Skip to main content
SpringerLink
Log in

Immune modulatory oligonucleotides in the prevention and treatment of allergen-induced eustachian tube dysfunction in the animal model

  • Published:
Current Allergy and Asthma Reports Aims and scope Submit manuscript

Abstract

This article reviews the current literature investigating the applications and success of immune modulatory oligonucleotides as immunotherapy to treat and prevent allergen-induced eustachian tube dysfunction in animal models. Synthetic DNA-based immunotherapy agents composed of unmethylated cytosine-guanine dinucleotides (CpG ODNs) that bind to Toll-like receptors have been found to have tremendous potential as therapeutic agents and adjuvants. CpG ODNs can induce a shift in the cytokine profile and immune response that favors the T-helper type 1 pathway and suppresses the T-helper type 2 pathway. This makes CpG ODNs promising candidates for treating allergic diseases. Current CpG ODN studies have demonstrated prevention and treatment of acute allergen inflammation of the eustachian tube in an animal model of otitis media. Immune modulatory oligonucleotides in immunotherapy, administered systemically or topically, have been shown to be safe and effective in the animal model.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Daly KA, Hunter LL, Giebink GS: Chronic otitis media with effusion. Pediatr Rev 1999, 20:85–93; quiz 94.

    Article  PubMed  CAS  Google Scholar 

  2. Doyle WJ: The link between allergic rhinitis and otitis media. Curr Opin Allergy Clin Immunol 2002, 2:21–25.

    Article  PubMed  Google Scholar 

  3. Nguyen LH, Manoukian JJ, Sobol SE, et al.: Similar allergic inflammation in the middle ear and the upper airway: evidence linking otitis media with effusion to the united airways concept. J Allergy Clin Immunol 2004, 114:1110–1115.

    Article  PubMed  Google Scholar 

  4. Irander K, Borres MP, Bjorksten B: Middle ear diseases in relation to atopy and nasal metachromatic cells in infancy. Int J Pediatr Otorhinolaryngol 1993, 26:1–9.

    Article  PubMed  CAS  Google Scholar 

  5. Tomonaga K, Kurono Y, Mogi G: The role of nasal allergy in otitis media with effusion. A clinical study. Acta Otolaryngol Suppl 1988, 458:41–47.

    Article  PubMed  CAS  Google Scholar 

  6. Jero J, Virtanen M, Eskola J, et al.: Factor predicting poor outcome of acute otitis media in children. In Sixth International Symposium on Recent Advances in Otitis Media. 1996. Hamilton, Ontario: BC Decker; 1996.

    Google Scholar 

  7. Rosenfeld RM, Culpepper L, Doyle KJ, et al.: Clinical practice guideline: otitis media with effusion. Otolaryngol Head Neck Surg 2004, 130(5 Suppl):S95–S118.

    Article  Google Scholar 

  8. Fireman P: Otitis media and eustachian tube dysfunction: connection to allergic rhinitis. J Allergy Clin Immunol 1997, 99:S787–S797.

    Article  PubMed  CAS  Google Scholar 

  9. Bernstein JM: Role of allergy in eustachian tube blockage and otitis media with effusion: a review. Otolaryngol Head Neck Surg 1996, 114:562–568.

    Article  PubMed  CAS  Google Scholar 

  10. Bernstein JM: Allergic disease and the middle ear. In Allergy and Immunology. An Otolaryngic Approach, edn 1. Edited by Krouse J. Philadelphia: Lippincott Williams & Wilkins; 2002:192–200.

    Google Scholar 

  11. Bluestone CD, Doyle WJ: Anatomy and physiology of eustachian tube and middle ear related to otitis media. J Allergy Clin Immunol 1988, 81:997–1003.

    Article  PubMed  CAS  Google Scholar 

  12. Lazo-Saenz JG, Galvan-Aguilera AA, Martinez-Ordaz VA, et al.: Eustachian tube dysfunction in allergic rhinitis. Otolaryngol Head Neck Surg 2005, 132:626–629.

    Article  PubMed  Google Scholar 

  13. Takahashi H, Hayashi M, Sato H, et al.: Primary deficits in eustachian tube function in patients with otitis media with effusion. Arch Otolaryngol Head Neck Surg 1989, 115:581–584.

    PubMed  CAS  Google Scholar 

  14. Miller GF Jr: Eustachian tubal function in normal and diseased ears. Arch Otolaryngol 1965, 81:41–48.

    PubMed  Google Scholar 

  15. Hurst DS, Venge P: Levels of eosinophil cationic protein and myeloperoxidase from chronic middle ear effusion in patients with allergy and/or acute infection. Otolaryngol Head Neck Surg 1996, 114:531–544.

    Article  PubMed  CAS  Google Scholar 

  16. Hurst DS, Amin K, Seveus L, et al.: Evidence of mast cell activity in the middle ears of children with otitis media with effusion. Laryngoscope 1999, 109:471–477.

    Article  PubMed  CAS  Google Scholar 

  17. Wright ED, Hurst D, Miotto D, et al.: Increased expression of major basic protein (MBP) and interleukin-5 (IL-5) in middle ear biopsy specimens from atopic patients with persistent otitis media with effusion. Otolaryngol Head Neck Surg 2000, 123:533–538.

    Article  PubMed  CAS  Google Scholar 

  18. Ebmeyer J, Furukawa M, Pak K, et al.: Role of mast cells in otitis media. J Allergy Clin Immunol 2005, 116:1129–1135.

    Article  PubMed  CAS  Google Scholar 

  19. Sobol SE, Taha R, Schloss MD, et al.: T(H)2 cytokine expression in atopic children with otitis media with effusion. J Allergy Clin Immunol 2002, 110:125–130.

    Article  PubMed  CAS  Google Scholar 

  20. Bernstein JM, Doyle WJ: Role of IgE-mediated hypersensitivity in otitis media with effusion: pathophysiologic considerations. Ann Otol Rhinol Laryngol Suppl 1994, 163:15–19.

    PubMed  CAS  Google Scholar 

  21. Tokunaga T, Yamamoto H, Shimada S, et al.: Antitumor activity of deoxyribonucleic acid fraction from Mycobacterium bovis BCG. I. Isolation, physicochemical characterization, and antitumor activity. J Natl Cancer Inst 1984, 72:955–962.

    PubMed  CAS  Google Scholar 

  22. Klinman DM, Currie D, Gursel I, et al.: Use of CpG oligodeoxynucleotides as immune adjuvants. Immunol Rev 2004, 199:201–216.

    Article  PubMed  CAS  Google Scholar 

  23. Nakamura I, Kajino K, Bamba H, et al.: Phenotypic stability of mature dendritic cells tuned by TLR or CD40 to control the efficiency of cytotoxic T cell priming. Microbiol Immunol 2004, 48:211–219.

    PubMed  CAS  Google Scholar 

  24. Klinman DM: Use of CpG oligodeoxynucleotides as immunoprotective agents. Expert Opin Biol Ther 2004, 4:937–946.

    Article  PubMed  CAS  Google Scholar 

  25. Heeg K, Dalpke A, Peter M, et al.: Structural requirements for uptake and recognition of CpG oligonucleotides. Int J Med Microbiol 2008, 298:33–38.

    Article  PubMed  CAS  Google Scholar 

  26. Dalpke A, Zimmermann S, Heeg K: CpG-oligonucleotides in vaccination: signaling and mechanisms of action. Immunobiology 2001, 204:667–676.

    Article  PubMed  CAS  Google Scholar 

  27. Dalpke A, Zimmermann S, Heeg K: CpG DNA in the prevention and treatment of infections. BioDrugs 2002, 16:419–431.

    Article  PubMed  CAS  Google Scholar 

  28. Hussain I, Kline JN: CpG oligodeoxynucleotides: a novel therapeutic approach for atopic disorders. Curr Drug Targets Inflamm Allergy 2003, 2:199–205.

    Article  PubMed  CAS  Google Scholar 

  29. Xu W, Tamura T, Takatsu K: CpG ODN mediated prevention from ovalbumin-induced anaphylaxis in mouse through B cell pathway. Int Immunopharmacol 2008, 8:351–361.

    Article  PubMed  CAS  Google Scholar 

  30. Hayashi T, Beck L, Rossetto C, et al.: Inhibition of experimental asthma by indoleamine 2,3-dioxygenase. J Clin Invest 2004, 114:270–279.

    PubMed  CAS  Google Scholar 

  31. Hayashi T, Raz E: TLR9-based immunotherapy for allergic disease. Am J Med 2006, 119:897.e1–897.e6.

    Article  CAS  Google Scholar 

  32. Takeshita F, Leifer CA, Gursel I, et al.: Cutting edge: role of Toll-like receptor 9 in CpG DNA-induced activation of human cells. J Immunol 2001, 167:3555–3558.

    PubMed  CAS  Google Scholar 

  33. Klinman DM: Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol 2004, 4:249–258.

    Article  PubMed  CAS  Google Scholar 

  34. Wilson HL, Dar A, Napper SK, et al.: Immune mechanisms and therapeutic potential of CpG oligodeoxynucleotides. Int Rev Immunol 2006, 25:183–213.

    Article  PubMed  CAS  Google Scholar 

  35. Kandimalla ER, Bhagat L, Zhu FG, et al.: A dinucleotide motif in oligonucleotides shows potent immunomodulatory activity and overrides species-specific recognition observed with CpG motif. Proc Natl Acad Sci U S A 2003, 100:14303–14308.

    Article  PubMed  CAS  Google Scholar 

  36. Krieg AM, Efler SM, Wittpoth M, et al.: Induction of systemic Th1-like innate immunity in normal volunteers following subcutaneous but not intravenous administration of CPG 7909, a synthetic B-class CpG oligodeoxynucleotide TLR9 agonist. J Immunother 2004, 27:460–471.

    Article  PubMed  CAS  Google Scholar 

  37. Matheu V, Treschow A, Teige I, et al.: Local therapy with CpG motifs in a murine model of allergic airway inflammation in IFN-beta knock-out mice. Respir Res 2005, 6:25.

    Article  PubMed  CAS  Google Scholar 

  38. Kodama S, Hirano T, Abe N, et al.: Local application of CpG oligodeoxynucleotide enhances nontypeable Haemophilus influenzae-specific mucosal IgA responses in the middle ear. Acta Otolaryngol 2007, 127:809–815.

    Article  PubMed  CAS  Google Scholar 

  39. Ebert CS Jr, Pollock HW, Dubin MG, et al.: Effect of intranasal histamine challenge on eustachian tube function. Int J Pediatr Otorhinolaryngol 2002, 63:189–198.

    Article  PubMed  Google Scholar 

  40. Zhang XD, Andrew ME, Hubbs AF, et al.: Airway responses in Brown Norway rats following inhalation sensitization and challenge with trimellitic anhydride. Toxicol Sci 2006, 94:322–329.

    Article  PubMed  CAS  Google Scholar 

  41. Knippels LM, Penninks AH, Spanhaak S, et al.: Oral sensitization to food proteins: a Brown Norway rat model. Clin Exp Allergy 1998, 28:368–375.

    Article  PubMed  CAS  Google Scholar 

  42. Sur S, Lam J, Bouchard P, et al.: Immunomodulatory effects of IL-12 on allergic lung inflammation depend on timing of doses. J Immunol 1996, 157:4173–4180.

    PubMed  CAS  Google Scholar 

  43. Flisberg K, Ingelstedt S, Ortegren U: The valve and “locking” mechanisms of the eustachian tube. Acta Otolaryngol Suppl 1963, 182:57–68.

    Article  Google Scholar 

  44. Ebert CS Jr, Rose AS, Blanks DA, et al.: Immune modulatory oligonucleotides in prevention of nasal allergen-induced eustachian tube dysfunction in rats. Otolaryngol Head Neck Surg 2007, 137:250–255.

    Article  PubMed  Google Scholar 

  45. Blanks DA, Ebert CS Jr, Eapen RP, et al.: Immune modulatory oligonucleotides in the prevention and treatment of OVA-induced eustachian tube dysfunction in rats. Otolaryngol Head Neck Surg 2007, 137:321–326.

    Article  PubMed  Google Scholar 

  46. Chaung HC: CpG oligodeoxynucleotides as DNA adjuvants in vertebrates and their applications in immunotherapy. Int Immunopharmacol 2006, 6:1586–1596.

    Article  PubMed  CAS  Google Scholar 

  47. Krieg AM: CpG DNA: trigger of sepsis, mediator of protection, or both? Scand J Infect Dis 2003, 35:653–659.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Otolaryngology-Head and Neck Surgery, University of North Carolina at Chapel Hill, CB# 7070, G0412 Neurosciences Hospital, Chapel Hill, NC, 27599-7070, USA

    Deidra A. Blanks

Authors
  1. Deidra A. Blanks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charles S. Ebert Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Deidra A. Blanks.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Blanks, D.A., Ebert, C.S. Immune modulatory oligonucleotides in the prevention and treatment of allergen-induced eustachian tube dysfunction in the animal model. Curr Allergy Asthma Rep 8, 508–512 (2008). https://doi.org/10.1007/s11882-008-0093-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11882-008-0093-8

Keywords

Search

Navigation