An adjuvant role for certain short bacterial immunostimulatory DNA sequences (ISSs) has recently been proposed on the basis of their ability to stimulate T helper-1 (Thl) responses in gene-vaccinated animals. We report here that noncoding, ISS-enriched plasmid DMAs or ISS oligonucleotides (ISS-ODNs) potently stimulate immune responses to coadministered antigens. The ISS-DNAs suppress IgE synthesis, but promote IgC and interferon-γ (IFN-γ) production. They furthermore initiate the production of IFN-γ, IFN-α, IFN-β, and interleukins 12 and 18, all of which foster Thl responses and enhance cell-mediated immunity. Consideration should be given to adding noncoding DNA adjuvants to inactivated or subunit viral vaccines that, by themselves, provide only partial protection from infection.
Manickan, E., Rouse, R.J., Yu, Z., Wire, W.S. & Rouse, B.T. Genetic immunization against herpes simplex virus. Protection is mediated by CD4+ T lymphocytes. J. Immunol. 155, 259–265 (1995).
Xiang, Z. & Ertl, H.C. Manipulation of the immune response to a plasmid-encoded viral antigen by coinoculation with plasmids expressing cytokines. Immunity 2, 129–135 (1995).
Raz, E. et al. Preferential induction of a Th1 immune response and inhibition of specific IgE antibody formation by plasmid DNA immunization. Proc. Natl. Acad. Sci. USA 93, 5141–5145 (1996).
Broide, D., Martin-Orozco, E., Roman, M., Carson, D.A. & Raz, E. Intradermal gene vaccination down-regulates both arms of the allergic response. J. Allergy Clin. Immunol. 99, s129 (1997).
Sato, Y. et al. Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 273, 352–354 (1996).
Bird, A.P. CpG islands as gene markers in the vertebrate nucleus. Trends Genet. 3, 342–347 (1987).
Yamamoto, S. et al. Unique palindromic sequences in synthetic oligonucleotides are required to induce IFN and augment IFN-mediated natural killer activity. J. Immunol. 148, 4072–4076 (1992).
Mosmann, T.R. & Coffman, R.L. TH1 and TH2 cells: Different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).
Raz, E. et al. Intradermal gene immunization: The possible role of DNA uptake in the induction of cellular immunity to viruses. Proc. Natl. Acad. Sci. USA. 91, 9519–9523 (1994).
Condon, C., Watkins, S.C., Celluzzi, C.M., Thompson, K. & Falo, L.D., Jr. DNA-based immunization by in vivo transfection of dendritic cells. Nature Med. 2, 1122–1128 (1996).
Corr, M., Lee, D.J., Carson, D.A. & Tighe, H. Gene vaccination with naked plasmid DNA: Mechanism of CTL priming. J. Exp. Med. 184, 1555–1560 (1996).
Brinkmann, V., Geiger, T., Alkan, S. & Heusser, C.H. Interferon alpha increases the frequency of interferon gamma-producing human CD4+ T cells. J. Exp. Med. 178, 1655–1663 (1993).
Yaegashi, Y., Nielsen, P., Sing, A., Galanos, C. & Freudenberg, M.A. Interferon beta, a cofactor in the interferon gamma production induced by gram-negative bacteria in mice. J. Exp. Med. 181, 953–960 (1995).
Trinchieri, G. Interleukin-12: A proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu. Rev. Immunol. 13, 251–276 (1995).
Okamura, H. et al. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 378, 88–91 (1995).
Kimura, Y. et al. Binding of oligoguanylate to scavenger receptors is required for oligonucleotides to augment NK cell activity and induce IFN. J. Biochem. 116, 991–994 (1994).
Cowdery, J.S., Chace, J.H., Yi, A.K. & Krieg, A.M. Bacterial DNA induces NK cells to produce IFN-gamma in vivo and increases the toxicity of lipopolysaccharides. J. Immunol. 156, 4570–4575 (1996).
Graham, B.S. & Wright, P. Candidate AIDS vaccine. N. Engl. J. Med. 333, 1331–1339 (1995).
Burke, R.L. Current status of HSV vaccine development. in The Human Herpesviruses (eds. Roizman, B., Whitley, R.J. & Lopez, C.). p 367 (Lippincott-Raven, Philadelphia, 1993).
Pertmer, T.M., Roberts, T.R. & Haynes, J.R. Influenza virus nucleoprotein-specific immunoglobulin G subclass and cytokine responses elicited by DNA vaccination are dependent on the route of vector DNA delivery. J. Virol. 70, 6119–6125 (1996).
Feltquate, D.M., Heaney, S., Webster, R.G. & Robinson, H.L. Different T helper cell types and antibody isbtypes generated by saline and gene gun DNA immunization. J. Immunol. 158, 2278–2284 (1997).
Fynan, E.F. et al. DNA vaccines: protective immunizations by parenteral, mucosal, and gene-gun inoculations. Proc. Natl. Acad. Sci. USA 90, 11478–11482 (1993).
Freund, J., Casals, J. & Hosmer, E.P. Sensitization and antibody formation after injection of tubercle bacilli and paraffin oil. Proc. Soc. Exp. Biol. Med. 37, 509–513 (1937).
Munoz, J. Effect of bacteria and bacterial products on antibody response. Adv. Immunol. 4, 397–440 (1964).
Raz, E. et al. Cationic lipid inhibit intradermal genetic vaccination. in: Vaccine 94. 71–75 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1994).
Pisetsky, D.S. Immune activation by bacterial DNA: A new genetic code. Immunity 5, 303–310 (1996).
Krieg, A.M. et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374, 546–549 (1995).
Halpern, M.D., Kurlander, R.J. & Pisetsky, D.S. Bacterial DNA induces murine interferon-gamma production by stimulation of interleukin-12 and tumor necrosis factor-alpha. Cell. Immunol. 167, 72–78 (1996).
Klinman, D.M., Yi, A.K., Beaucage, S.L., Conover, J. & Krieg, A.M. CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, inter-leukin 12, and interferon gamma. Proc Natl. Acad. Sci. USA 93, 2879–2883 (1996).
Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994).
Fearon, D.T. & Locksley, R.M. The instructive role of innate immunity in the acquired immune response. Science 272, 50–53 (1996).
Geng, Y., Gulbins, E., Altman, A. & Lotz, M. Monocyte deactivation by interleukin 10 via inhibition of tyrosine kinase activity and the Ras signaling pathway. Proc. Natl. Acad. Sci. USA 91, 8602–8606 (1994).
Bradley, L.M., Dalton, D.K. & Croft, M. A direct role for IFN-gamma in regulation of Thl cell development. J. Immunol. 157, 1350–1358 (1996).
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Roman, M., Martin-Orozco, E., Goodman, J. et al. Immunostimulatory DNA sequences function as T helper-1-promoting adjuvants. Nat Med 3, 849–854 (1997). https://doi.org/10.1038/nm0897-849
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