Current Allergy and Asthma Reports

, Volume 1, Issue 2, pp 164–173 | Cite as

Novel drugs for treating asthma

  • Trevor T. Hansel
  • Peter J. Barnes
Article

Abstract

The health burden of asthma is increasing globally at an alarming rate, providing a strong impetus for the development of new therapeutics, particularly drugs that may prevent development of the disease. Currently available inhaled bronchodilators and anti-inflammatory drugs are effective in most asthmatic patients, but this palliative therapy requires long-term daily administration. Despite considerable efforts by the pharmaceutical industry, it has been difficult to develop novel therapeutic agents, the leukotriene antagonists being the only new class of asthma treatments to be licensed in the past 30 years. It is clearly important to understand more about the underlying mechanisms of asthma and about how currently used drugs work before rational improvements in therapy can be expected. There are numerous therapies in clinical development that combat the inflammation found in asthma, specifically targeting eosinophils, IgE, adhesion molecules, cytokines (interleukin-4, -5, -13) and chemokines, inflammatory mediators, and cell signaling (kinase inhibitors). In particular, there is the obvious need for new therapy for severe asthma that is poorly controlled by high-dose corticosteroids as well as agents to counter acute emergency asthma. A long-term goal is to develop disease-modifying immunotherapy that could be introduced in childhood to alter the natural history of asthma. Thanks to the extensive efforts of the pharmaceutical industry, we can expect the introduction of a range of novel therapies for asthma in the near future.

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References and Recommended Reading

  1. 1.
    Sakula A: A history of asthma: the FitzPatrick lecture 1987. J R Coll Physicians Lond 1988, 22:36–44.PubMedGoogle Scholar
  2. 2.
    Bielory L, Lupoli K: Herbal interventions in asthma and allergy. J Asthma 1999, 36:1–65. This is a comprehensive review of herbal therapies.PubMedGoogle Scholar
  3. 3.
    Pauwels RA, Lofdahl CG, Postma DS, et al.: Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997, 337:1405–1411.PubMedCrossRefGoogle Scholar
  4. 4.
    Kavuru M, Melamed J, Gross G, et al.: Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 2000, 105:1108–1116. This article describes the use of salmeterol and fluticasone in a single inhaler.PubMedCrossRefGoogle Scholar
  5. 5.
    Laviolette M, Malmstrom K, Lu S, et al.: Montelukast added to inhaled beclomethasone in treatment of asthma. Am J Respir Crit Care Med 1999, 160:1862–1868. This is a major study of montelukast as an "add-on."PubMedGoogle Scholar
  6. 6.
    Evans DJ, Taylor DA, Zetterstrom O, et al.: A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med 1997, 337:1412–1418.PubMedCrossRefGoogle Scholar
  7. 7.
    Hansel T, Barnes P: New Drugs for Asthma, Allergy and COPD: Progress in Respiratory Research, vol 31. Basel: Karger; 2001. This is a comprehensive and recent review of new drugs in development, written mainly by authors from the pharmaceutical industry.CrossRefGoogle Scholar
  8. 8.
    Shrewsbury S, Pyke S, Britton M: Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA). BMJ 2000, 320:1368–1373.PubMedCrossRefGoogle Scholar
  9. 9.
    Shapiro G, Lumry W, Wolfe J, et al.: Combined salmeterol 50 mcg and Fluticasone Propionate 250 mcg in the diskus device for the treatment of asthma. Am J Respir Crit Care Med 2000, 161:527–534.PubMedGoogle Scholar
  10. 10.
    Nelson HS, Bensch G, Pleskow WW, et al.: Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. J Allergy Clin Immunol 1998, 102:943–952.PubMedCrossRefGoogle Scholar
  11. 11.
    Gawchik SM, Saccar CL, Noonan M, et al.: The safety and efficacy of nebulized levalbuterol compared with racemic albuterol and placebo in the treatment of asthma in pediatric patients. J Allergy Clin Immunol 1999, 103:615–621.PubMedCrossRefGoogle Scholar
  12. 12.
    Cockcroft DW, Davis BE, Swystun VA, Marciniuk DD: Tolerance to the bronchoprotective effect of beta2-agonists: comparison of the enantiomers of salbutamol with racemic salbutamol and placebo. J Allergy Clin Immunol 1999, 103:1049–1053.PubMedCrossRefGoogle Scholar
  13. 13.
    Buchheit KH, Fozard JR: KATP channel openers for the treatment of airways hyperreactivity. Pulm Pharmacol Ther 1999, 12:103–105.PubMedCrossRefGoogle Scholar
  14. 14.
    Barnes PJ: New drugs for asthma. Clin Exp Allergy 1996, 26:738–745.PubMedCrossRefGoogle Scholar
  15. 15.
    Kraan J, Vink-Klooster H, Postma DS: The NK-2 receptor antagonist SR 48968C does not improve AMP-hyperresponsiveness and FEV1 in allergic asthma. Eur Respir J 1999, 14:288s.Google Scholar
  16. 16.
    Kudlacz EM: Combined tachykinin receptor antagonists for the treatment of respiratory diseases. Exp Opin Invest Drugs 1998, 7:1055–1062.CrossRefGoogle Scholar
  17. 17.
    Barnes PJ: Molecular mechanisms of steroid action in asthma. J Allergy Clin Immunol 1996, 97:159–168.PubMedCrossRefGoogle Scholar
  18. 18.
    Taylor DA, Jensen MW, Kanabar V, et al.: A dose-dependent effect of the novel inhaled corticosteroid ciclesonide on airway responsiveness to adenosine-5’-monophosphate in asthmatic patients. Am J Respir Crit Care Med 1999, 160:237–243.PubMedGoogle Scholar
  19. 19.
    Vayssiere BM, Dupont S, Choquart A, et al.: Synthetic glucocorticoids that dissociate transactivation and AP-1 transrepression exhibit anti-inflammatory activity in vivo. Mol Endocrinol 1997, 11:1245–1255.PubMedCrossRefGoogle Scholar
  20. 20.
    Lipworth BJ: Leukotriene-receptor antagonists. Lancet 1999, 353:57–62. This is an excellent review.PubMedCrossRefGoogle Scholar
  21. 21.
    Drazen JM, Israel E, O’byrne PM: Treatment of asthma with drugs modifying the leukotriene pathway. N Engl J Med 1999, 340:197–206. This is an excellent review.PubMedCrossRefGoogle Scholar
  22. 22.
    Crowther SD, Rees PJ: Current treatment of asthma—focus on leukotrienes. Emerging Drugs 2000, 1:1021–1040.Google Scholar
  23. 23.
    Busse W, Nelson H, Wolfe J, et al.: Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma. J Allergy Clin Immunol 1999, 103:1075–1080. This is an important head-to-head comparison of a long-acting b2-agonist and a leukotriene antagonist.PubMedCrossRefGoogle Scholar
  24. 24.
    Hoshino M, Sim J, Shimizu K, et al.: Effect of AA-2414, a thromboxane A2 receptor antagonist, on airway inflammation in subjects with asthma. J Allergy Clin Immunol 1999, 103:1054–1061.PubMedCrossRefGoogle Scholar
  25. 25.
    Evans DJ, Barnes PJ, Cluzel M, O’connor BJ: Effects of a potent platelet-activating factor antagonist, SR27417A, on allergen-induced asthmatic responses. Am J Respir Crit Care Med 1997, 156:11–16.PubMedGoogle Scholar
  26. 26.
    Yates DH, Kharitonov SA, Thomas PS, Barnes PJ: Endogenous nitric oxide is decreased in asthmatic patients by an inhibitor of inducible nitric oxide synthase. Am J Respir Crit Care Med 1996, 154:247–250.PubMedGoogle Scholar
  27. 27.
    He S, Gaca MD, Walls AF: A role for tryptase in the activation of human mast cells: modulation of histamine release by tryptase and inhibitors of tryptase. J Pharmacol Exp Ther 1998, 286:289–297.PubMedGoogle Scholar
  28. 28.
    Molino M, Barnathan ES, Numerof R, et al.: Interactions of mast cell tryptase with thrombin receptors and PAR-2. J Biol Chem 1997, 272:4043–4049.PubMedCrossRefGoogle Scholar
  29. 29.
    Lock SH, Kay AB, Barnes NC: Double-blind, placebocontrolled study of cyclosporin A as a corticosteroid-sparing agent in corticosteroid-dependent asthma. Am J Respir Crit Care Med 1996, 153:509–514.PubMedGoogle Scholar
  30. 30.
    Redington AE, Hardinge FM, Madden J, et al.: Cyclosporin A treatment and airways inflammation in corticosteroid-dependent asthma. Allergy 1998, 53:94–98.PubMedCrossRefGoogle Scholar
  31. 31.
    Marin MG: Low-dose methotrexate spares steroid usage in steroid-dependent asthmatic patients: a meta-analysis. Chest 1997, 112:29–33.PubMedGoogle Scholar
  32. 32.
    Barnes PJ: Therapeutic strategies for allergic diseases. Nature 1999, 402:B31-B38.PubMedCrossRefGoogle Scholar
  33. 33.
    Barnes PJ, Adcock IM: Transcription factors and asthma. Eur Respir J 1998, 12:221–234.PubMedCrossRefGoogle Scholar
  34. 34.
    Kankaanranta H, De Souza PM, Barnes PJ, et al.: SB 203580, an inhibitor of p38 mitogen-activated protein kinase, enhances constitutive apoptosis of cytokine-deprived human eosinophils. J Pharmacol Exp Ther 1999, 290:621–628.PubMedGoogle Scholar
  35. 35.
    Ott VL, Cambier JC: Activating and inhibitory signaling in mast cells: new opportunities for therapeutic intervention? J Allergy Clin Immunol 2000, 106:429–440.PubMedCrossRefGoogle Scholar
  36. 36.
    Yousefi S, Hoessli DC, Blaser K, et al.: Requirement of Lyn and Syk tyrosine kinases for the prevention of apoptosis by cytokines in human eosinophils. J Exp Med 1996, 183:1407–1414.PubMedCrossRefGoogle Scholar
  37. 37.
    Zhang D, Yang L, Cohn L, et al.: Inhibition of allergic inflammation in a murine model of asthma by expression of a dominant-negative mutant of GATA-3. Immunity 1999, 11:473–482.PubMedCrossRefGoogle Scholar
  38. 38.
    Wolffe AP, Hayes JJ: Chromatin disruption and modification. Nucleic Acids Res 1999, 27:711–720. This is a superb review of this attractive target for new drugs.PubMedCrossRefGoogle Scholar
  39. 39.
    Torphy TJ: Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 1998, 157:351–370.PubMedGoogle Scholar
  40. 40.
    Dyke H, Montana JG: The therapeutic potential of PDE4 inhibitors. Emerging Drugs 2000, 8:1301–1325. This is one of a pair of excellent reviews.Google Scholar
  41. 41.
    Giembycz MA: Phosphodiesterase 4 inhibitors and the treatment of asthma: Where are we now and where do we go from here? Drugs 2000, 59:193–212. This is one of a pair of excellent reviews.PubMedCrossRefGoogle Scholar
  42. 42.
    Schudt C, Gantner F, Tenors H, Hatzelmann A: Therapeutic potential of selective PDE inhibitors in asthma. Pulm Pharmacol Ther 1999, 12:123–129.PubMedCrossRefGoogle Scholar
  43. 43.
    Spina D, Landells LJ, Page CP: The role of theophylline and phosphodiesterase4 isoenzyme inhibitors as anti-inflammatory drugs. Clin Exp Allergy 1998, 28(suppl 3):24–34.PubMedGoogle Scholar
  44. 44.
    Schmidt D, Dent G, Rabe KF: Selective phosphodiesterase inhibitors for the treatment of bronchial asthma and chronic obstructive pulmonary disease. Clin Exp Allergy 1999, 29(suppl 2):99–109.PubMedGoogle Scholar
  45. 45.
    Torphy TJ, Barnette MS, Underwood DC, et al.: ArifloTM (SB 207499), a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD: from concept to clinic. Pulm Pharmacol Ther 1999, 12:131–135.PubMedCrossRefGoogle Scholar
  46. 46.
    Barnette MS, Christensen SB, Essayan DM, et al.: SB 207499 (Ariflo), a potent and selective second-generation phosphodiesterase 4 inhibitor: in vitro anti-inflammatory actions. J Pharmacol Exp Ther 1998, 284:420–428.PubMedGoogle Scholar
  47. 47.
    Christensen SB, Guider A, Forster CJ, et al.: 1,4-cyclohexanecarboxylates: Potent and selective inhibitors of phosophodiesterase 4 for the treatment of asthma. J Med Chem 1998, 41:821–835.PubMedCrossRefGoogle Scholar
  48. 48.
    Norman P: PDE4 inhibitors 1998. Exp Opin Ther Patents 1998, 8:771–784.CrossRefGoogle Scholar
  49. 49.
    Fick RB: Anti-IgE as novel therapy for the treatment of asthma. Curr Opin Pulm Med 1999, 5:76–80.PubMedCrossRefGoogle Scholar
  50. 50.
    Chang TW: The pharmacological basis of anti-IgE therapy. Nat Biotechnol 2000, 18:157–162. This is an excellent article on the biochemistry and immunology of anti-IgE.PubMedCrossRefGoogle Scholar
  51. 51.
    Milgrom H, Fick RB Jr, Su JQ, et al.: Treatment of allergic asthma with monoclonal anti-IgE antibody: rhuMAb-E25 Study Group. N Engl J Med 1999, 341:1966–1973. This article describes promising results with anti-IgE for moderate to severe asthma.PubMedCrossRefGoogle Scholar
  52. 52.
    Adelroth E, Rak S, Haahtela T, et al.: Recombinant humanized mAb-E25, an anti-IgE mAb, in birch pollen-induced seasonal allergic rhinitis. J Allergy Clin Immunol 2000, 106:253–259.PubMedCrossRefGoogle Scholar
  53. 53.
    Frew AJ: Effects of anti-IgE in asthmatic subjects. Am J Respir Crit Care Med 1997, 155:1828–1834.Google Scholar
  54. 54.
    Fahy JV, Fleming HE, Wong HH, et al.: The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am J Respir Crit Care Med 1997, 155:1828–1834.PubMedGoogle Scholar
  55. 55.
    Cernadas M, De Sanctis GT, Krinzman SJ, et al.: CD23 and allergic pulmonary inflammation: potential role as an inhibitor. Am J Respir Cell Mol Biol 1999, 20:1–8.PubMedGoogle Scholar
  56. 56.
    Chung KF, Barnes PJ: Cytokines in asthma. Thorax 1999, 54:825–857. This is a state-of-the-art review.PubMedGoogle Scholar
  57. 57.
    Pauwels RA: Cytokines and their receptors as therapeutic targets in asthma. Clin Exp Allergy 1998, 28(suppl 3):1–5.Google Scholar
  58. 58.
    Borish LC, Nelson HS, Bensch G, et al.: Phase I/II study of soluble interleukin-4 receptor (IL-4R) in adults with moderate asthma. Eur Respir J 1999, 14:288s.Google Scholar
  59. 59.
    Wills-Karp M, Luyimbazi J, Xu X, et al.: Interleukin-13: central mediator of allergic asthma. Science 1998, 282:2258–2260.PubMedCrossRefGoogle Scholar
  60. 60.
    Grünig G, Warnock M, Wakil AE, et al.: Requirement for IL-13 independently of IL-4 in experimental asthma. Science 1998, 282:2261–2263.PubMedCrossRefGoogle Scholar
  61. 61.
    Foster PS: STAT6: an intracellular target for the inhibition of allergic disease. Clin Exp Allergy 1999, 29:12–16.PubMedCrossRefGoogle Scholar
  62. 62.
    Kaplan MH, Schindler U, Smiley ST, Grusby MJ: Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 1996, 4:313–319.PubMedCrossRefGoogle Scholar
  63. 63.
    Losman JA, Chen XP, Hilton D, Rothman P: Cutting edge: SOCS-1 is a potent inhibitor of IL-4 signal transduction. J Immunol 1999, 162:3770–3774.PubMedGoogle Scholar
  64. 64.
    Burchard EG, Silverman EK, Rosenwasser LJ, et al.: Association between a sequence variant in the IL-4 gene promoter and FEV(1) in asthma. Am J Respir Crit Care Med 1999, 160:919–922.PubMedGoogle Scholar
  65. 65.
    Singh AD, Sanderson CJ: Anti-interleukin 5 strategies as a potential treatment for asthma. Thorax 1997, 52:483–485.PubMedGoogle Scholar
  66. 66.
    Palframan RT, Collins PD, Severs NJ, et al.: Mechanisms of acute eosinophil mobilization from the bone marrow stimulated by interleukin 5: the role of specific adhesion molecules and phosphatidylinositol 3-kinase. J Exp Med 1998, 188:1621–1632.PubMedCrossRefGoogle Scholar
  67. 67.
    Leckie MJ, Ten Brinke A, Khan J, et al.: Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness and the late asthmatic response. Lancet 2000, in press.Google Scholar
  68. 68.
    Mckinnon M: An interleukin 5 mutant distinguishes between two functional responses in human eosinophils. J Exp Med 1997, 186:121–129.PubMedCrossRefGoogle Scholar
  69. 69.
    Adachi T, Alam R: The mechanism of IL-5 signal transduction. Am J Physiol 1998, 275:C623-C633.PubMedGoogle Scholar
  70. 70.
    Feldman M, Taylor P, Paleolog E, et al.: Anti-TNF alpha therapy is useful in rheumatoid arthritis and Crohn’s disease: analysis of the mechanism of action predicts utility in other diseases. Transplant Proc 1998, 30:4126–4127.PubMedCrossRefGoogle Scholar
  71. 71.
    Pretolani M, Goldman M: IL-10: a potential therapy for allergic inflammation. Immunol Today 1997, 18:277–280.PubMedCrossRefGoogle Scholar
  72. 72.
    Borish L, Aarons A, Rumbyrt J, et al.: Interleukin-10 regulation in normal subjects and patients with asthma. J Allergy Clin Immunol 1996, 97:1288–1296.PubMedCrossRefGoogle Scholar
  73. 73.
    Lim S, Crawley E, Woo P, Barnes PJ: Haplotype associated with low interleukin-10 production in patients with severe asthma. Lancet 1998, 352:113.PubMedCrossRefGoogle Scholar
  74. 74.
    Hasko G, Szabo C: IL-12 as a therapeutic target for pharmacological modulation in immune-mediated and inflammatory diseases: regulation of T helper 1/T helper 2 responses. Br J Pharmacol 1999, 127:1295–1304.PubMedCrossRefGoogle Scholar
  75. 75.
    Wills-Karp M: Interleukin-12 as a target for modulation of the inflammatory response in asthma. Allergy 1998, 53:113–119.PubMedCrossRefGoogle Scholar
  76. 76.
    Gately MK, Renzetti LM, Magram J, et al.: The interleukin-12/ interleukin-12-receptor system: role in normal and pathological immune responses. Ann Rev Immunol 1998, 16:495–521.CrossRefGoogle Scholar
  77. 77.
    Leonard JP, Sherman ML, Fisher GL, et al.: Effect of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-g production. Blood 1997, 90:2541–2548.PubMedGoogle Scholar
  78. 78.
    Bryan SA, O’Connor BJ, Matti S, et al.: Effects of recombinant human interleukin-12 on eosinophils, airway hyperreactivity and the late asthmatic response. Lancet 2000, in press.Google Scholar
  79. 79.
    Prescott SL, Macaubas C, Smallacombe T, et al.: Reciprocal age-related patterns of allergen-specific T-cell immunity in normal vs. atopic infants. Clin Exp Allergy 1998, 28(suppl 5):39–44.PubMedCrossRefGoogle Scholar
  80. 80.
    Hansen G, Berry G, Dekruyff RH, Umetsu DT: Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. J Clin Invest 1999, 103:175–183.PubMedGoogle Scholar
  81. 81.
    Hofstra CL, Van AI, Hofman G, et al.: Prevention of Th2-like cell responses by coadministration of IL-12 and IL-18 is associated with inhibition of antigen-induced airway hyperresponsiveness, eosinophilia, and serum IgE levels. J Immunol 1998, 161:5054–5060.PubMedGoogle Scholar
  82. 82.
    Boguniewicz M, Martin RJ, Martin D, et al.: The effects of nebulized recombinant interferon-gamma in asthmatic airways. J Allergy Clin Immunol 1995, 95:133–135.PubMedCrossRefGoogle Scholar
  83. 83.
    Kim MK, Brandley BK, Anderson MB, Bochner BS: Antagonism of selectin-dependent adhesion of human eosinophils and neutrophils by glycomimetics and oligosaccharide compounds. Am J Respir Cell Mol Biol 1998, 19:836–841.PubMedGoogle Scholar
  84. 84.
    Musser JH, Anderson MB, Levy DE: Glycomimetics as selectin inhibitors. Curr Pharm Design 1995, 1:221–232.Google Scholar
  85. 85.
    Kogan TP, Dupre B, Bui H, et al.: Novel synthetic inhibitors of selectin-mediated cell adhesion: synthesis of 1, 6-bis[3-(3-carboxymethylphenyl)-4-(2-alpha-D-mannopyranosyloxy) phenyl]hexane (TBC1269). J Med Chem 1998, 41:1099–1111.PubMedCrossRefGoogle Scholar
  86. 86.
    Austrup F, Vestweber D, Borges E, et al.: P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflamed tissues. Nature 1997, 385:81–83.PubMedCrossRefGoogle Scholar
  87. 87.
    Davis LS, Kavanaugh AF, Nichols LA, Lipsky PE: Induction of persistent T cell hyperresponsiveness in vivo by monoclonal antibody to ICAM-1 in patients with rheumatoid arthritis. J Immunol 1995, 154:3525–3537.PubMedGoogle Scholar
  88. 88.
    Glover JM, Leeds JM, Mant TG, et al.: Phase I safety and pharmacokinetic profile of an intercellular adhesion molecule-1 antisense oligodeoxynucleotide (ISIS 2302). J Pharmacol Exp Ther 1997, 282:1173–1180.PubMedGoogle Scholar
  89. 89.
    Bennett CF: Antisense oligonucleotide therapeutics. Exp Opin Invest Drugs 1999, 8:237–253.CrossRefGoogle Scholar
  90. 90.
    Lin KG, Castro AC: Very late antigen 4 (VLA4) antagonists as anti-inflammatory agents. Curr Opin Chem Biol 1998, 2:453–457.PubMedCrossRefGoogle Scholar
  91. 91.
    Jackson DY, Quan C, Artis DR, et al.: Potent a4b1 peptide antagonists as potential anti-inflammatory agents. J Med Chem 1997, 40:3359–3368.PubMedCrossRefGoogle Scholar
  92. 92.
    Lobb RR, Adams SP: Small molecule antagonists of alpha 4 integrins: novel drugs for asthma. Exp Opin Invest Drugs 1999, 8:935–945. This is a comprehensive VLA-4 antagonist review.CrossRefGoogle Scholar
  93. 93.
    Lin K, Ateeq HS, Hsiung SH, et al.: Selective, tight-binding inhibitors of integrin alpha4beta1 that inhibit allergic airway responses. J Med Chem 1999, 42:920–934.PubMedCrossRefGoogle Scholar
  94. 94.
    Heath H, Qin S, Rao P, et al.: Chemokine receptor usage by human eosinophils The importance of CCR3 demonstrated using an antagonistic monoclonal antibody. J Clin Invest 1997, 99:178–184.PubMedCrossRefGoogle Scholar
  95. 95.
    Luster AD: Chemokines-chemotactic cytokines that mediate inflammation. N Engl J Med 1998, 338:436–445.PubMedCrossRefGoogle Scholar
  96. 96.
    Ying S, Robinson DS, Meng Q, et al.: Enhanced expression of eotaxin and CCR3 mRNA and protein in atopic asthma: association with airway hyperresponsiveness and predominant co-localization of eotaxin mRNA to bronchial epithelial and endothelial cells. Eur J Immunol 1997, 27:3507–3516.PubMedCrossRefGoogle Scholar
  97. 97.
    Saunders J, Tarby CM: Opportunities for novel therapeutic agents acting at chemokine receptors. Drug Discov Today 1999, 4:80–92.PubMedCrossRefGoogle Scholar
  98. 98.
    Sallusto F, Mackay CR, Lanzavecchia A: Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells. Science 1997, 277:2005–2007.PubMedCrossRefGoogle Scholar
  99. 99.
    Uguccioni M, Mackay CR, Ochensberger B, et al.: High expression of the chemokine receptor CCR3 in human blood basophils: role in activation by eotaxin, MCP-4, and other chemokines. J Clin Invest 1997, 100:1137–1143.PubMedGoogle Scholar
  100. 100.
    Bonecchi R, Bianchi G, Bordignon PP, et al.: Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med 1998, 187:129–134.PubMedCrossRefGoogle Scholar
  101. 101.
    Elsner J, Petering H, Hochstetter R, et al.: The CC chemokine antagonist Met-RANTES inhibits eosinophil effector functions through the chemokine receptors CCR1 and CCR3. Eur J Immunol 1997, 27:2892–2898.PubMedCrossRefGoogle Scholar
  102. 102.
    Burastero SE, Rossi GA: Immunomodulation by interference with co-stimulatory molecules: therapeutic perspectives in asthma. Thorax 1999, 54:554–557.PubMedCrossRefGoogle Scholar
  103. 103.
    Robinson DS: T cell costimulation: a potential therapeutic target in asthma. Clin Exp Allergy 1998, 28:788–790.PubMedCrossRefGoogle Scholar
  104. 104.
    Kline JN, Waldschmidt TJ, Businga TR, et al.: Cutting edge: modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J Immunol 1998, 160:2555–2559.PubMedGoogle Scholar
  105. 105.
    Broide D, Schwarze J, Tighe H, et al.: Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation, and airway hyperresponsiveness in mice. J Immunol 1998, 161:7054–7062.PubMedGoogle Scholar
  106. 106.
    Sur S, Wild JS, Choudhury BK, et al.: Long term prevention of allergic lung inflammation in a mouse model of asthma by CpG oligodeoxynucleotides. J Immunol 1999, 162:6284–6293. This article presents promising experimental data.PubMedGoogle Scholar
  107. 107.
    Metzger WJ, Nyce JW: Oligonucleotide therapy of allergic asthma. J Allergy Clin Immunol 1999, 104:260–266.PubMedCrossRefGoogle Scholar
  108. 108.
    Durban Immunotherapy Trial Group: Immunotherapy with Mycobacterium vaccae in patients with newly diagnosed pulmonary tuberculosis: a randomised controlled trial. Lancet 1999, 354:116–119.CrossRefGoogle Scholar
  109. 109.
    Norman PS: Immunotherapy: past and present. J Allergy Clin Immunol 1998, 102:1–10. This is a superb review of a controversial area.PubMedCrossRefGoogle Scholar
  110. 110.
    Platts-Mills TA, Mueller GA, Wheatley LM: Future directions for allergen immunotherapy. J Allergy Clin Immunol 1998, 102:335–343.PubMedCrossRefGoogle Scholar
  111. 111.
    Chapman MD, Smith AM, Vailes LD, et al.: Recombinant allergens for diagnosis and therapy of allergic disease. J Allergy Clin Immunol 2000, 106:409–418.PubMedCrossRefGoogle Scholar
  112. 112.
    Marcotte GV, Braun CM, Norman PS, et al.: Effects of peptide therapy on ex vivo T-cell responses. J Allergy Clin Immunol 1998, 101:506–513.PubMedCrossRefGoogle Scholar
  113. 113.
    Durham SR, Till SJ: Immunologic changes associated with allergen immunotherapy. J Allergy Clin Immunol 1998, 102:157–164.PubMedCrossRefGoogle Scholar
  114. 114.
    Tsitoura DC, Blumenthal RL, Berry G, et al.: Mechanisms preventing allergen-induced airways hyperreactivity: role of tolerance and immune deviation. J Allergy Clin Immunol 2000, 106:239–246.PubMedCrossRefGoogle Scholar
  115. 115.
    Haselden BM, Kay AB, Larche M: Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions. J Exp Med 1999, 189:1885–1894.PubMedCrossRefGoogle Scholar
  116. 116.
    Rogers DF, Laurent GJ: New ideas on the pathophysiology and treatment of lung disease. Thorax 1998, 53:200–203.PubMedCrossRefGoogle Scholar
  117. 117.
    Mathieu M, Gougat C, Jaffuel D, et al.: The glucocorticoid receptor gene as a candidate for gene therapy in asthma. Gene Ther 1999, 6:245–252.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc. 2001

Authors and Affiliations

  • Trevor T. Hansel
    • 1
  • Peter J. Barnes
    • 2
  1. 1.National Heart and Lung Institute (NHLI) Clinical Studies UnitRoyal Brompton HospitalLondonUK
  2. 2.Department of Thoracic MedicineNHLI, Imperial CollegeLondonUK

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