Abstract
Asthma and other atopic disorders have increased in prevalence and severity over the past three decades. Reduced risk of atopic disease associated with early life exposure to infections and microbes has raised the possibility that pathogen-associated molecular patterns (PAMPs) may confer protection against allergic disorders, a concept that has been named the “Hygiene Hypothesis”. This relationship is most likely mediated through the induction of specific patterns of anti-atopic immune responses that follow engagement of innate immune mechanisms. Bacterial DNA is one such immunostimulatory microbe-associated ligand, whose properties can be mimicked by oligodeoxynucleotides (ODN) containing unmethylated cytosine-guanine dinucleotides in specific base sequences (CpG motifs), motifs characteristic of prokaryotic DNA that have been suppressed in eukaryotic DNA. Based initially on observations that CpG ODN induced Th1-type patterns of immune responses, we proposed that CpG ODN might represent a novel therapeutic strategy for the prevention and treatment of atopic disorders. Current understanding suggests multiple mechanisms of action of CpG ODN, but our initial hypothesis has been supported by extensive studies demonstrating, in animal models, efficacy in both incipient and established atopic asthma. These preclinical studies are now being translated into clinical trials exploring this new approach to immunotherapy for atopic disease.
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References
Asthma-United States. 1982–1992. MMWR Morb Mortal Wkly Rep 1995;51–52:952–5.
Riedler J, Braun-Fahrlander C, Eder W, Schreuer M, Waser M, Maisch S, et al. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 2001;9288:1129–33.
Braun-Fahrlander C, Riedler J, Herz U, Eder W, Waser M, Grize L, et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med 2002;12:869–77.
von Mutius E, Martinez FD, Fritzsch C, Nicolai T, Reitmeir P, Thiemann HH. Skin test reactivity and number of siblings. Bmj 1994;6930:692–5.
Strachan DP. Hay fever, hygiene, and household size. Bmj 1989;6710:1259–60.
Shaheen SO, Aaby P, Hall AJ, Barker DJ, Heyes CB, Shiell AW, et al. Measles and atopy in Guinea-Bissau. Lancet 1996;9018:1792–6.
Waser M, von Mutius E, Riedler J, Nowak D, Maisch S, Carr D, et al. Exposure to pets, and the association with hay fever, asthma, and atopic sensitization in rural children. Allergy 2005;2:177–84.
Yazdanbakhsh M, van den Biggelaar A, Maizels RM. Th2 responses without atopy: immunoregulation in chronic helminth infections and reduced allergic disease. Trends Immunol 2001;7:372–7.
Yazdanbakhsh M, Kremsner PG, van Ree R. Allergy, parasites, and the hygiene hypothesis. Science 2002;5567:490–4.
Prescott SL, Macaubas C, Holt BJ, Smallacombe TB, Loh R, Sly PD, et al. Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the Th2 cytokine profile. J Immunol 1998;10:4730–7.
Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 1995;6522:546–9.
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;12:4570–5.
Klinman DM, Yi AK, Beaucage SL, Conover J, Krieg AM. CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon gamma. Proc Natl Acad Sci USA 1996;7:2879–83.
Kline JN, Waldschmidt TJ, Businga TR, Lemish JE, Weinstock JV, Thorne PS, et al. Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J Immunol 1998;6:2555–9.
Kitagaki K, Jain VV, Businga TR, Hussain I, Kline JN. Immunomodulatory effects of CpG oligodeoxynucleotides on established Th2 responses. Clin Diagn Lab Immunol 2002;6:1260–9.
Jain VV, Kitagaki K, Businga T, Hussain I, George C, O’Shaughnessy P, et al. CpG-oligodeoxynucleotides inhibit airway remodeling in a murine model of chronic asthma. J Allergy Clin Immunol 2002;6:867–72.
Jain VV, Businga TR, Kitagaki K, George CL, O’Shaughnessy PT, Kline JN. Mucosal immunotherapy with CpG oligodeoxynucleotides reverses a murine model of chronic asthma induced by repeated antigen exposure. Am J Physiol Lung Cell Mol Physiol 2003;5:L1137–46.
Kitagaki K, Businga TR, Kline JN. Oral administration of CpG-ODNs suppresses antigen-induced asthma in mice. Clin Exp Immunol 2006;2:249–59.
Kline JN, Kitagaki K, Businga TR, Jain VV. Treatment of established asthma in a murine model using CpG oligodeoxynucleotides. Am J Physiol Lung Cell Mol Physiol 2002;1:L170–9.
Chace JH, Hooker NA, Mildenstein KL, Krieg AM, Cowdery JS. Bacterial DNA-induced NK cell IFN-gamma production is dependent on macrophage secretion of IL-12. Clin Immunol Immunopathol 1997;2:185–93.
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;10:1623–31.
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;6:1258–64.
Yi AK, Yoon JG, Yeo SJ, Hong SC, English BK, Krieg AM. Role of mitogen-activated protein kinases in CpG DNA-mediated IL-10 and IL-12 production: central role of extracellular signal-regulated kinase in the negative feedback loop of the CpG DNA-mediated Th1 response. J Immunol 2002;9:4711–20.
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Kline, J.N. Immunotherapy of asthma using CpG oligodeoxynucleotides. Immunol Res 39, 279–286 (2007). https://doi.org/10.1007/s12026-007-0083-2
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DOI: https://doi.org/10.1007/s12026-007-0083-2