 

  • McCluskie MJ, Davis HL (1998) 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

    PubMed  CAS  Google Scholar 

  • McCluskie MJ, Davis HL (1998) 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

    PubMed  CAS  Google Scholar 

  • Messina JP, Gilkeson GS, Pisetsky DS (1991) Stimulation of in vitro murine lymphocyte proliferation by bacterial DNA. J Immunol 147: 1759–1764

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Pokric B, Sladic D, Juros S, Cajavec S (1993) Application of the immune complex for immune protection against viral disease. Vaccine 11: 655–659

    Article  PubMed  CAS  Google Scholar 

  • Rappuoli R, Douce G, Dougan G, Pizza M (1995) Genetic detoxification of bacterial toxins: a new approach to vaccine development. Int Arch Allergy Immunol 108: 327–333

    Article  PubMed  CAS  Google Scholar 

  • Roman M, Martinorozco E, Goodman S, Nguyen MD, Sato Y, Ronaghy A, Kornbluth RS, Richman DD, Carson DA, Raz E (1997) Immunostimulatory DNA sequences function as T helper-l-promoting adjuvants. Nature Med 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 D, Quinn TJ, Thorne PS, Sayeed S, Yi A-K, 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 

  • Spangler BD (1992) Structure and function of cholera toxin and the related Escherichia coli heat-labile enterotoxin. Microbiological Rev 56: 622–647

    CAS  Google Scholar 

  • Sun S, Kishimoto H, Sprent J (1998) DNA as an adjuvant: capacity of insect DNA and synthetic oligodeoxynucleotides to augment T cell responses to specific antigen. J Exp Med 187: 1145–1150

    Article  PubMed  CAS  Google Scholar 

  • Threadgill DS, McCormick LL, McCool TL, Greenspan NS, Schreiber JR (1998) Mitogenic synthetic polynucleotides suppress the antibody response to a bacterial polysaccharide. Vaccine 16: 76–82

    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 (1998) Antitumor activity of deoxyribonucleic acid fraction from Mycobacterium bonis GCG. I. Isolation, physicochemical characterization and antitumor activity. JNCI 72: 955–962

    Google Scholar 

  • Verweij WR, de Haan L, Holtrop M, Agsteribbe E, Brands R, van Scharrenburg GJ, Wilschut J (1998) Musosal immunoadjuvant activity of recombinant Escherichia coil heat-labile enterotoxin and its B subunit: induction of systemic IgG and secretory IgA responses in mice by intranasal immunization with influenza virus surface antigen. Vaccine 16: 2069–2076

    Article  PubMed  CAS  Google Scholar 

  • Weeratna R, CL Bm, Krieg AM, Davis HL (1998) Reduction of antigen expression from DNA vaccines by co-administered oligonucleotides. Antisense Nucleic Acid Drug Devel 8: 351–356

    Article  CAS  Google Scholar 

  • Weiner GJ, Liu H-M, Wooldridge JE, Dahle CE, Krieg AM (1997) Immunostimulatory oligodeoxynucleotides containing the CpG motif are effective as immune adjuvants in tumor antigen immunization. Proc Natl Acad Sci USA 94: 10833–10837

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Yamamoto S, Yamamoto Y, Kataoka T, Kuramoto E, Yano O. 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 S, Kiyono H, Yamamoto M, Imaoka K, Fujihashi K, Van Ginkel FW, Noda M, Takeda Y. McGhee JR (1997) A nontoxic mutant of cholera toxin elicits Th2-type responses for enhanced mucosal immunity. Proceedings of the National Academy of Sciences of the United States of America 94: 5267–5272

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto S, Takeda Y, Yamamoto M, Kurazono H, Imaoka K, Yamamoto M, Fujihashi K, Noda M, Kiyono H, McGhee JR (1997) Mutants in the ADP-ribosyltransferase cleft of cholera toxin lack diarrheagenicity but retain adjuvanticity. Journal of Experimental Medicine 185: 1203–1210

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto M, Briles DE, Yamamoto S, Ohmura M, Kiyono H, McGhee JR (1998) A nontoxic adjuvant for mucosal immunity to pneumococcal surface protein A. J Inmumol 161: 4115–4121

    CAS  Google Scholar 

  • Yi A-K, Klinman DM, Martin TL, Matson S, A.M. K (1996) Rapid immune activation by CpG motifs in bacterial DNA: Systemic induction of IL-6 transcription through an antioxidant-sensitive pathway. J Immunol 157: 5394–5402

    CAS  Google Scholar 

  • Yi A-K, Hornbeck P, Lafrenz DE, Krieg AM (1996) CpG DNA rescue of murine B lymphoma cells from anti-IgM induced growth arrest and programmed cell death is associated with increased expression of c-myc and bcl-XL. J Immunol 157: 4918–4925

    PubMed  CAS  Google Scholar 

  • Zhao Q, Matson S, Herrera CJ, Fisher E, Yu H, Krieg AM (1993) Comparison of cellular binding and uptake of antisense phosphodiester, phosphorothioate and mixed phosphorothioate and methylphosphonate oligonucleotides. Antisense Res Develop 3: 53–66

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2000 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Davis, H.L. (2000). Use of CpG DNA for Enhancing Specific Immune Responses. 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_12

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-59672-8_12

  • 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