Skip to main content

Advertisement

Log in

Immunomodulators in asthma therapy

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

Abstract

New developments in the field of allergy and immunology have yielded a variety of novel therapeutic approaches in recent years, and more agents are at the clinical trial stage. Among the therapeutic approaches discussed in this review are Toll-like receptor agonists, immunostimulatory oligodeoxynucleotides, orally and parenterally administered cytokine blockers, and specific cytokine receptor antagonists. Transcription factor modulators targeting syk kinase, peroxisome proliferator-activated receptor-γ, and nuclear factor-κB are also being evaluated in the treatment of asthma. The anti-IgE monoclonal antibody omalizumab has established effectiveness in patients with allergic asthma, but the criteria for selecting patients who are most likely to benefit from it are less clear. This review summarizes data from human clinical trials with immunomodulators to discuss the rationale for their use, their efficacy, and adverse events associated with them.

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

Access this article

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. Casale TB, Stokes JR: Immunomodulators for allergic respiratory disorders. J Allergy Clin Immunol 2008, 121:288–296.

    Article  CAS  PubMed  Google Scholar 

  2. Fiedler G: Long-term efficacy of short course subcutaneous immunotherapy containing monophosphoryl lipid A adjuvant administered in a clinical setting [abstract P1769]. Allergy 2008, 63:612–621.

    Article  Google Scholar 

  3. Krieg AM: Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov 2006, 5:471–484.

    Article  CAS  PubMed  Google Scholar 

  4. Bhattacharjee RN, Akira S: Modifying Toll-like receptor 9 signaling for therapeutic use. Mini Rev Med Chem 2006, 6:287–291.

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  6. Kline JN: Eat dirt: CpG DNA and immunomodulation of asthma. Proc Am Thorac Soc 2007, 4:283–288.

    Article  CAS  PubMed  Google Scholar 

  7. Higgins D, Rodriquez R, Milley R, et al.: Modulation of immunogenicity and allergenicity by controlling the number of immunostimulatory oligonucleotides linked to Amb a 1. J Allergy Clin Immunol 2006, 118:504–510.

    Article  CAS  PubMed  Google Scholar 

  8. Creticos PS, Shroeder JT, Hamilton RG, et al.: Immunotherapy with ragweed-toll-like receptor agonist vaccine for allergic rhinitis. N Engl J Med 2006, 355:1445–1455.

    Article  CAS  PubMed  Google Scholar 

  9. Tulic MK, Fiset PO, Christodoulopoulos P, et al.: Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response. J Allergy Clin Immunol 2004, 113:235–241.

    Article  CAS  PubMed  Google Scholar 

  10. Gauvreau GM, Hessel EM, Boulet LP, et al.: Immunostimulatory sequences regulate interferon-inducible genes but not allergic airway responses. Am J Respir Crit Care Med 2006, 174:15–20.

    Article  CAS  PubMed  Google Scholar 

  11. Blaziene A: CYT003-QbG10, a novel allergen-independent immunotherapy, shown to be safe and efficacious in placebo-controlled phase II study [abstract 19]. Presented at the Annual Meeting of the American College of Allergy, Asthma and Immunology. Seattle, WA; November 6–11, 2008.

  12. Lamkhioued B, Soussi Gounni A, Hamid Q, et al.: The CCR-3 receptor is involved in eosinophil differentiation and is upregulated by TH2 cytokines in CD341 progenitor cells. J Immunol 2003, 170:537–547.

    CAS  PubMed  Google Scholar 

  13. Martinez-Moczygemba M, Huston DP: Biology of common B receptor-signaling cytokines: IL-3, IL-5 and GM-CSF. J Allergy Clin Immunol 2003, 112:653–665.

    Article  CAS  PubMed  Google Scholar 

  14. Gauvreau GM, Boulet LP, Cockcroft DW, et al.: Antisense therapy against CCR3 and the common beta chain attenuates allergen-induced eosinophilic responses. Am J Respir Crit Care Med 2008, 177:952–958.

    Article  CAS  PubMed  Google Scholar 

  15. Ishiura Y, Fujimura M, Yamamoto H, et al.: Effect of an orally active Th2 cytokine inhibitor, suplatast on “atopic cough” tosilate. Arzneimittelforschung 2008, 58:297–302.

    CAS  PubMed  Google Scholar 

  16. Agrawal DK, Cheng G, Kim MJ, Kiniwa M: Interaction of suplatast tosilate (IPD) with chloride channels in human blood eosinophils: a potential mechanism underlying its anti-allergic and anti-asthmatic effects. Clin Exp Allergy 2008, 38:305–312.

    CAS  PubMed  Google Scholar 

  17. Tanaka A, Minoguchi K, Samson KT, et al.: Inhibitory effects of suplatast tosilate on the differentiation and function of monocyte-derived dendritic cells from patients with asthma. Clin Exp Allergy 2007, 37:1083–1089.

    Article  CAS  PubMed  Google Scholar 

  18. Yoshihara S, Ono M, Yamada Y, et al.: Early intervention with suplatast tosilate for prophylaxis of pediatric atopic asthma: a pilot study. Pediatr Allergy Immunol 2009 Jan 30 (Epub ahead of print).

  19. Borish LC, Nelson HS, Corren J, et al.: Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol 2001, 107:963–970.

    Article  CAS  PubMed  Google Scholar 

  20. Haldar P, Brightling CE, Hargadon B, et al.: Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009, 360:973–984.

    Article  CAS  PubMed  Google Scholar 

  21. Nair P, Pizzichini MM, Kjarsgaard M, et al.: Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009, 360:985–993.

    Article  CAS  PubMed  Google Scholar 

  22. Walsh GM: Reslizumab, a humanized anti-IL-5 mAb for the treatment of eosinophil-mediated inflammatory conditions. Curr Opin Mol Ther 2009, 11:329–336.

    PubMed  Google Scholar 

  23. Borowski A, Kuepper M, Horn U, et al.: Interleukin-13 acts as an apoptotic effector on lung epithelial cells and induces pro-fibrotic gene expression in lung fibroblasts. Clin Exp Allergy 2008, 38:619–628.

    Article  CAS  PubMed  Google Scholar 

  24. Blanchard C, Mishra A, Saito-Akei H, et al.: Inhibition of human interleukin-13-induced respiratory and oesophageal inflammation by anti-human-interleukin-13 antibody (CAT-354). Clin Exp Allergy 2005, 35:1096–1103.

    Article  CAS  PubMed  Google Scholar 

  25. Bree A, Schlerman FJ, Wadanoli M, et al.: IL-13 blockade reduces lung inflammation after Ascaris suum challenge in cynomolgus monkeys. J Allergy Clin Immunol 2007, 119:1251–1257.

    Article  CAS  PubMed  Google Scholar 

  26. MedImmune Cambridge (formerly Cambridge Antibody Technology): MedImmune advances asthma program with start of a phase 2 trial in Europe and Australia and first U.S.-based clinical trial for antibody targeting IL-13. http://phx.corporate-ir.net/phoenix.zhtml?c=83037&p=irolinvestornewsArticle&ID=1129725&highlight=. Accessed August 28, 2009.

  27. Blease K: Therapeutics targeting IL-13 for the treatment of pulmonary inflammation and airway remodeling. Curr Opin Investig Drugs 2008, 9:1180–1184.

    CAS  PubMed  Google Scholar 

  28. Corren J, Busse W, Meltzer E, et al.: Efficacy and safety of AMG 317, an IL-4Ra antagonist, in atopic asthmatic subjects: a randomized, double-blind, placebo-controlled study. J Allergy Clin Immunol 2009, 123:732.

    Article  Google Scholar 

  29. Aerovance: Aerovance announces positive top-line results from phase 2a trial of inhaled AEROVANT in asthma patients. Available at http://www.aerovance.com/news/press-releases/Press-Releases/Aerovance-Announces-Positive-Top-Line-Results-from-Phase-2a-Trial-of-Inhaled-AEROVANT-in-Asthma-Patients-88. Accessed August 28, 2009.

  30. Aerovance: Aerovance announces phase IIb clinical trial with AEROVANT for the treatment of uncontrolled asthma. Available at http://www.aerovance.com/news/press-releases/Press-Releases/Aerovance-Initiates-Phase-IIb-Clinical-Trial-with-AEROVANT-for-the-Treatment-of-Uncontrolled-Asthma-80. Accessed August 28, 2009.

  31. Busse WW, Israel E, Nelson HS, et al.; Daclizumab Asthma Study Group: Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. Am J Respir Crit Care Med 2008, 178:1002–1008.

    Article  CAS  PubMed  Google Scholar 

  32. Wenzel SE, Barnes PJ, Bleecker ER, et al.; T03 Asthma Investigators: A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med 2009, 179:549–558.

    Article  CAS  PubMed  Google Scholar 

  33. Barnes PJ: Novel signal transduction modulators for the treatment of airway diseases. Pharmacol Ther 2006, 109:238–245.

    Article  CAS  PubMed  Google Scholar 

  34. Rigel Pharmaceuticals: Rigel announces initiation of phase 1 trial of R343 for allergic asthma by its partner Pfizer [press release]. Available at http://ir.rigel.com/phoenix.zhtml?c=120936&p=irol-newsArticle&ID=1084738. Accessed June 12, 2009.

  35. Meltzer EO, Berkowitz RB, Grossbard EB: An intranasal syk-kinase inhibitor (R112) improves the symptoms of seasonal allergic rhinitis in a park environment. J Allergy Clin Immunol 2005, 115:791–796.

    Article  CAS  PubMed  Google Scholar 

  36. Spears M, McSharry C, Thomson NC: Peroxisome proliferator-activated receptor gamma agonists as potential anti-inflammatory agents in asthma and chronic obstructive pulmonary disease. Clin Exp Allergy 2006, 36:1494–1504.

    Article  CAS  PubMed  Google Scholar 

  37. Belvisi MG, Hele DJ: Peroxisome proliferator-activated receptors as novel targets in lung disease. Chest 2008, 134:152–157.

    Article  CAS  PubMed  Google Scholar 

  38. ClinicalTrials.gov: The use of rosiglitazone to treat asthma. Available at http://clinicaltrials.gov/ct2/show/NCT00614874. Accessed June 12, 2009.

  39. ClinicalTrials.gov: Pioglitazone hydrochloride to treat asthma. Available at http://clinicaltrials.gov/ct2/show/NCT00604578. Accessed June 12, 2009.

  40. Lin H, Boesel K, Griffith D, et al.: Omalizumab rapidly decreases nasal allergic response and FcepsilonRI on basophils. J Allergy Clin Immunol 2004, 113:297–302.

    Article  CAS  PubMed  Google Scholar 

  41. van Rensen EL, Evertse CE, van Schadewijk WA, et al.: Eosinophils in bronchial mucosa of asthmatics after allergen challenge: effect of anti-IgE treatment. Allergy 2009, 64:72–80.

    Article  PubMed  Google Scholar 

  42. Busse W, Corren J, Lanier BQ, et al.: Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 2001, 108:184–190.

    Article  CAS  PubMed  Google Scholar 

  43. Milgrom H, Berger W, Nayak A, et al.: Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics 2001, 108:e36.

    Article  CAS  PubMed  Google Scholar 

  44. Soler M, Matz J, Townley R, et al.: The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 2001, 18:254–261.

    Article  CAS  PubMed  Google Scholar 

  45. Corren J, Casale TB, Deniz Y, Ashby M: Omalizumab, a recombinant humanized anti-IgE antibody, reduces asthma-related emergency room visits and hospitalizations in patients with allergic asthma. J Allergy Clin Immunol 2003, 111:87–90.

    Article  CAS  PubMed  Google Scholar 

  46. Berger W, Ostrom N, Soler M, et al.: Omalizumab significantly reduces asthma exacerbations in patients with severe persistent asthma: a pooled analysis. J Allergy Clin Immunol 2005, 115:S75.

    Article  Google Scholar 

  47. National Asthma Education and Prevention Program: Guidelines for the Diagnosis and Management of Asthma: Expert Panel Report 3. Bethesda, MD: National Institutes of Health/National Heart, Lung, and Blood Institute; 2007. [Publication no. 08-4051.] Available at http://www.nhlbi.nih.gov/guidelines/asthma.

    Google Scholar 

  48. Holgate ST, Chuchalin AG, Hebert J, et al.: Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma. Clin Exp Allergy 2004, 34:632.

    Article  CAS  PubMed  Google Scholar 

  49. Johansson A, Nopp H, Öman J, et al.: The size of the disease relevant IgE antibody fraction in relation to ‘total-IgE’ predicts the efficacy of anti-IgE (Xolair) treatment. Allergy 2009 Apr 14 (Epub ahead of print).

  50. Wu AC, Paltiel AD, Kuntz KM, et al.: Cost-effectiveness of omalizumab in adults with severe asthma: results from the Asthma Policy Model. J Allergy Clin Immunol 2007, 120:1146–1152.

    Article  CAS  PubMed  Google Scholar 

  51. Xolair [package insert]. South San Francisco, CA: Genentech; East Hanover, NJ: Novartis; 2008.

  52. US Food and Drug Administration: Omalizumab (marketed as Xolair). Available at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm085291.htm. Accessed August 28, 2009.

  53. Limb SL, Starke PR, Lee CE, Chowdhury BA: Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma. J Allergy Clin Immunol 2007, 120:1378–1381.

    Article  CAS  PubMed  Google Scholar 

  54. Corren J, Casale TB, Lanier B, et al.: Safety and tolerability of omalizumab. Clin Exp Allergy 2009, 39:788–797.

    Article  CAS  PubMed  Google Scholar 

  55. Cox L, Platts-Mills TAE, Finegold I, et al.: American Academy of Allergy Asthma & Immunology/American College of Allergy, Asthma and Immunology Task Force Joint Task Force Report on omalizumab-associated anaphylaxis. J Allergy Clin Immunol 2007, 120:1373–1377.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Thomas B. Casale.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dimov, V.V., Stokes, J.R. & Casale, T.B. Immunomodulators in asthma therapy. Curr Allergy Asthma Rep 9, 475–483 (2009). https://doi.org/10.1007/s11882-009-0070-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11882-009-0070-x

Keywords

Navigation