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  • Review Article
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New targets for allergic rhinitis — a disease of civilization

Nature Reviews Drug Discovery volume 2, pages 903–915 (2003)Cite this article

Key Points

  • Allergic rhinitis is a common manifestation of atopy whose prevalence world wide is increasing in association with a Western-type lifestyle.

  • Pathogenesis involves the selective upregulation of Th2 type lymphocytes in the nasal mucosal driven by exposure to seasonal or perennial aeroallergens.

  • Activation of Th2 cells leads to the release of cytokines that induce isotype switching of B cells to IgE production and the recruitment and activation of mast cells and circulating secondary effector leukocytes.

  • While topical corticosteroids and H1-antihistamines are effective treatments for allergic rhinitis, incomplete clinical responses and concern over side effects has led to a search for new ways offer intervening.

  • Improved ways of stabilising mast cells, the identification of novel mediators and their receptors and an understanding of intracellular signalling pathways of effector cells offer new opportunities for therapeutic intervention.

  • Blockade of IgE, the activation signal for allergic rhinitis, using monoclonal antibodies or vaccine strategies are being introduced for the treatment of asthma and accompanying atopic disorders which includes allergic rhinitis.

  • New forms or allergen-specific immunotherapy (SIT and SLIT) and ways to improve efficacy and reduce side effects include the use of recombinant mutated allergens, peptides and CpG DNA oligonucleotides (Immunostimulatory Sequences-ISS)

  • An understanding of the molecular mechanisms of leukocyte adhesion, migration and activation is leading to therapeutics including adhesion molecular antagonists, chemokine inhibitors and receptor antagonists and agents that inhibit mediator release including Type 4 PDE inhibitors.

  • In the long term, modification of the mechanisms underlying the increased expression of atopy is likely to have a greater overall impact on allergic rhinitis than any specific therapy targeting the nasal mucosa.

Abstract

Allergic rhinitis is an inflammatory disorder of the nasal mucosa, mediated by TH2 lymphocytes, which is linked to atopy and whose prevalence is increasing in association with a Western lifestyle. The production of allergen-specific IgE, activation of mucosal mast cells and the recruitment and activation of effector leukocytes provides potential therapeutic targets, including selective inhibition of cytokines, adhesion molecules and signalling pathways. Blockade of IgE, using monoclonal antibodies and vaccine strategies, is a new approach for interrupting the allergic cascade, whereas the use of recombinant mutated allergens, peptides and DNA oligonucleotides will lead to improved efficacy and reduced side effects of immunotherapy to induce tolerance.

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Figure 1: Cell and mediator pathways underlying the pathogenesis of allergic rhinitis.
Figure 2: Interaction between allergens and IgE to activate mast cells via the high-affinity receptor FcεRI.
Figure 3: Schematic representation of the hygiene hypothesis.
Figure 4: Central role of the TH2 type lymphocyte in the orchestration of the chronic allergic phenotype.
Figure 5: Interactions between cytokines and endothelial cells in the recruitment of inflammatory leukocytes.
Figure 6: Cytokine reactions involved in shaping the immune response to inhaled allergens.
Figure 7: Generic structure of CpG DNA oligonucleotides and a conjugate.
Figure 8: Interaction of the non-anaphylactic IgG anti-human monoclonal antibody omalizumab with IgE to prevent mast cell sensitization.
Figure 9: Chemical structure of two selective phosphodiesterase type IV inhibitors.

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References

  1. Skoner, D. P. Allergic rhinitis: definition, epidemiology, pathophysiology, detection and diagnosis. J. Allergy Clin. Immunol. 108, S2–S8 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Law, A. W., Reed, S. D., Sundy, J. S. & Schulman, K. A. Direct costs of allergic rhinitis in the United States: estimates from the 1996 Medical Expenditure Panel Survey. J. Allergy Clin. Immunol. 111, 296–300 (2003).

    Article  PubMed  Google Scholar 

  3. Sullivan, S. D. & Weiss, K. B. Health economics of asthma and rhinitis. II. Assessing the value of interventions. J. Allergy Clin. Immunol. 107, 203–210 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Crystal-Peters, J., Neslusan, C., Crown, W. H. & Torres, A. Treating allergic rhinitis in patients with comorbid asthma: the risk of asthma-related hospitalizations and emergency department visits. J. Allergy Clin. Immunol. 109, 57–62 (2002). Allergic rhinitis carries a high co-morbidity with other atopic disorders including asthma, as highlighted by the WHO ARIA report.

    Article  PubMed  Google Scholar 

  5. Cookson, W. Genetics and genomics of asthma and allergic diseases. Immunol. Rev. 190, 195–206 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Umetsu, D. T., McIntire, J. J., Akbari, O., Macaubas, C. & De Kruyff, R. H. Asthma: an epidemic of dysregulated immunity. Nature Immunol. 3, 715–720 (2002). This timely review emphasizes the importance of T-cell tolerance in protecting against atopic disease and describes how this can be harnessed for new treatments.

    Article  CAS  Google Scholar 

  7. Matricardi, P. M., Rosmini, F., Paneta, V., Ferrigao, L. & Bonini, S. Hayfever and asthma in relation to markers of infection in the United States. J. Allergy Clin. Immunol. 110, 381–387 (2002).

    Article  PubMed  Google Scholar 

  8. Kay, A. B. Allergy and allergic diseases. N. Engl. J. Med. 344, 109–113 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Pullerits, T., Praks, L., Ristioja, V. & Lottval, J. Comparison of a nasal glucocorticoid, antileukotriene and a combination of antileukotriene and antihistamine in the treatment of seasonal allergic rhinitis. J. Allergy Clin. Immunol. 109, 949–955 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Oppenheimer, J. J. & Casale, T. B. Next generation antihsitamines: therapeutic rationale, accomplishments and advances. Expert Opin. Investig. Drugs. 11, 807–817 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Baroody, F. M. & Naclerio, R. M. Antiallergic effects of H1-receptor antagonists. Allergy 55 (Suppl 64), 17–27 (2000).

    Article  PubMed  Google Scholar 

  12. Hofstra, C. L., Desai, P. J., Thurmond, R. L. & Fung-Leung, W. P. Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells. J. Pharmacol. Exp. Ther. 305, 1212–1221 (2003). The identification of histamine H 4 receptors has provided a new target for the design of antihistamine drugs for the treatment of allergic inflammation.

    Article  CAS  PubMed  Google Scholar 

  13. Higashi, N., Taniguchi, M., Mita, H., Ishii, T. & Akiyama, K. Nasal blockage and urinary leukotriene E4 concentration in patients with seasonal allergic rhinitis. Allergy 58, 476–480 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Philip, G. et al. Montelukast for treating seasonal allergic rhinitis: a random double-blind, placebo-controlled trial performed in the sprin. Clin. Exp. Allergy 32, 1020–1028 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Topuz, B. & Ogmen, G. G. Monelukast as an adjuvant to mainstay therapies in patients seasonal allergic rhinitis. Clin. Exp. Allergy 33, 823–826 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Nayak, A. S., Philip, G., Lu, S., Malice, M. P. & Reiss, T. F. Efficacy and tolerability of montelukast alone or in combination with loratadine in seasonal allergic rhinitis: a multicentre, randomized, double-blind, placebo-controlled trial performed in the fall. Ann. Allergy Asthma Immunol. 88, 592–600 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Evans, J. F. Cysteinyl leukotriene receptors. Prostaglandins Other Lipid Mediat. 68–69, 587–597 (2002).

    Article  PubMed  Google Scholar 

  18. Arimura, A. et al. Prevention of allergic inflammation by a novel prostaglandin receptor antagonist, S-5751. J. Pharmacol. Exp. Ther. 298, 411–419 (2001).

    CAS  PubMed  Google Scholar 

  19. Sugimoto, H. et al. An orally bioavailable small molecule antagonist of CRTH2, ramatroban (BAY u3405), inhibits prostaglandin D2-induced eosinophil migration in vitro. J. Pharmacol. Exp. Ther. 305, 347–352 (2003). The mast cell eicosanoid prostaglandin D 2 has created a new target for therapy by blockade of the DP 1 and the newly recognized DP 2 receptors.

    Article  CAS  PubMed  Google Scholar 

  20. Vanderslice, P. et al. Human mast cell tryptase: Multiple cDNAs and genes reveal a multigene serine protease family. Proc. Natl Acad. Sci. USA 87, 3811–3815 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wong, G. W. et al. Biochemical and functional characaterization of human transmembrane tryptase (TMT), tryptase-γ. J. Biol. Chem. 277, 41906–41915 (2003).

    Article  CAS  Google Scholar 

  22. Newhouse, B. J. Tryptase inhibitiors — Review of the recent patent literature. IDrugs 5, 682–688 (2002).

    CAS  PubMed  Google Scholar 

  23. Boye, J. A. Mast cells: beyond IgE. J. Allergy Clin. Immunol. 111, 24–32 (2003).

    Article  CAS  Google Scholar 

  24. Duan, W. et al. Antiinflammatory effects of genistein, a tyrosine kinase inhibitor on a guinea pig model of asthma. Am. J. Respir. Crit. Care Med. 167, 185–192 (2003).

    Article  PubMed  Google Scholar 

  25. Katz, H. R. et al. Mouse mast cell gp 49B1 contains two immunoreceptor tyrosine-based inhibition motifs and suppresses mast cell activation when colligated with the high affinity receptor for IgE. Proc. Natl Acad. Sci. USA 93, 10809–10814 (1996). Receptors linked to immuno-receptor typosine-based inhibitory motifs such as gp49B can be harnessed to disable mast cell activation–secretion coupling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Daheshia, M. et al. Increased severity of local and systemic anaphylactic reactions in gp49B1-deficient mice. J. Exp. Med. 194, 227–233 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Costa, J. J. et al. Recombinant human stem cell factor (kit ligand) promotes human mast cells and melanocyte hyperplasia and functional activation in vivo. J. Exp. Med. 183, 2681–2686 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Tatton, l., Morley, G. M., Chopra, R. & Khwaja, A. The Src-selective kinase inhibitor PP1 also inhibits Kit and B tyrosine kinases. J. Biol. Chem. 278, 4847–4853 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Duffy, S. M., Lawley, W. J., Conley, E. C. & Bradding, P. Resting and activation-dependent ion channels in human mast cells. J. Immunol. 167, 4261–4270 (2001). The identification of specific ion channels on mast cells linked to cell activation offers a new way to stabilize mast cells with selective blockers.

    Article  CAS  PubMed  Google Scholar 

  30. Bradding, P., Okayama, Y., Kambe, N. & Saito, H. Ion channel gene expression in human lung, skin and cord blood derived mast cells. J. Leukoc. Biol. 73, 614–620 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Baraniak, S. N. Sensory parasympathetic and sympathetic neural influences in the nasal mucosa. J. Allergy Clin. Immunol. 90, 1045–1050 (1992).

    Article  Google Scholar 

  32. Barnes, P. J. Neurogenetic inflammation in the airways. Respir. Physiol. 125, 145–154 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Fajac, I., Braunstein, G., Ickovic, M. R., Lacranicque, J. & Frossard, N. Selective recruitment of eosinophils by substance P after repeated allergen exposure in allergic rhinitis. Allergy 50, 970–975 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Austen, C. E., Foreman, J. C. & Scadding, G. H. Reduction by Hoe 140, the β2 kinin receptor antagonist, of antigen-induced nasal blockage. Br. J. Pharmacol. 111, 969–971 (1994).

    Article  Google Scholar 

  35. Uddman, R., Cantera, L., Cardell, L. O. & Edvinnsson, L. Expression of NPY Y1 and CGRP1 receptors in human nasal mucosa: implications in allergic rhinitis. Ann. Otol. Rhinol. Laryngol. 108, 969–973 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Korsegren, M. et al. Neural expression and increased lavage fluid levels of secretoneurin in seasonal allergic rhinitis. Am. J. Respir. Crit. Care Med. 167, 1504–1508 (2003).

    Article  Google Scholar 

  37. Duzendorfer, S. et al. Secretoneurin, a novel neuropeptide is a potent chemoattractant for human eosinophils. Blood 91, 1527–1532 (1998). The importance of neurogenic inflammation in chronic rhinitis is highlighted by the discovery of secretoneurin that has potent eosinophil chemo-attractant properties.

    Google Scholar 

  38. Frew, A. J. Immunotherapy of allergy disease. J. Allergy Clin. Immunol. 111, S712–S719 (2003).

    Article  PubMed  Google Scholar 

  39. Nelson, H. S. Advances in upper airway diseases and allergen immunotherapy. J. Allergy Clin. Immunol. 111, S793–S798 (2003).

    Article  PubMed  Google Scholar 

  40. Moller, C. et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT study). J. Allergy Clin. Immunol. 109, 251–256 (2002).

    Article  PubMed  Google Scholar 

  41. Pajno, G. B., Barberio, G., De Luca, F., Morabito, L. & Parmiani, S. Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-year follow-up study. Clin. Exp. Allergy 31, 1392–1397 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Malling, H. J. Is sublingual immunotherapy clinically effective? Curr. Opin. Allergy Clin. Immunol. 2, 523–531 (2002).

    Article  PubMed  Google Scholar 

  43. Durham, S. R. et al. Long-term clinical efficacy of grass-pollen immunotherapy. N. Engl. J. Med. 341, 468–475 (1999). This key study illustrates the long-term benefits obtained with allergen-specific immunotherapy in allergic rhinitis once therapy has stopped, with remission extending to greater than three years.

    Article  CAS  PubMed  Google Scholar 

  44. Di Rienzo, V. et al. Long-lasting effect of sub-lingual immunotherapy in children with asthma due to house dust mite: a 10 year prospective study. Clin. Exp. Allergy 33, 206–210 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Canonica, G. W. & Passalacqua, G. Non-injection routes for immunotherapy. J. Allergy Clin. Immunol. 111, 437–448 (2003).

    Article  PubMed  Google Scholar 

  46. Walker, S. M., Verhoef, A., Till, S. J. & Durham, S. R. Grass pollen immunotherapy for hayfever is associated with increases in local nasal but not peripheral TH1:TH2 cyotkine ratios. Immunology 105, 56–62 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Nasser, S. M., Ying, S., Meng, Q., Kay, A. B. & Ewan, P. W. Interleukin-10 levels increase in cutaneous biopsies of patients undergoing wasp venom immunotherapy. Eur. J. Immunol. 31, 3704–3713 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. McHugh, R. S. & Shevach, E. M. The role of suppressor T cells in regulation of immune responses. J. Allergy Clin. Immunol. 110, 693–702 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. TePas, E. C. & Umetsu, D. T. Immunotherapy of asthma and allergic disease. Curr. Opin. Pediatr. 12, 574–578 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Hamid, Q. A., Schotman, E., Jacobsen, M. R., Walker, S. M. & Durham, S. R. Increases in IL-12 messenger RNA+ cells accompany inhibition of allergen-induced late skin responses after successful grass pollen immunotherapy. J. Allergy Clin. Immunol. 99, 254–269 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Yazdanbahsh, M., Kremsner, P. G. & van Ree, R. Allergy parasites and the hygiene hypothesis. Science 296, 490–494 (2002).

    Article  Google Scholar 

  52. Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Fox P3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol. 4, 330–336 (2003).

    Article  CAS  Google Scholar 

  53. Shimizu, J. et al. Stimulation of CD25+ CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nature Immunol. 3, 135–142 (2002).

    Article  CAS  Google Scholar 

  54. Bystry, R. S., Aluvihare, U., Welch, K. A., Kallikoardis, M. & Betz, A. G. B cells and professional APCs recruit regulatory T cells via CCL4. Nature Immunol. 2, 1126–1132 (2001).

    Article  CAS  Google Scholar 

  55. Ebner, C. Immunological mechanisms operative in allergen-specific immunotherapy. Int. Arch. Allergy Immunol. 119, 1–5 (1999). This review summarizes some of the immunological pathways that are harnessed in the beneficial effects of allergen immunotherapy.

    Article  CAS  PubMed  Google Scholar 

  56. Briner, T. J., Kuo, M. C., Keating, K. M., Rogers, B. L. & Greenstein, J. L. Peripheral T-cell tolerance induced in naive and primed mice by subcutaneous injection of peptides form the major cat allergen Fel d 1. Proc. Natl Acad. Sci. USA 90, 7608–7612 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Norman, P. S. et al. Treatment of cat allergy with T cell reactive peptides. Am. J. Resp. Crit. Care Med. 154, 1623–1628 (1996).

    Article  CAS  PubMed  Google Scholar 

  58. Oldfield, W. L., Larché, M. & Kay, A. B. Effect of T-cell peptides derived from fel D 1 on allergic reactions and cytokine production in patients sensitive to cats: a randomised controlled trial. Lancet 360, 47–53 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Haselden, B. M., Kay, A. B. & Larché, M. IgE-dependent MHC-restricted T cell peptide epitope-induced late asthmatic reactions. J. Exp. Med. 189, 1885–1894 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Haselden, B. M. et al. Late asthmatic reactions provoked by intradermal injection of T-cell peptide epitopes are not associated with bronchial mucosal infiltration of eosinophils or TH2-type cells or with elevated concentrations of histamine or eicosanoids in bronchoalveolar fluid. J. Allergy Clin. Immunol. 108, 394–401 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Broide, D. H. & Raz, E. in Lung Biology in Health and Disease Vol 177 (eds Eissa, N. T. & Huston, D. P.) 839–865 (Marcel Dekker, New York, in the press).

  62. Horner, A. A., Van Uden, J. H., Zubeldia, J. M., Broide, D. & Raz, E. DNA-based immunotherapeutics for the treatment of allergic disease. Immunol. Rev. 179, 102–118 (2001). This review summarizes the interactions between non-methylated CpG oligonucleotides from microorganisms and protective pathways in allergic disease through an interaction with TLR9.

    Article  CAS  PubMed  Google Scholar 

  63. Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Roman, M. et al. Immunostimulatory DNA sequences function as T helper-1-promoting adjuvants. Nature Med. 3, 849–854 (1997).

    Article  CAS  PubMed  Google Scholar 

  65. Horner, A. A. et al. Immmunostimulatory DNA inhibits IL-4 dependent IgE synthesis by human B cells. J. Allergy Clin. Immunol. 108, 417–423 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Broide, D. et al. Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation and airway hyperresponsiveness in mice. J. Immunol. 161, 7054–7062 (1998).

    CAS  PubMed  Google Scholar 

  67. Kline, J. N. et al. Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J. Immunol. 160, 2555–2559 (1998).

    CAS  PubMed  Google Scholar 

  68. Ikeda, R. K. et al. Resolution of airway inflammation following ovalbumin inhalation: comparison of ISS DNA and corticosteroids. Am. J. Resp. Cell Mol. Biol. 28, 655–683 (2003).

    Article  CAS  Google Scholar 

  69. Hussain, I. et al. Modulation of murine allergic rhinosinusitis by CpG oligodeoxynucleotides. Layrngoscope 112, 1819–1826 (2002).

    Article  CAS  Google Scholar 

  70. Creticos, P. et al. Immunotherapy with immunostimulatory oligonucleotides linked to purified ragweed Amb a 1 allergen: Effects on antibody production, nasal allergen provocation, and ragweed seasonal rhinitis. J. Allergy Clin. Immunol. 109, 743–744 (2002). Immunotherapy with covalently linked CpG oligonucleotides with the major ragweed allergen has improved efficacy compared with allergen alone.

    Article  Google Scholar 

  71. Henderson, W. R. Jr, Chi, E. Y. & Maliszewski, C. R. IL-4 receptor inhibits airway inflammation following allergen challenge in a mouse model of asthma. J. Immunol. 164, 1086–1095 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Cieslewicz, G. et al. The late, but not early, asthmatic response is dependent on IL-5 and correlates with eosinophil infiltration. J. Clin. Invest. 104, 301–308 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Marshall, J. D. et al. Immunostimulatory sequence DNA linked to the Amb a 1 allergen promotes TH1 cytokine expression while downregulating TH2 cytokine expression in PBMCs from human patients with ragweed allergy. J. Allergy Clin. Immunol. 108, 191–197 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Tighe, H. et al. Conjugation of immunostimulatory DNA to the short ragweed allergen Amb a 1 enhances it immunogenicity and reduces its allergenicity. J. Allergy Clin. Immunol. 106, 124–134 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Chang, T. W. The pharmacological basis of anti-IgE therapy. Nature Biotechnol. 18, 157–163 (2000).

    Article  CAS  Google Scholar 

  76. Presta, S. R. et al. Humanization of an antibody directed against IgE. J. Immunol. 151, 2623–2632 (1993).

    CAS  PubMed  Google Scholar 

  77. Lazaar, A. L. Technology evaluation omalizumab. Genetech/ Novartis/Tanox. Curr. Opin. Mol. Ther. 5, 81–89 (2003).

    CAS  PubMed  Google Scholar 

  78. Casale, T. B. et al. Effect of omalizumab on symptoms of seasonal allergic rhinitis: a randomized controlled trial. JAMA 286, 2956–2967 (2001). A new approach to treating allergic rhinitis and associated atopic disease is described using a monoclonal antibody directed to the Fc portion of IgE to prevent its binding to receptors on mast cells.

    Article  CAS  PubMed  Google Scholar 

  79. Adelroth, E. et al. Recombinant humanized on A6-E25, an anti-IgE mAb, in birch-pollen-induced seasonal allergic rhinitis. J. Allergy Clin. Immunol. 106, 253–259 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Kuehr, J. et al. Efficacy of combination treatment with anti-IgE plus specific immunotherapy in polysensitized children and adolescents with seasonal allergic rhinitis. J. Allergy Clin. Immunol. 109, 274–280 (2002). A combination of anti-IgE and allergen-specific immunotherapy (SIT) improves efficacy and offers promise for the use of IgE blockade to increase protection against the side effects of SIT.

    Article  CAS  PubMed  Google Scholar 

  81. Plewako, H. et al. The effect of omalizumab on nasal allergic inflammation. J. Allergy Clin. Immunol. 110, 68–71 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. MacGlashan, D. W. Jr. et al. Down regulation of FcεR1 expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J. Immunol. 158, 1438–1445 (1997).

    CAS  PubMed  Google Scholar 

  83. Novak, N., Kraft, S. & Bieber, T. Unravelling the mission of FcεR1 on antigen presenting cells. J. Allergy Clin. Immunol. 111, 38–44 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Vernesson, M., Ledin, A., Johansson, J. & Hellman, L. Generation of therapeutic antibody response against IgE through vaccination. FASEB J. 16, 875–877 (2002).

    Article  CAS  Google Scholar 

  85. Nadler, M. J. & Kinet, J. P. Uncovering new complexities in mast cell signalling. Nature Immunol. 3, 707–708 (2002).

    Article  CAS  Google Scholar 

  86. Christodoulopulos, P., Cameron, L., Durham, S. & Hamid, Q. Molecular pathology of allergic disease. II: Upper airway disease. J. Allergy Clin. Immunol. 105, 211–223 (2000).

    Article  Google Scholar 

  87. Wills-Karp, M. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu. Rev. Immunol. 17, 255–281 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Foster, P. S. et al. Interleukin-5 and eosinophils as therapeutic targets for asthma. Trends Mol. Med. 8, 162–167 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Borish, L. C et al. Efficacy of soluble IL-4 receptor for the treatment if adults with asthma. J. Allergy Clin. Immunol. 107, 963–970 (2001). An understanding of the Fc ε ;R1- and Fc ε R2-binding sites on human IgE has created a new opportunity for the development of a peptide vaccine for treating atopic diseases.

    Article  CAS  PubMed  Google Scholar 

  90. Borrish, L. C. et al. Interleukin-4 receptor in moderate atopic asthma. A phase 1/randomized, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 160, 1816–1823 (1999).

    Article  Google Scholar 

  91. Atamas, S. P., Choi, J., Yurovsky, V. V. & White, B. An alternative splice variant of human IL-4, IL-4 inhibits IL-4 stimulated T cell proliferation. J. Immunol. 156, 435–441 (1996).

    CAS  PubMed  Google Scholar 

  92. Kruse, N., Tony, H. P. & Sebald, W. Conversion of human IL-4 into a high affinity antagonist by a single aminoacid replacement. EMBO J. 11, 3237–3244 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wills-Karp, M. et al. Interleukin 13: central mediator of allergic asthma. Science 282, 2258–2261 (1998).

    Article  CAS  PubMed  Google Scholar 

  94. Skowron, M., Peret, E., Marano, F., Caput, D. & Tournier, F. Intelruekin-13 alters mucociliary differentiation of human nasal epithelial cells. Chest 123, 373S–374S (2003).

    Article  PubMed  Google Scholar 

  95. Wynn, T. A. IL-13 effector functions. Annu. Rev. Immunol. 21, 425–456 (2003). This review summarizes the key features of IL-13 as a major therapeutic target in chronic allergic diseases that include immunological, inflammatory and structural cell effects.

    Article  CAS  PubMed  Google Scholar 

  96. Kleinjan, A. et al. Increase in IL-8, IL-10, IL-13 and RANTES mRNA levels (in situ hybridization) in the nasal mucosa after nasal allergen provocation. J. Allergy Clin. Immunol. 103, 441–450 (1999).

    Article  CAS  PubMed  Google Scholar 

  97. Andrews, A. L., Holloway, J. W., Puddicombe, S. L., Holgate, S. T. & Davies, D. E. Kinetic analysis of interleukin-13 receptor complex. J. Biol. Chem. 277, 46073–46078 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Wood, N. et al. Enhanced interleukin (IL)-13 responses in mice lacking IL-13 receptor α2. J. Exp. Med. 197, 703–709 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wills-Karp, M. & Chiaramonte, M. Interleukin-13 in asthma. Curr. Opin. Pulm. Med. 9, 21–27 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Wills-Karp, M. Murine models of asthma in understanding immune dysregulation in human asthma. Immopharmacology 48, 263–268 (2000).

    Article  CAS  Google Scholar 

  101. Oshima, Y. & Puri, R. A novel antagonist that blocks the biological activity of human IL-13 in immune and non-immune cells. FASEB J. 15, 1469–1471 (2001).

    Article  CAS  PubMed  Google Scholar 

  102. Leckie, M. J. et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness and the late asthmatic response. Lancet 356, 2144–2148 (2000). This report describes the failure of IL-5 blockade to attenuate allergen-provoked late-phase allergic responses in the airways despite depleting circulating and tissue eosinophils.

    Article  CAS  PubMed  Google Scholar 

  103. Kips, J. C. et al. Effect of SECH 55700, a humanized anti-human interleukin-5 antibody in severe persistent asthma. Am. J. Respir. Crit. Care Med. 167, 1655–1659 (2003).

    Article  PubMed  Google Scholar 

  104. Flood-Page, P. T., Menzies-Gow, A. N., Kay, A. B. & Robinson, D. S. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am. J. Respir. Crit. Care Med. 167, 199–204 (2003).

    Article  PubMed  Google Scholar 

  105. Saito, H. et al. Pathogenesis of murine experimental allergic rhinitis: a study of local and systemic consequences of IL-5 deficiency. J. Immunol. 168, 3017–3023 (2003).

    Article  Google Scholar 

  106. Zhou, C. Y., Crocker, I. C., Koenig, G., Romero, F. A. & Townley, R. G. Anti-interleukin-4 inhibits IgE production in a murine model of atopic asthma. J. Asthma 34, 195–201 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Tanaka, H., Nagai, H. & Macda, Y. Effect of anti IL-4 and anti-IL-5 antibodies on allergic airway hyperresponsiveness in mice. Life Sci. 62, PL169–PL174 (1998).

    Article  CAS  PubMed  Google Scholar 

  108. Terada, N. et al. The kinetics of allergen-induced eotaxin level in nasal lavage fluid: its key role in eosinophil recruitment in nasal mucosa. Am. J. Respir. Crit. Care Med. 164, 575–579 (2001). Eotaxins are chemokines with properties linked to eosinophil recruitment into the nasal mucosa in rhinitis.

    Article  CAS  PubMed  Google Scholar 

  109. Gorski, P. et al. Eotaxin but not MCP-3 induces eosinophil influx into nasal fluid in allergic patients. Allergy 57, 519–528 (2002).

    Article  CAS  PubMed  Google Scholar 

  110. Cooper, J. A. Jr., Ridgeway, A. L., Pearson, J. & Culbreth, R. R. Attenuation of interleukin 8-induced nasal inflammation by an inhibitor peptide. Am. J. Respir. Crit. Care Med. 163, 1198–1205 (2001).

    Article  PubMed  Google Scholar 

  111. Mattes, J. et al. Intrinsic defect in T cell production of interleukin (IL)-13 in the absence of both IL-5 and eotaxin precludes the development of eosinophilia and airways hyperreacitivity in experimental asthma. J. Exp. Med. 195, 1433–1444 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Von Hertzen, L. & Haahtela, T. Could the risk of asthma and atopy be reduced by a vaccine that induces a strong T-helper Type 1 response? Am. J. Respir. Cell Mol. Biol. 22, 139–142 (2000).

    Article  CAS  PubMed  Google Scholar 

  113. Barnes, P. J. Cytokine-directed therapies in asthma. Allergol. Int. 52, 53–63 (2003).

    Article  CAS  Google Scholar 

  114. Bryan, S. A. et al. Effects of recombinant human interleukin-12 on eosinophils, airway hyperresponsiveness and the late asthmatic response. Lancet 356, 2149–2153 (2000).

    Article  CAS  PubMed  Google Scholar 

  115. Castro, M., Chaplin, D. D., Walter, M. J. & Holtzman, M. J. Could asthma be worsened by stimulation of the T-helper Type 1 immune response? Am. J. Respir. Cell Mol. Biol. 22, 143–146 (2000). Although the hygiene hypothesis has suggested augmentation of T H 1 responses as a possible mechanism for the prevention of disease, this publication draws attention to the possible downside of this approach in established allergic disease.

    Article  CAS  PubMed  Google Scholar 

  116. Zuang-Amorim, C. et al. Long-term protective and antigen-specific effect of heat killed Mycobacterium vaccae in a murine model of allergic pulmonary inflammation. J. Immunol. 169, 1492–1499 (2002).

    Article  Google Scholar 

  117. Camporota, L. et al. The effect of Mycobacterium vaccae on allergen-induced airway response in atopic asthma. Eur. Respir J. 21, 287–293 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. Zuang-Amorin, C. et al. Suppression of airway eosinophila by killed mycobacterium vaccae-induced allergen-specific regulatory T cells. Nature Med. 8, 625–629 (2002).

    Article  CAS  Google Scholar 

  119. Kalliomäki, M. et al. Probiotics in the primary prevention of atopic disease: a randomised placebo controlled trial. Lancet 357, 1076–1079 (2001).

    Article  PubMed  Google Scholar 

  120. Helin, T., Haahtela, S. & Haahtela, T. No effect of oral treatment with an intestinal bacterial strain, Lactobacillus rhamnosus (ATCC 53103) on birch pollen allergy: a placebo-controlled double-blind study. Allergy 57, 243–246 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Braunstahl, G. H. et al. Nasal allergen provocation induces adhesion molecule expression and tissue eosinophilia in upper and lower airways. J. Allergy Clin. Immunol. 107, 469–476 (2001).

    Article  CAS  PubMed  Google Scholar 

  122. Symon, F. A., Walsh, G. M., Watson, S. R. & Wardlaw, A. J. Eosinophil adhesion to nasal polyp endothelium is P-selectin dependent. J. Exp. Med. 180, 371–376 (1994).

    Article  CAS  PubMed  Google Scholar 

  123. Broide, D. H., Sullivan, S., Gifford, T. & Sriraarao, P. Inhibition of pulmonary eosinophilia in P-selectin- and ICAM-1-deficient mice. Am. J. Respir. Cell Mol. Biol. 18, 218–225 (1998). Vascular adhesion molecules are good therapeutic targets in chronic allergic rhinitis. This paper describes the pivotal role of P-selection with ICAM–1 in the recruitment in the recruitment of leukocytes during the allergic cascade.

    Article  CAS  PubMed  Google Scholar 

  124. Sriramarao, P. et al. E-selectin preferentially supports neutrophils but not eosinophil rolling under conditions of flow in vitro and in vivo. J. Immunol. 157, 4672–4680 (1996).

    CAS  PubMed  Google Scholar 

  125. Jackson, D. Y. α4 integrin antagonists. Curr. Pharm. Des. 8, 1229–1253 (2002).

    Article  CAS  PubMed  Google Scholar 

  126. Anwar, A. R., Moqbel, R., Walsh, G. M., Kay, A. B. & Wardlaw, A. J. Adhesion to fibronectin prolongs eosinophil survival. J. Exp. Med. 177, 839–843 (1993).

    Article  CAS  PubMed  Google Scholar 

  127. Henderson, W. R. Jr. et al. Blockade of CD49d (α4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma. J. Clin. Invest. 100, 3083–3092 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Abraham, W. M. et al. A small-molecule, tight-binding inhibitor of the integrin α4β1 blocks antigen-induced airway responses and inflammation in experimental asthma in sheep. Am. J. Respir. Crit. Care Med. 162, 603–661 (2000).

    Article  CAS  PubMed  Google Scholar 

  129. Giembycz, C. A. Phosphodiesterase 4 inhibitors and the treatment of asthma. Drugs 59, 193–212 (2002).

    Article  Google Scholar 

  130. Schmidt, B. M. et al. The phosphodiesterase 4 inhibitor rofulimast is effective in the treatment of allergic rhinitis. J. Allergy Clin. Immunol. 108, 503–506 (2001).

    Article  Google Scholar 

  131. Sorbera, L. A., Leeson, P. A. & Castaner, J. Rofumilast, BY-217. Drugs of the Future 25, 1261–1264 (2000).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. RIIR Division, School of Medicine, University of Southampton, Mail point 810, Level D, Centre Block Southampton General Hospital, Southampton, SO16 6YD, UK

    Stephen T. Holgate

  2. Department of Medicine, University of California San Diego, Basic Science Building, 9500 Gilman Drive, La Jolla, 92093 -0635, California, USA

    David Broide

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Correspondence to Stephen T. Holgate.

Related links

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DATABASES

LocusLink

chemokine ligand 11

DP1

F2RL1

forkhead box P3

IL-10

IL-12

MCP-1

MCP-3

SCGF

tachykinin precursor 1

tachykinin 3

TLR4

transforming growth factor-β

VCAM-1

Glossary

DESENSITIZE

The use of allergens or modified allergens to induce immunological tolerance.

CHROMONES

Anti-allergic drugs originally derived from Rhellin from the plant Amni visnaga.

ATOPY

The genetic susceptibility to produce IgE antibodies against common environmental allergens.

CpG DNA

Also known as immunostimulatory sequences (ISS), these are sequence-specific non-methylated DNA molecules of cytosine and guanosine, modelled on those present in microorganisms, which have the capacity to stimulate Toll-like receptor-9 found on antigen-presenting cells and to modify immune responses.

AUTACOID

Low-molecular-weight mediators that participate in cell–cell communication.

EICOSANOID

Mediators derived from polysaturated fatty acids.

LEUKOCYTE IMMUNOGLOBULIN-LIKE RECEPTORS

Cell-surface molecules whose activation leads to the phosphorylation of immuno-receptor tyrosine-based motifs (ITIMS) on adjacent receptors such as FcεR1.

SIT

Allergen-specific immunotherapy that uses incremental small doses of subcutaneously injected allergen to induce immunological tolerance.

SLIT

Sublingual immunotherapy, which uses a higher concentration of allergen than used in SIT to induce tolerance via the buccal mucosa and draining lymphoid tissue.

AMB A 1

The major allergen of ragweed pollen.

FCεR1 AND FCεR2

The high- and low-affinity receptors for IgE present on mast cells, basophils and dendritic cells.

ISOTYPE SWITCHING

The capacity of B lymphocytes to redirect their immunoglobulin (Ig) synthesis from IgM to another Ig subclass

CAMS

Cell adhesion molecules including intercellular (ICAM) and vascular (VCAM) members that are expressed on endothelial cells, upregulated by cytokines and involved in leukocyte adhesion and activation.

MYCOBACTERIUM VACCAE

A non-disease-causing mycobacterium found in the soil as a saprophyte.

SELECTINS

Glycoproteins that are expressed on endothelial cells involved in leukocyte rolling (P selectin) or adhesion (E-selectin).

VERY LATE ANTIGEN-4

(VLA-4). An integrin α4β1 that selectively binds to VCAM-1 and to CS-1 region of fibronectin.

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Holgate, S., Broide, D. New targets for allergic rhinitis — a disease of civilization. Nat Rev Drug Discov 2, 903–915 (2003). https://doi.org/10.1038/nrd1224

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