CpG DNA as a Th1 trigger

International Archives of Allergy and Immunology

Volumn 121, Issue 2, 2000, Pages 87-97

  Heeg, Klaus ^a   Zimmermann, Stefan ^a  

^a PHILIPPS UNIVERSITY MARBURG   (Germany)

Author keywords

Bacterial DNA; CpG; Synthetic oligodeoxynucleotides; Th1; Vaccination

Indexed keywords

BACTERIAL DNA; CYTOKINE; DNA; IMMUNOLOGICAL ADJUVANT; IMMUNOMODULATING AGENT; OLIGONUCLEOTIDE; VACCINE;

ALLERGY; CPG ISLAND; CYTOKINE PRODUCTION; IMMUNOSTIMULATION; PRIORITY JOURNAL; REVIEW; T LYMPHOCYTE ACTIVATION; TH1 CELL; VACCINATION;

EID: 0034011930     PISSN: 10182438     EISSN: None     Source Type: Journal    
DOI: 10.1159/000024303     Document Type: Review

References (128)

1. Bast RC Jr, Zbar B, Borsos T, Rapp HJ: BCG and cancer. N Engl J Med 1974;290:1458-1469.
2. Yamamoto S, Kuramoto E, Shimada S, Tokunaga T: In vitro augmentation of natural killer cell activity and production of interferon-alpha/beta and -gamma with deoxyribonucleic acid fraction from Mycobacterium bovis BCG. Jpn J Cancer Res 1988;79:866-873.
3. Kuramoto E, Yano O, Kimura Y, Baba M, Makino T, Yamamoto S, Yamamoto T, Kataoka T, Tokunaga T: Oligonucleotide sequences required for natural killer cell activation. Jpn J Cancer Res 1992;83:1128-1131.
4. Yamamoto S, Yamamoto T, Kataoka T, Kuramoto E, Yano O, Tokunaga T: Unique palindromic sequences in synthetic oligonucleotides are required to induce IFN and augment IFN-mediated natural killer activity. J Immunol 1992;148:4072-4076.
5. Yamamoto S, Yamamoto T, Shimada S, Kuramoto E, Yano O, Kataoka T, Tokunaga T: DNA from bacteria, but not from vertebrates, induces interferons, activates natural killer cells and inhibits tumor growth. Microbiol Immunol 1992;36:983-997.
6. Terada K, Okuhara E, Kawarada Y: Antigen DNA isolated from immune complexes in plasma of patients with systemic lupus erythematosus hybridizes with the Escherichia coli lac Z gene. Clin Exp Immunol 1991;85:66-69.
7. Messina JP, Gilkeson GS, Pisetsky DS: Stimulation of in vitro murine lymphocyte proliferation by bacterial DNA. J Immunol 1991;147: 1759-1764.
8. Messina JP, Gilkeson GS, Pisetsky DS: The influence of DNA structure on the in vitro stimulation of murine lymphocytes by natural and synthetic polynucleotide antigens. Cell Immunol 1993;147:148-157.
9. Wagner RW: Gene inhibition using antisense oligodeoxynucleotides. Nature 1994;372:333-335.
10. Krieg AM, Gause WC, Gourley MF, Steinberg AD: A role for endogenous retroviral sequences in the regulation of lymphocyte activation. J Immunol 1989;143;2448-2451.
11. Mojcik CF, Gourley MF, Klinman DM, Krieg AM, Gmelig-Meyling F, Steinberg AD: Administration of a phosphorothioate oligonucleotide antisense to murine endogenous retroviral MCF env causes immune effects in vivo in a sequence-specific manner. Clin Immunol Immunopathol 1993;67:130-136.
12. Branda RF, Moore AL, Mathews L, McCormack JJ, Zon G: Immune stimulation by an antisense oligomer complementary to the rev gene of HIV-1. Biochem Pharmacol 1993;45: 2037-2043.
13. Pisetsky DS, Reich CF: Stimulation of murine lymphocyte proliferation by a phosphorothioate oligonucleotide with antisense activity for herpes simplex virus. Life Sci 1994;54:101-107.
14. Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM: CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 1995;374:546-549.
15. Bird AP: DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res 1980;8:1499-1504.
16. Pisetsky DS: Immune activation by bacterial DNA: A new genetic code. Immunity 1996;5: 303-310.
17. Krieg AM: An innate immune defense mechanism based on the recognition of CpG motifs in microbial DNA. J Lab Clin Med 1996;128: 128-133.
18. Lipford GB, Heeg K, Wagner H: Bacterial DNA as immune cell activator. Trends Microbiol 1998;6:496-500.
19. Heeg K, Sparwasser T, Lipford GB, Häcker H, Zimmermann S, Wagner H: Bacterial DNA as an evolutionary conserved ligand signalling danger of infection to immune cells. Eur J Clin Microbiol Infect Dis 1998;17:464-469.
20. Wagner H: Bacterial CpG DNA activates immune cells to signal infectious danger. Adv Immunol 1999;73:329-368.
21. Krieg AM: Lymphocyte activation by CpG dinucleotide motifs in prokaryotic DNA. Trends Microbiol 1996;4:73-76.
22. Brightbill HD, Libraty DH, Krutzik SR, Yang RB, Belisle JT, Bleharski JR, Maitland M, Norgard MV, Plevy SE, Smale ST, Brennan PJ, Bloom BR, Godowski PJ, Modlin RL: Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 1999;285:732-736.
23. Burge C, Campbell AM, Karlin S: Over-and under-representation of short oligonucleotides in DNA sequences. Proc Natl Acad Sci USA 1992;89:1358-1362.
24. Karlin S, Doerfler W, Cardon LR: Why is CpG suppressed in the genomes of virtually all small eukaryotic viruses but not in those of large eukaryotic viruses? J Virol 1994;68:2889-2897.
25. Sun S, Kishimoto H, Sprent J: DNA as an adjuvant: Capacity of insect DNA and synthetic oligodeoxynucleotides to augment T cell response to specific antigen. J Exp Med 1998; 187:1145-1150.
26. Klinman DM, Yamshchikov G, Ishigatsubo Y: Contribution of CpG motifs to the immunogenicity of DNA vaccines. J Immunol 1997;158: 3635-3639.
27. Wloch MK, Pasquini S, Ertl HC, Pisetsky DS: The influence of DNA sequence on the immunostimulatory properties of plasmid DNA vectors. Hum Gene Ther 1998;9:1439-1447.
28. Krieg AM, Yi AK, Schorr J, Davis H: The role of CpG oligonucleotides in DNA vaccines. Trends Microbiol 1998;6:23-27.
29. Li E, Beard C, Jacnisch R: Role for DNA methylation in genomic imprinting. Nature 1993; 366:362-365.
30. Fisher TL, Terhorst T, Cao X, Wagner RW: Intracellular disposition and metabolism of fluorescently-labeled unmodified and modified oligonucleotides microinjected into mammalian cells. Nucleic Acid Res 1993;21:3857-3865.
31. Stein CA, Subasinghe C, Shinozuka K, Cohen JS: Physicochemical properties of phosphorothioate oligodeoxynucleotides. Nucleic Acids Res 1988;16:3209-3221.
32. Zhao Q, Matson S, Herrera CJ, Fisher E, Yu H, Krieg AM: Comparison of cellular binding and uptake of antisense phosphodiester, phosphorothioate, and mixed phosphorothioate and methylphosphonate oligonucleotides. Antisense Res Dev 1993;3:53-66.
33. Stein CA, Cheng YC: Antisense oligonucleotides as therapeutic agents - is the bullet really magical? Science 1993;261:1004-1012.
34. Goeckeritz BE, Flora M, Witherspoon K, Vos Q, Lees A, Dennis GJ, Pisetsky DS, Klinman DM, Snapper CM, Mond JJ: Multivalent cross-linking of membrane Ig sensitizes murine B cells to a broader spectrum of CpG-containing oligodeoxynucleotide motifs, including their methylated counterparts, for stimulation of proliferation and Ig secretion. Int Immunol 1999;11:1693-1700.
35. Krieg AM, Matson S, Fisher E: Oligodeoxynucleotide modifications determine the magnitude of B cell stimulation by CpG motifs. Antisense Nucleic Acid Drug Dev 1996;6:133139.
36. Ballas ZK, Rasmussen WL, Krieg AM: Induction of NK activity in murine and human cells by CpG motifs in oligodeoxynucleotides and bacterial DNA. J Immunol 1996;157:1840-1845.
37. Liang H, Nishioka Y, Reich CF, Pisetsky DS, Lipsky PE: Activation of human B cells by phosphorothioate oligonucleotides. J Clin Invest 1996;98:1119-1129.
38. Bauer M, Heeg K, Wagner H, Lipford GB: DNA activates human immune cells through a CpG sequence-dependent manner. Immunology 1999;97:699-705.
39. Hartmann G, Weiner GJ, Krieg AM: CpG DNA: A potent signal for growth, activation, and maturation of human dendritic cells. Proc Natl Acad Sci USA 1999;96:9305-9310.
40. Loke SL, Stein CA, Zhang XH, Mori K, Nakanishi M, Subasinghe C, Cohen JS, Neckers LM: Characterization of oligonucleotide transport into living cells. Proc Natl Acad Sci USA 1989;86:3474-3478.
41. Stein CA, Tonkinson JL, Zhang LM, Yakubov I., Gervasoni J, Taub R, Rotenberg SA: Dynamics of the internalization of phosphodiester oligodeoxynucleotides in HL60 cells. Biochemistry 1993;32:4855-4861.
42. Stein CA, Narayanan R: Antisense oligodeoxynucleotides. Curr Opin Oncol 1994;6:587-594.
43. Temsamani J, Kubert M, Tang J, Padmapriya A, Agrawal S: Cellular uptake of oligodeoxynucleotide phosphorothioates and their analogs. Antisense Res Dev 1994;4:35-42.
44. Bennett RM, Gahor GT, Merritt MM: DNA binding to human leukocytes. Evidence for a receptor-mediated association, internalization, and degradation of DNA. J Clin Invest 1985; 76:2182-2190.
45. Kimura Y, Sonehara K, Kuramoto E, Makino T, Yamamoto S, Yamamoto T, Kataoka T, Tokunaga T: Binding of oligoguanylate to scavenger receptors is required for oligonucleotides to augment NK cell activity and induce IFN. J Biochem (Tokyo) 1994;116:991-994.
46. Pearson AM, Rich A, Krieger M: Polynucleotide binding to macrophage scavenger receptors depends on the formation of base-quartet-stabilized four-stranded helices. J Biol Chem 1993;268:3546-3554.
47. Benimetskaya L, Loike JD, Khaled Z, Loike G, Silverstein SC, Cao L, El Khoury J, Cai TQ, Stein CA: Mac-1 (CD11b/CD18) is an oligodeoxynucleotide-binding protein. Nat Med 1997;3:414-420.
48. Macfarlane DE, Manzel L: Antagonism of immunostimulatory CpG-oligodeoxynucleotides by quinacrine, chloroquine, and structurally related compounds. J Immunol 1998;160:1122-1131.
49. Häcker H, Mischak H, Miethke T, Liptay S, Schmid R, Sparwasser T, Heeg K, Lipford GB, Wagner H: CpG-DNA specific activation of antigen presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. EMBO J 1998;17:6230-6240.
50. Yi AK, Krieg AM: Rapid induction of mitogen-activated protein kinases by immune stimulatory CpG DNA. J Immunol 1998;161:4493-4497.
51. Lipford GB, Bendigs S, Heeg K, Wagner H: Poly-guanosine motifs and not immunostimulatory bacterial CpG-motifs costimulate antigen reactive CD8 T cells in vitro. Submitted.
52. Yi AK, Krieg AM: CpG DNA rescue from anti-IgM-induced WEHI-231 B lymphoma apoptosis via modulation of I kappa B alpha and I kappa B beta and sustained activation of nuclear factor-kappa B/c-Rel. J Immunol 1998; 160:1240-1245.
53. Sparwasser T, Koch ES, Vabulas RM, Heeg K, Lipford GB, Ellwart J, Wagner H: Bacterial DNA and immunostimulating CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur J Immunol 1998; 28:2045-2054.
54. Medzhitov R, Janeway CA: Innate immunity: Impact on the adaptive immune response. Curr Opin Immunol 1997;9:4-9.
55. Sparwasser T, Miethke T, Lipford GB, Erdmann A, Häcker H, Heeg K, Wagner H: Macrophages sense pathogens via DNA motifs: Induction of tumor necrosis factor-alpha-mediated shock. Eur J Immunol 1997;27:1671-1679.
56. Stacey KJ, Sweet MJ, Hume DA: Macrophages ingest and are activated by bacterial DNA. J Immunol 1996;157:2116-2122.
57. Martin-Orozco E, Kobayashi H, Van Uden J, Nguyen MD, Kornbluth RS, Raz E: Enhancement of antigen-presenting cell surface molecules involved in cognate interactions by immunostimulatory DNA sequences. Int Immunol 1999;11:1111-1118.
58. Jakob T, Walker PS, Krieg AM, Udey MC, Vogel JC: Activation of cutaneous dendritic cells by CpG-containing oligodeoxynucleotides: A role for dendritic cells in the augmentation of Th1 responses by immunostimulatory DNA. J Immunol 1998;161:3042-3049.
59. Sun S, Beard C, Jaenisch R, Jones P, Sprent J: Mitogenicity of DNA from different organisms for murine B cells. J Immunol 1997;159:3119-3125.
60. Yi AK, Klinman DM, Martin TL, Matson S, Krieg AM: Rapid immune activation by CpG motifs in bacterial DNA. Systemic induction of IL-6 transcription through an antioxidant-sensitive pathway. J Immunol 1996;157:5394-5402.
61. Yi AK, Tuetken R, Redford T, Waldschmidt M, Kirsch J, Krieg AM: CpG motifs in bacterial DNA activate leukocytes through the pH-dependent generation of reactive oxygen species. J Immunol 1998;160:4755-4761.
62. Yi AK, Chace JH, Cowdery JS, Krieg AM: IFN-gamma promotes IL-6 and IgM secretion in response to CpG motifs in bacterial DNA and oligodeoxynucleotides. J Immunol 1996; 156:558-564.
63. Yi AK, Hornbeck P, Lafrenz DE, Krieg AM: 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 1996;157:4918-4925.
64. Yi AK, Chang M, Peckham DW, Krieg AM, Ashman RF: CpG oligodeoxyribonucleotides rescue mature spleen B cells from spontaneous apoptosis and promote cell cycle entry. J Immunol 1998;160:5898-5906.
65. Sun S, Cai Z, Langlade-Demoyen P, Kosaka H, Brunmark A, Jackson MR, Peterson PA, Sprent J: Dual function of drosophila cells as APCs for naive CD8+ T cells: Implications for tumor immunotherapy. Immunity 1996;4: 555-564.
66. Bendigs S, Salzer U, Lipford GB, Wagner H, Heeg K: CpG-oligodeoxynucleotides costimulate primary T cells in the absence of APC. Eur J Immunol 1999;29:1209-1218.
67. Heeg K: CpG-DNA costimulates antigen reactive T cells. Curr Top Microhiol Immunol 2000;247:93-105.
68. Sun S, Zhang X, Tough DF, Sprent J: Type I interferon-mediated stimulation of T cells by CpG DNA. J Exp Med 1998;188:2335-2342.
69. Cowdery JS, Chace JH, Yi AK, Krieg AM: Bacterial DNA induces NK cells to produce IFN-gamma in vivo and increases the toxicity of lipopolysaccharides. J Immunol 1996;156: 4570-4575.
70. Chace JH, Hooker NA, Mildenstein KL, Krieg A. Cowdery JS: Bacterial DNA-induced NK cell IFN-gamma production is dependent on macrophage secretion of IL-12. Clin Immunol Immunopathol 1997;84:185-193.
71. Halpern MD, Kurlander RJ, Pisetsky DS: Bacterial DNA induces murine interferon-gamma production by stimulation of interleukin-12 and tumor necrosis factor-alpha. Cell Immunol 1996;167:72-78.
72. Iho S, Yamamoto T, Takahashi T, Yamamoto S: 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 1999;163:3642-3652.
73. Sparvasser T, Miethke T, Lipford GB, Borschert K, Häcker H, Heeg K, Wagner H: Bacterial DNA causes septic shock. Nature 1997; 386:336-337.
74. Lipford GB, Sparwasser T, Zimmermann S, Heeg K, Wagner H: CpG-DNA-mediated transient lymphoadenopathy is associated with a state of Th1 predisposition to antigen-driven responses. Submitted.
75. Klinman DM, Conover J, Coban C: Repeated administration of synthetic oligodeoxynucleotides expressing CpG motifs provides longterm protection against bacterial infection. Infect Immun 1999;67:5658-5663.
76. Krieg AM, Love-Homan L, Yi AK, Harty JT: CpG DNA induces sustained IL-12 expression in vivo and resistance to Listeria monocytogenes challenge. J Immunol 1998;161:2428-2434.
77. Weiner GJ, Liu HM, Wooldridge JF, Dahle CE, Krieg AM: Immunostimulatory oligodeoxynucleotides containing the CpG motif are effective as immune adjuvants in tumor antigen immunization. Proc Natl Acad Sci USA 1997; 94:10833-10837.
78. Roman M, Martin-Orozco E, Goodman JS, Nguyen M-D, Sato Y, Ronaghy A, Kornhluth RS, Richman DD, Carson DA, Raz E: Immunostimulatory DNA sequences function as T helper-1-promoting adjuvants. Nat Med 1997; 3:849-854.
79. Lipford GB, Bauer M, Blank C, Reiter R, Wagner H, Heeg K: CpG-containing synthetic oligonucleotides promote B and cytotoxic T cell responses to protein antigen: A new class of vaccine adjuvants. Eur J Immunol 1997;27: 2340-2344.
80. Davis HL, Weeranta R, Waldschmidt TJ, Tygrett L, Schorr J, Krieg AM: CpG DNA is a potent enhancer of specific immunity in mice immunized with recombinant hepatitis B surface antigen. J Immunol 1998;160:870-876.
81. Jones TR, Obaldia N 3rd, Gramzinski RA, Charoenvit Y, Kolodny N, Kitov S, Davis HL, Krieg AM, Hoffman SL: Synthetic oligodeoxynucleotides containing CpG motifs enhance immunogenicity of a peptide malaria vaccine in Aotus monkeys. Vaccine 1999;17:3065-3071.
82. Chu RS, Targoni OS, Krieg AM, Lehmann PV, Harding CV: CpG oligodeoxynucleotides act as adjuvants that switch on T helper 1 (Th1) immunity. J Exp Med 1997;186:1623-1631.
83. Carson DA, Raz E: Oligonucleotide adjuvants for T helper 1 (Th1)-specific vaccination. J Exp Med 1997;186:1621-1622.
84. Moldoveanu Z, Love-Homan L, Huang WQ, Krieg AM: CpG DNA, a novel immune enhancer for systemic and mucosal immunization with influenza virus. Vaccine 1998;16: 1216-1224.
85. Horner AA, Ronaghy A, Cheng PM, Nguyen MD. Cho HJ, Broide D, Raz E: Immunostimulatory DNA is a potent mucosal adjuvant. Cell Immunol 1998;190:77-82.
86. McCluskie MJ, Davis HL: CpG DNA as mucosal adjuvant. Vaccine 1999;18:231-237.
87. Bevan MJ: Antigen presentation to cytotoxic T lymphocytes in vivo. J Exp Med 1995;182: 639-641.
88. Moore MW, Carbone FR, Bevan MJ: Introduction of soluble protein into the class I pathway of antigen processing and presentation. Cell 1988;54:777-785.
89. Lipford GB, Wagner H, Heeg K: Vaccination with immunodominant peptides encapsulated in Quil A-containing liposomes induces peptide-specific primary CD8+ cytotoxic T cells. Vaccine 1994;12:73-80.
90. Rock KL: A new foreign policy: MHC class I molecules monitor the outside world. Immunol Today 1996;17:131-137.
91. Bachmann MF, Lutz MB, Layton GT, Harris SJ, Fehr T, Reseigno M, Ricciardi-Castagnoli P: Dendritic cells process exogenous viral proteins and virus-like particles for class I presentation to CD8+ cytotoxic T lymphocytes. Eur J Immunol 1996;26:2595-2600.
92. Paglia P, Chiodoni C, Rodolfo M, Colombo MP: Murine dendritic cells loaded in vitro with soluble protein prime cytotoxic T lymphocytes against tumor antigen in vivo. J Exp Med 1996; 183:317-322.
93. Sparwasser T, Hültner L, Koch ES, Luz A, Lipford GB, Wagner H: Immunostimulatory CpG-oligodeoxynucleotides cause extramedullary murine hemopoiesis. J Immunol 1999;162: 2368-2374.
94. Lang R, Hültner L, Lipford GB, Wagner H, Heeg K: Guanosine-rich oligodeoxynucleotides induce proliferation of macrophage progenitors in cultures of murine bone marrow. Eur J Immunol 1999;29:3496-3506.
95. Lipford GB, Sparwasser T, Bauer M, Zimmermann S, Koch ES, Heeg K, Wagner H: Immunostimulatory DNA: Sequence-dependent production of potentially harmful or useful cytokines. Eur J Immunol 1997;27:3420-3426.
96. Mosmann TR, Sad S: The expanding universe of T cell subsets: Th1, Th2 and more. Immunol Today 1996;17:138-146.
97. Robinson D, Shibuya K, Mui A, Zonin F, Murphy E, Sana T, Hartley SB, Menon S, Kastelein R, Bazan F, O'Garra A: IGIF does not drive Th1 development but synergizes with IL-12 for interferon-gamma production and activates IRAK and NFkappaB. Immunity 1997;7:571-581.
98. Raz E, Tighe H, Sato Y, Corr M, Dudler JA, Roman M, Swain SL, Spiegelberg HL, Carson DA: Preferential induction of a Th1 immune response and inhibition of specific IgE antibody formation by plasmid DNA immunization. Proc Natl Acad Sci USA 1996;93:5141-5145.
99. Zimmermann S, Egeter O, Hausmann S, Lipford GB, Röcken M, Wagner H, Heeg K: CpG oligodeoxynucleotides trigger protective and curative Th1 responses in lethal murine leishmaniasis. J Immunol 1998;160:3627-3630.
100. Locksley RM, Louis JA: Immunology of leishmaniasis. Curr Opin Immunol 1992;4:413-418.
101. Stenger S, Donhauser N, Thüring H, Röllinghoff M, Bogdan C: Reactivation of latent leishmaniasis by inhibition of inducible nitric oxide synthase. J Exp Med 1996;183:1501-1514.
102. Walker PS, Scharlon-Kersten T, Krieg AM, Love-Homan L, Rowton ED, Udey MC, Vogel JC: Immunostimulatory oligodeoxynucleotides promote protective immunity and provide systemic therapy for leishmaniasis via IL-I2-and IFN-gamma-dependent mechanisms. Proc Natl Acad Sci USA 1999;96: 6970-6975.
103. Stacey KJ, Blackwell JM: Immunostimulatory DNA as an adjuvant in vaccination against Leishmania major. Infect Immun 1999;67: 3719-3726.
104. Kline JN, Waldschmidt TJ, Businga TR, Lemish JE, Weinstock JV, Thorne PS, Krieg AM: Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J Immunol 1998;160:2555-2559.
105. Kline JN, Krieg AM, Waldschmidt TJ, Ballas ZK, Jain V, Businga TR: CpG oligodeoxynucleotides do not require TH1 cytokines to prevent eosinophilic airway inflammation in a murine model of asthma. J Allergy Clin Immunol 1999;104:1258-1264.
106. Broide D, Schwarze J, Tighe H, Gifford T, Nguyen MD, Malek S, Van Uden J, Martin-Orozco E, Gelfand EW, Raz E: Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation, and airway hyperresponsiveness in mice. J Immunol 1998;161: 7054-7062.
107. Broide D, Raz E: DNA-based immunization for asthma. Int Arch Allergy Immunol 1999; 118:453-456.
108. Bohle B, Jahn-Schmid B, Maurer D, Kraft D, Ebner C: Oligodeoxynucleotides containing CpG motifs induce IL-12, IL-18 and IFN-gamma production in cells from allergic individuals and inhibit IgE synthesis in vitro. Eur J Immunol 1999;29:2344-2353.
109. Schwartz DA, Quinn TJ, Thorne PS, Sayeed S, Yi AK, Krieg AM: CpG motifs in bacterial DNA cause inflammation in the lower respiratory tract. J Clin Invest 1997;100:1-6.
110. Deng GM, Nilsson IM, Verdrengh M, Collins LV, Tarkowski A: Intra-articularly localized bacterial DNA containing CpG motifs induces arthritis. Nat Med 1999;5:702-705.
111. Hilton DJ, Richardson RT, Alexander WS, Viney EM, Willson TA, Sprigg NS, Starr R, Nicholson SE, Metcalf D, Nicola NA: Twenty proteins containing a C-terminal SOCS box form five structural classes. Proc Natl Acad Sci USA 1998;95:114-119.
112. Tsunoda I, Tolley ND, Theil DJ, Whitton JL, Kobayashi H, Fujinami RS: Exacerbation of viral and autoimmune animal models for multiple sclerosis by bacterial DNA. Brain Pathol 1999;9:481-493.
113. Krieg AM, Love-Homan L, Yi AK, Harty JT: CpCi DNA induces sustained IL-12 expression in vivo and resistance to Listeria monocytogenes challenge. J Immunol 1998;161: 2428-2434.
114. Krieg AM, Wu T, Wecratna R, Efler SM, Love-Homan L, Yang L, Yi AK, Short D, Davis HL: Sequence motifs in adenoviral DNA block immune activation by stimulatory CpG motifs. Proc Natl Acad Sci USA 1998;95:12631-12636.
115. Hartmann G, Krieg AM: CpG DNA and LPS induce distinct patterns of activation in human monocytes. Gene Ther 1999;6:893-903.
116. Tang DC, DeVit M, Johnston SA: Genetic immunization is a simple method for eliciting an immune response. Nature 1992;356:152-154.
117. Sato Y, Roman M, Tighe H, Lee D, Corr M, Nguyen MD, Silverman GJ, Lotz M, Carson DA, Raz E: Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 1996;273:352-354.
118. Weeratna R, Brazolot Millan CL, Krieg AM, Davis HL: Reduction of antigen expression from DNA vaccines by coadministered oligodeoxynucleotides. Antisense Nucleic Acid Drug Dev 1998;8:351-356.
119. McCluskie MJ, Brazolot Millan CL, Gramzinski RA, Robinson HL, Santoro JC, Fuller JT, Widera G, Haynes JR, Purcell RH, Davis HL: Route and method of delivery of DNA vaccine influence immune response in mice and non-human primates. Mol Med 1999;5: 287-300.
120. Spiegelberg HL, Tighe H, Roman M, Broide D. Raz E: Inhibition of IgE formation and allergic inflammation by allergen gene immunization and by CpG motif immunostimulatory oligodeoxynucleotides. Allergy 1998;53: 93-97.
121. Goodman JS, Van Uden JH, Kobayashi H, Broide D, Raz E: DNA immunotherapeutics: New potential treatment modalities for allergic disease. Int Arch Allergy Immunol 1998; 116:177-187.
122. Spiegelberg HL, Broide D, Tighe H, Roman M, Raz E: Inhibition of allergic inflammation in the lung by plasmid DN A allergen immunization. Pediatr Pulmonol Suppl 1999;18: 118-121.
123. Metzger WJ, Nyce JW: Oligonucleotide therapy of allergic asthma. J Allergy Clin Immunol 1999;104:260-266.
124. Alm JS, Lilja G, Pershagen G, Scheynius A: Early BCG vaccination and development of atopy. Lancet 1997;350:400-403.
125. Shirakawa T, Enomoto T, Shimazu SI, Hopkin JM: The inverse association between tuberculin responses and atopic disorder. Science 1997;275:77-79.
126. Ring J: Allergy and modern society: Does 'Western life style' promote the development of allergies? Int Arch Allergy Immunol 1997; 113:7-10.
127. Erb KJ, Holloway JW, Sobeck A, Moll H, Le Gros G: Infection of mice with Mycobacterium bovis-Bacillus Calmette-Guérin (BCG) suppresses allergen-induced airway-cosino-philia. J Exp Med 1998;187:561-569.
128. Wang CC, Rook GAW: Inhibition of an established allergic response to ovalbumin in BALB/c mice by killed Mycobacterium vaccae. Immunology 1998;93:307-313.