Emerging Nonsteroidal Anti-Inflammatory Therapies Targeting Specific Mechanisms in Asthma and Allergy

  • Leif Bjermer
  • Zuzana Diamant
Part of the Allergy Frontiers book series (ALLERGY, volume 5)

Our current understanding of asthma pathophysiology has changed considerably during the last 20 years. From being regarded as an inflammatory disorder mainly affecting the central airways, asthma is now recognized as a heterogeneous, systemic disorder, involving the respiratory tract from nose to peripheral airways. Chronic inflammation in asthma is associated with the development of structural changes within the airways (the so-called “remodelling”) and airway hyperresponsiveness. While most asthma phenotypes are easily controlled with fairly low doses of corti-costeroids, others appear more or less steroid-resistant. Inflammation involving mast cells and neutrophils is an example of such underlying mechanisms. Another example of corticosteroid resistance is over production of cysteinyl leukotrienes or tumour necrosis factor (TNF) - α in other asthma phenotypes [1, 2]. All together, this motivates the search for more systemic therapies, complementary to corticos-teroid treatment. In this chapter, we will highlight some present and future non-steroidal therapies, all given by systemic route.


Allergic Rhinitis Airway Inflammation Allergy Clin Immunol Allergic Asthma Respir Crit 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Peters-Golden M, Swern A, Bird SS, et al. Influence of body mass index on the response to asthma controller agents. Eur Respir J. 2006; 27 (3):495–503CrossRefPubMedGoogle Scholar
  2. 2.
    Lazarus SC, Chinchilli VM, Rollings NJ, et al. NHLBI's Asthma Clinical Research Network. Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med. 2007;.175 (8):783–90CrossRefPubMedGoogle Scholar
  3. 3.
    Holtzman MJ. Arachidonic acid metabolism. Implications of biological chemistry for lung function and disease. American Review of Respiratory Disease 1991; 143:188–203PubMedGoogle Scholar
  4. 4.
    Diamant Z, Sampson AP. Anti-inflammatory mechanisms of leukotriene modulators. Clin Exp Allergy 1999; 29 (11):1449–1453CrossRefPubMedGoogle Scholar
  5. 5.
    Panettieri RA, Tan EM, Ciocca V, Luttmann MA, Leonard TB, Hay DW. Effects of LTD4 on human airway smooth muscle cell proliferation, matrix expression, and contraction In vitro: differential sensitivity to cysteinyl leukotriene receptor antagonists. Am J Respir Cell Mol Biol. 1998; 19 (3):453–461PubMedGoogle Scholar
  6. 6.
    Holgate ST, Peters-Golden M, Panettieri RA, Henderson WR. Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling. J Allergy Clin Immunol. 2003; 111 (1 SUPPL):S18–34CrossRefPubMedGoogle Scholar
  7. 7.
    Diamant Z, van der Molen T. Treating asthma: is there a place for leukotriene receptor antagonists? Respir Med. 2005; 99 (6):655–662CrossRefPubMedGoogle Scholar
  8. 8.
    Bäck M, Sultan A, Ovchinnikova O, Hansson GK. 5-Lipoxygenase-activating protein: a potential link between innate and adaptive immunity in atherosclerosis and adipose tissue inflammation. Circ Res. 2007; 100 (7):946–949CrossRefPubMedGoogle Scholar
  9. 9.
    Marian E, Baraldo S, Visentin A, Papi A, Saetta M, Fabbri LM, et al. Up-regulated membrane and nuclear leukotriene B4 receptors in COPD. Chest 2006; 129 (6):1523–1530CrossRefPubMedGoogle Scholar
  10. 10.
    Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2008;
  11. 11.
    Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, Menten J, et al. Montelukast reduces asthma exacerbations in 2–5-year-old children with intermittent asthma. Am J Respir Crit Care Med. 2005; 171 (4):315–322CrossRefPubMedGoogle Scholar
  12. 12.
    Virchow JC, Bachert C. Efficacy and safety of montelukast in adults with asthma and allergic rhinitis. Respir Med. 2006; 100 (11):1952–1959CrossRefPubMedGoogle Scholar
  13. 13.
    Dahlén B, Nizankowska E, Szczeklik A, Zetterström O, Bochenek G, Kumlin M, et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirinintolerant asthmatics. Am J Respir Crit Care Med. 1998; 157 (4 PT 1):1187–1194PubMedGoogle Scholar
  14. 14.
    Fujimura M, Nishioka S, Kumabashiri I, Matsuda T, Mifune J. Effects of aerosol administration of a thromboxane synthetase inhibitor (OKY-046) on bronchial responsiveness to acetyl-choline in asthmatic subjects. Chest 1990; 98 (2):276–279CrossRefPubMedGoogle Scholar
  15. 15.
    Terao S, Shiraishi M, Matsumoto T, Ashida Y. Thromboxane A2 antagonist—discovery of seratrodast. Yakugaku Zasshi 1999; 119:377–390PubMedGoogle Scholar
  16. 16.
    Matsumoto T, Ashida Y, Tsukuda R. Pharmacological modulation of immediate and late airway response and leukocyte infiltration in the guinea pig. J Pharmacol Exp Ther. 1994; 269:1236–1244PubMedGoogle Scholar
  17. 17.
    Kostenis E, Ulven T. Emerging roles of DP and CRTH2 in allergic inflammation. Trends in Molecular Medicine 2006; 12:148–158CrossRefPubMedGoogle Scholar
  18. 18.
    Motobayashi Y, Imagawa W, Saida K. [Ramatroban (Baynas): a review of its pharmacological and clinical profile]. Nippon Yakurigaku Zasshi Japanese J Pharmacol. 2001; 118:397–402Google Scholar
  19. 19.
    Uller L, Mathiesen J.M, Alenmyr L, Korsgren M, Ulven T, Högberg T, Andersson G, Persson C.G, Kostenis E. Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation. Respiratory Research 2007; 8:16CrossRefPubMedGoogle Scholar
  20. 20.
    Ulven T, Kostenis E. Minor structural modifications convert the dual TP/CRTH2 antagonist rama-troban into a highly selective and potent CRTH2 antagonist. J Med Chem. 2005; 48:897–900CrossRefPubMedGoogle Scholar
  21. 21.
    Fan Chung K. Phosphodiesterase inhibitors in airways disease. Eur J Pharmacol. 2006; 533:110–117CrossRefPubMedGoogle Scholar
  22. 22.
    Rybalkin SD, Rybalkina IG, Shimizu-Albergine M, Tang XB, Beavo JA. PDE5 is converted to an activated state upon cGMP binding to the GAF A domain. EMBO Journal 2003; 22:469–478CrossRefPubMedGoogle Scholar
  23. 23.
    Barnes PJ. Theophylline: new perspectives for an old drug. Am J Respir Crit Care Med. 2003; 167:813–818CrossRefPubMedGoogle Scholar
  24. 24.
    Lipworth BJ. Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 2005; 365:167–175CrossRefPubMedGoogle Scholar
  25. 25.
    Nowak D. Management of asthma with anti-immunoglobulin E: a review of clinical trials of omalizumab. Respiratory Medicine 2006; 100:1907–1917CrossRefPubMedGoogle Scholar
  26. 26.
    Novartis prescription information 2009;
  27. 27.
    Djukanovic R, Wilson SJ, Kraft M, Jarjour NN, Steel M, Chung KF, Bao W, Fowler-Taylor A, Matthews J, Busse WW, Holgate ST, Fahy JV. Effects of treatment with anti-immunoglob-ulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med. 2004; 170:583–593CrossRefPubMedGoogle Scholar
  28. 28.
    Vignola AM, Humbert M, Bousquet J, Boulet LP, Hedgecock S, Blogg M, Fox H, Surrey K. Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with concomitant allergic asthma and persistent allergic rhinitis: SOLAR. Allergy 2004; 59:709–717CrossRefPubMedGoogle Scholar
  29. 29.
    Humbert M, Beasley R, Ayres J, Slavin R, Hébert J, Bousquet J, Beeh K.M, Ramos S, Canonica GW, Hedgecock S, Fox H, Blogg M, Surrey K. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005; 60:309–316CrossRefPubMedGoogle Scholar
  30. 30.
    Bousquet J, Van Cauwenberge P, Ait Khaled N, et al. Pharmacologic and anti-IgE treatment of allergic rhinitis ARIA update (in collaboration with GA2LEN). Allergy 2006; 61 (9):1086–1096 ReviewCrossRefPubMedGoogle Scholar
  31. 31.
    Casale TB, Busse WW, Kline JN, Ballas ZK, Moss MH, Townley RG, et al. Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis. J Allergy Clin Immunol. 2006; 117 (1):134–140CrossRefPubMedGoogle Scholar
  32. 32.
    Klunker S, Saggar LR, Seyfert-Margolis V, Asare AL, Casale TB, Durham SR, et al. Combination treatment with omalizumab and rush immunotherapy for ragweed-induced allergic rhinitis: Inhibition of IgE-facilitated allergen binding. J Allergy Clin Immunol. 2007;vol-ume and pages??Google Scholar
  33. 33.
    Chang TW, Wu PC, Hsu CL, Hung AF. Anti-IgE antibodies for the treatment of IgE-mediated allergic diseases. Adv Immunol. 2007; 93:63–119CrossRefPubMedGoogle Scholar
  34. 34.
    Freeman J. Furter observations on the treatment of Hay Fever by Hypodermic inoculations of pollen vaccine. Lancet 1911;178(4594):814–817CrossRefGoogle Scholar
  35. 35.
    Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2003; 4:CD001186Google Scholar
  36. 36.
    Roll A, Hofbauer G, Ballmer-Weber BK, Schmid-Grendelmeier P. Safety of specific immu-notherapy using a four-hour ultra-rush induction scheme in bee and wasp allergy. Journal of Investigational Allergology & Clinical Immunology 2006; 16:79–85Google Scholar
  37. 37.
    Tripodi S, Di Rienzo Businco A, Benincori N, Scala G, Pingitore G. Safety and tolerability of ultra-rush induction, less than one hour, of sublingual immunotherapy in children. International Archives of Allergy and Immunology 2006; 139:149–152CrossRefPubMedGoogle Scholar
  38. 38.
    Amin HS, Liss GM, Bernstein DI. Evaluation of near-fatal reactions to allergen immuno-therapy injections. J Allergy Clin Immunol. 2006; 117:169–175CrossRefPubMedGoogle Scholar
  39. 39.
    Jacobsen L, Niggemann B, Dreborg S, Ferdousi HA, Halken S, Høst A, Koivikko A, Norberg LA, Valovirta E, Wahn U, Möller C. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy 2007; 62:943–948CrossRefPubMedGoogle Scholar
  40. 40.
    Abramson MJ, Puy R.M, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database of Systematic Reviews 2003; 4:CD001186Google Scholar
  41. 41.
    Calamita Z, Saconato H, Pelá AB, Atallah AN. Efficacy of sublingual immunotherapy in asthma: systematic review of randomized-clinical trials using the Cochrane Collaboration method. Allergy 2006; 61:1162–1172CrossRefPubMedGoogle Scholar
  42. 42.
    Coffman RL, Carty J. A T cell activity that enhances polyclonal IgE production and its inhibition by interferon-gamma. J Immunol. 1986; 136:949–954PubMedGoogle Scholar
  43. 43.
    Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. Journal of Immunology 1986; 136:2348–2357Google Scholar
  44. 44.
    Steinman L. A brief history of T (H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med. 2007; 13 (2):139–145CrossRefPubMedGoogle Scholar
  45. 45.
    Howarth PH, Babu KS, Arshad HS, Lau L, Buckley M, McConnell W, Beckett P, Al Ali M., Chauhan A, Wilson SJ, Reynolds A, Davies DE, Holgate ST. Tumor necrosis factor (TNF alpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 2005; 60:1012–1018CrossRefPubMedGoogle Scholar
  46. 46.
    Ohkawara Y, Yamauchi K, Tanno Y, Tamura G, Ohtani H, Nagura H, et al. Human lung mast cells and pulmonary macrophages produce tumor necrosis factor-alpha in sensitized lung tissue after IgE receptor triggering. Am J Respir Cell Mol Biol. 1992; 7 (4):385–392PubMedGoogle Scholar
  47. 47.
    Russo C, Polosa R. TNF-alpha as a promising therapeutic target in chronic asthma: a lesson from rheumatoid arthritis. Clin Sci (Lond). 2005; 109 (2):135–142CrossRefGoogle Scholar
  48. 48.
    Cembrzynska-Nowak M, Szklarz E, Inglot AD, Teodorczyk-Injeyan JA. Elevated release of tumor necrosis factor-alpha and interferon-gamma by bronchoalveolar leukocytes from patients with bronchial asthma. Am Rev Respir Dis. 1993; 147 (2):291–295PubMedGoogle Scholar
  49. 49.
    Russo C, Polosa R. TNF-alpha as a promising therapeutic target in chronic asthma: a lesson from rheumatoid arthritis. Clin Sci (Lond). 2005; 109 (2):135–142CrossRefGoogle Scholar
  50. 50.
    The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. European Network for Understanding Mechanisms of Severe Asthma. Eur Respir J. 2003; 22 (3):470–477CrossRefGoogle Scholar
  51. 51.
    Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, Green RH, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med. 2006; 354 (7):697–708CrossRefPubMedGoogle Scholar
  52. 52.
    Rouhani FN, Meitin CA, Kaler M, Miskinis-Hilligoss D, Stylianou M, Levine SJ. Effect of tumor necrosis factor antagonism on allergen-mediated asthmatic airway inflammation. Respir Med. 2005; 99 (9):1175–1182CrossRefPubMedGoogle Scholar
  53. 53.
    Lampinen M, Rak S, Venge P. The role of interleukin-5, interleukin-8 and RANTES in the chemotactic attraction of eosinophils to the allergic lung. Clin Exp Allergy 1999; 29 (3):314–322CrossRefPubMedGoogle Scholar
  54. 54.
    Shi HZ, Xiao CQ, Zhong D, Qin SM, Liu Y, Liang GR, et al. Effect of inhaled interleukin-5 on airway hyperreactivity and eosinophilia in asthmatics. Am J Respir Crit Care Med. 1998; 157 (1):204–209PubMedGoogle Scholar
  55. 55.
    Leckie MJ, ten Brinke A, Khan J, Diamant Z, O'Connor BJ, Walls CM, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000; 356 (9248):2144–2148CrossRefPubMedGoogle Scholar
  56. 56.
    Kelly EA, Busse WW, Jarjour NN. Inhaled budesonide decreases airway inflammatory response to allergen. Am J Respir Crit Care Med 2000;162(3 PT 1):883–90.PubMedGoogle Scholar
  57. 57.
    Haselden BM, Larche M, Meng Q, Shirley K, Dworski R, Kaplan AP, et al. Late asthmatic reactions provoked by intradermal injection of T-cell peptide epitopes are not associated with bronchial mucosal infiltration of eosinophils or T(H)2-type cells or with elevated concentrations of histamine or eicosanoids in bronchoalveolar fluid. J Allergy Clin Immunol. 2001; 108 (3):394–401CrossRefPubMedGoogle Scholar
  58. 58.
    Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med. 2003; 167:199–204CrossRefPubMedGoogle Scholar
  59. 59.
    Flood-Page P, Swenson C, Faiferman I, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med. 2007; 176 (11):1062–1071CrossRefPubMedGoogle Scholar
  60. 60.
    Coffman RL, Ohara J, Bond MW, Carty J, Zlotnik A, Paul WE. B cell stimulatory factor-1 enhances the IgE response of lipopolysaccharide-activated B cells. J Immunol. 1986; 136 (12):4538–4541PubMedGoogle Scholar
  61. 61.
    Sudowe S, Arps V, Vogel T, Kolsch E. The role of interleukin-4 in the regulation of sequential isotype switch from immunoglobulin G1 to immunoglobulin E antibody production. Scand J Immunol. 2000; 51 (5):461–471CrossRefPubMedGoogle Scholar
  62. 62.
    Steinke JW, Borish L. Th2 cytokines and asthma. Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists. Respir res. 2001; 2 (2):66–70CrossRefPubMedGoogle Scholar
  63. 63.
    Leonard C, Tormey V, Burke C, Poulter LW. Allergen-induced cytokine production in atopic disease and its relationship to disease severity. Am J Respir Cell Mol Biol. 1997; 17 (3):368–375PubMedGoogle Scholar
  64. 64.
    Shi HZ, Deng JM, Xu H, Nong ZX, Xiao CQ, Liu ZM, et al. Effect of inhaled interleukin-4 on airway hyperreactivity in asthmatics. Am J Respir Crit Care Med. 1998; 157 (6 PT 1):1818–1821PubMedGoogle Scholar
  65. 65.
    Borish LC, Nelson HS, Corren J, Bensch G, Busse WW, Whitmore JB, et al. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol. 2001; 107 (6):963–970CrossRefPubMedGoogle Scholar
  66. 66.
    Zurawski SM, Vega F, Huyghe B, Zurawski G. Receptors for interleukin-13 and interleukin-4 are complex and share a novel component that functions in signal transduction. EMBO Journal 1993; 12:2663–2670PubMedGoogle Scholar
  67. 67.
    Wills-Karp M. Interleukin-13 in asthma pathogenesis. Immunological Reviews 2004; 202:175–190CrossRefPubMedGoogle Scholar
  68. 68.
    Trudeau J, Hu H, Chibana K, Chu HW, Westcott JY, Wenzel SE. Selective downregulation of prostaglandin E2-related pathways by the Th2 cytokine IL-13. J Allergy Clin Immunol 2006; 117:1446–1454CrossRefPubMedGoogle Scholar
  69. 69.
    Fukushi J, Ono M, Morikawa W, Iwamoto Y, Kuwano M. The activity of soluble VCAM-1 in angiogenesis stimulated by IL-4 and IL-13. J Immunol. 2000; 165:2818–2823PubMedGoogle Scholar
  70. 70.
    Perkins C, Wills-Karp M, Finkelman FD. IL-4 induces IL-13-independent allergic airway inflammation. J Allergy Clin Immunol. 2006; 118:410–419CrossRefPubMedGoogle Scholar
  71. 71.
    Tomkinson A, Duez C, Cieslewicz G, Pratt J.C, Joetham A, Shanafelt MC, Gundel R, Gelfand EW. A murine IL-4 receptor antagonist that inhibits IL-4- and IL-3-induced responses prevents antigen-induced airway eosinophilia and airway hyperresponsiveness. J Immunol. 2001; 166:5792–5800PubMedGoogle Scholar
  72. 72.
    Hultner L, Druez C, Moeller J, Uyttenhove C, Schmitt E, Rude E, et al. Mast cell growth-enhancing activity (MEA) is structurally related and functionally identical to the novel mouse T cell growth factor P40/TCGFIII (interleukin 9). Eur J Immunol. 1990; 20 (6):1413–1416CrossRefPubMedGoogle Scholar
  73. 73.
    Renauld JC, Kermouni A, Vink A, Louahed J, Van Snick J. Interleukin-9 and its receptor: involvement in mast cell differentiation and T cell oncogenesis. J Leukoc Biol. 1995; 57 (3):353–360PubMedGoogle Scholar
  74. 74.
    Louahed J, Kermouni A, Van Snick J, Renauld JC. IL-9 induces expression of granzymes and high-affinity IgE receptor in murine T helper clones. J Immunol. 1995; 154 (10):5061–5070PubMedGoogle Scholar
  75. 75.
    Cheng G, Arima M, Honda K, Hirata H, Eda F, Yoshida N, Fukushima F, Ishii Y, Fukuda T. Anti-interleukin-9 antibody treatment inhibits airway inflammation and hyperreactivity in mouse asthma model. Am J Respir Crit Care Med. 2002; 166:409–416CrossRefPubMedGoogle Scholar
  76. 76.
    Pretolani M, Goldman M. Cytokines involved in the downregulation of allergic airway inflammation. Res Immunol. 1997; 148 (1):33–38CrossRefPubMedGoogle Scholar
  77. 77.
    Staples KJ, Bergmann M, Barnes PJ, Newton R. Stimulus-specific inhibition of IL-5 by cAMP-elevating agents and IL-10 reveals differential mechanisms of action. Biochem Biophys Res Commun. 2000; 273 (3):811–815CrossRefPubMedGoogle Scholar
  78. 78.
    Borish L, Aarons A, Rumbyrt J, Cvietusa P, Negri J, Wenzel S. Interleukin-10 regulation in normal subjects and patients with asthma. J Allergy Clin Immunol. 1996; 97 (6):1288–1296CrossRefPubMedGoogle Scholar
  79. 79.
    Matsumoto K, Gauvreau GM, Rerecich T, Watson RM, Wood LJ, O'Byrne PM. IL-10 production in circulating T cells differs between allergen-induced isolated early and dual asthmatic responders. J Allergy Clin Immunol. 2002; 109 (2):281–286CrossRefPubMedGoogle Scholar
  80. 80.
    Hawrylowicz C, Richards D, Loke TK, Corrigan C, Lee T. A defect in corticosteroid-induced IL-10 production in T lymphocytes from corticosteroid-resistant asthmatic patients. J Allergy Clin Immunol. 2002; 109 (2):369–370CrossRefPubMedGoogle Scholar
  81. 81.
    Stelmach I, Jerzynska J, Kuna P. A randomized, double-blind trial of the effect of glucocorti-coid, antileukotriene and beta-agonist treatment on IL-10 serum levels in children with asthma. Clin Exp Allergy 2002; 32 (2):264–269CrossRefPubMedGoogle Scholar
  82. 82.
    Van Deventer SJ, Elson CO, Fedorak RN. Multiple doses of intravenous interleukin 10 in steroid-refractory Crohn's disease. Crohn's Disease Study Group. Gastroenterology 1997; 113 (2):–9Google Scholar
  83. 83.
    Zeibecoglou K, Ying S, Meng Q, Poulter LW, Robinson DS, Kay AB. Macrophage subpopulations and macrophage-derived cytokines in sputum of atopic and nonatopic asthmatic subjects and atopic and normal control subjects. J Allergy Clin Immunol. 2000; 106 (4):697–704CrossRefPubMedGoogle Scholar
  84. 84.
    Walter MJ, Kajiwara N, Karanja P, Castro M, Holtzman MJ. Interleukin 12 p40 production by barrier epithelial cells during airway inflammation. J Exp Med. 2001; 193 (3):339–351CrossRefPubMedGoogle Scholar
  85. 85.
    van der Pouw Kraan TC, Boeije LC, de Groot ER, Stapel SO, Snijders A, Kapsenberg ML, et al. Reduced production of IL-12 and IL-12-dependent IFN-gamma release in patients with allergic asthma. J Immunol 1997; 158 (11):5560–5565PubMedGoogle Scholar
  86. 86.
    Blanco-Quiros A, Gonzalez H, Arranz E, Lapena S. Decreased interleukin-12 levels in umbilical cord blood in children who developed acute bronchiolitis. Pediatr Pulmonol. 1999; 28 (3):175–180CrossRefPubMedGoogle Scholar
  87. 87.
    Rinas U, Horneff G, Wahn V. Interferon-gamma production by cord-blood mononuclear cells is reduced in newborns with a family history of atopic disease and is independent from cord blood IgE-levels. Pediatr Allergy Immunol. 1993; 4 (2):60–64CrossRefPubMedGoogle Scholar
  88. 88.
    Chou CC, Huang MS, Hsieh KH, Chiang BL. Reduced IL-12 level correlates with decreased IFN-gamma secreting T cells but not natural killer cell activity in asthmatic children. Ann Allergy Asthma Immunol. 1999; 82 (5):473–484CrossRefGoogle Scholar
  89. 89.
    Schwarze J, Hamelmann E, Cieslewicz G, Tomkinson A, Joetham A, Bradley K, et al. Local treatment with IL-12 is an effective inhibitor of airway hyperresponsiveness and lung eosino-philia after airway challenge in sensitized mice. J Allergy Clin Immunol. 1998; 102 (1):86–93CrossRefPubMedGoogle Scholar
  90. 90.
    Meyts I, Hellings PW, Hens G, Vanaudenaerde BM, Verbinnen B, Heremans H, Matthys P, Bullens DM, Overbergh L, Mathieu C, De Boeck K, Ceuppens JL. IL-12 contributes to allergen-induced airway inflammation in experimental asthma. J Immunol. 2006; 177:6460–6470PubMedGoogle Scholar
  91. 91.
    Bryan SA, O'Connor BJ, Matti S, Leckie MJ, Kanabar V, Khan J, et al. Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000; 356 (9248):2149–2153CrossRefPubMedGoogle Scholar
  92. 92.
    Brightling C, Berry M, Amrani Y. Targeting TNF-alpha: a novel therapeutic approach for asthma. J Allergy Clin Immunol. 2008;121 (1):5–10; quiz 11–2. Epub 2007 Nov 26. Review.CrossRefPubMedGoogle Scholar
  93. 93.
    Ma Y, Hayglass KT, Becker AB, Halayko AJ, Basu S, Simons FE, Peng Z. Novel cytokine peptide-based vaccines: an interleukin-4 vaccine suppresses airway allergic responses in mice. Allergy 2007; 62:–682Google Scholar
  94. 94.
    Ma Y, Hayglass KT, Becker AB, Fan Y, Yang X, Basu S, Srinivasan G, Simons FE, Halayko AJ, Peng Z. Novel Recombinant IL-13 Peptide-based Vaccine Reduces Airway Allergic Inflammatory Responses in Mice. Am J Respir Crit Care Med. 2007Google Scholar
  95. 95.
    Peng Z, Liu Q, Wang Q, Rector E, Ma Y,Warrington R. Novel IgE peptide-based vaccine prevents the increase of IgE and down-regulates elevated IgE in rodents. Clinical and Experimental Allergy 2007; 37:1041–1048CrossRefGoogle Scholar
  96. 96.
    Yoo J, Tcheurekdjian H, Lynch SV, Cabana M, Boushey HA. Microbial manipulation of immune function for asthma prevention: inferences from clinical trials. Proc Am Thorac Soc. 2007; 4:–282Google Scholar
  97. 97.
    Kalliomäki M, Salminen S, Poussa T, Isolauri E. Probiotics during the first 7 years of life: a cumulative risk reduction of eczema in a randomized, placebo-controlled trial. J Allergy Clin Immunol. 2007; 119:1011–1021CrossRefGoogle Scholar
  98. 98.
    Del Giudice MM., Rocco A, Capristo C. Probiotics in the atopic march: highlights and new insights. Digestive and Liver Disease 2006; 38 (Suppl 2):S–S290.Google Scholar
  99. 99.
    Abrahamsson TR, Jakobsson T, Böttcher MF, Fredrikson M, Jenmalm MC, Björkstén B, et al. Probiotics in prevention of IgE-associated eczema: a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol 2007; 119 (5):1–80CrossRefGoogle Scholar
  100. 100.
    Taylor AL, Dunstan JA, Prescott SL. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial. J Allergy Clin Immunol. 2007; 119 (1):–91Google Scholar
  101. 101.
    Diamant Z, Page CP. Heparin and related molecules as a new treatment for asthma. Pulm Pharmacol Ther. 2000; 13:1–4CrossRefPubMedGoogle Scholar
  102. 102.
    Ludwig RJ, Alban S, Boehncke WH. Structural requirements of heparin and related molecules to exert a multitude of anti-inflammatory activities. Mini Rev Med Chem. 2006; 6 (9):1–23CrossRefGoogle Scholar
  103. 103.
    Diamant Z, Timmers MC, Van der Veen H, et al. Effect of inhaled heparin on allergen-induced early and late asthmatic responses in patients with atopic asthma. Am J Respir Crit Care Med. 1996; 153 (6 Pt 1):1–5Google Scholar
  104. 104.
    Vancheri C, Mastruzzo C, Armato F, et al. Intranasal heparin reduces eosinophil recruitment after nasal allergen challenge in patients with allergic rhinitis. J Allergy Clin Immunol. 2001; 108 (5):–8Google Scholar
  105. 105.
    Zeng D, Prosperini G, Russo C, Spicuzza L, Cacciola RR, Di Maria GU, et al. Heparin attenuates symptoms and mast cell degranulation induced by AMP nasal provocation. J Allergy Clin Immunol. 2004; 114 (2):–20Google Scholar
  106. 106.
    Seeds AE, et al. The effect of inhaled heparin and related glycosaminoglycans on allergen-induced eosinophil infiltration in guinea-pigs. Pulm Pharmacol. 1995; 8(2–3):97–105CrossRefPubMedGoogle Scholar
  107. 107.
    Zeng D, Prosperini G, Russo C, Spicuzza L, Cacciola RR, Di Maria GU, et al. Heparin attenuates symptoms and mast cell degranulation induced by AMP nasal provocation. J Allergy Clin Immunol. 2004; 114 (2):–20Google Scholar
  108. 108.
    Passowicz-Muszynska E, Jankowska R, Krasnowska M. [The effect of inhaled low molecular weight heparin on cell composition in bronchoalveolar lavage fluid and serum levels of soluble receptor IL-2 in bronchial asthma patients] Pol Merkuriusz Lek 2002; 12 (69):–20(Polish)Google Scholar
  109. 107.
    Ahmed T, Gonzalez BJ, Danta I. Prevention of exercise-induced bronchoconstriction by inhaled low-molecular-weight heparin Am J Respir Crit Care Med. 1999; 160 (2):–81Google Scholar
  110. 110.
    Duong M, Cockcroft D, Boulet LP, Ahmed T, Iverson H, Atkinson DC, Stahl EG, Watson R, Davis B, Milot J, Gauvreau GM, O'Byrne PM. The effect of IVX-0142, a heparin-derived hypersulfated disaccharide, on the allergic airway responses in asthma. Allergy 2008; 63 (9):1–201CrossRefGoogle Scholar
  111. 111.
    Doukas J, Eide L, Stebbins K, Racanelli-Layton A, Dellamary L, Martin M, Dneprovskaia E, Noronha G, Acevedo LM, Soll R, Wrasidlo W, Cheresh DA. Aerosolized Phosphoinositide 3-Kinase {gamma}/{delta}Inhibitor TG–115 as a Therapeutic Candidate for Asthma and Chronic Obstructive Pulmonary Disease. J Pharmacol Exp Ther. 2008; [Epub ahead of print]Google Scholar
  112. 112.
    Park SJ, Min KH, Lee YC. Phosphoinositide 3-kinase delta inhibitor as a novel therapeutic agent in asthma. Respirology. 2008; 13 (6):–71Google Scholar
  113. 113.
    Dorn A, Kippenberger S. Clinical application of CpG-, non-CpG-, and antisense oligodeoxy-nucleotides as immunomodulators. Curr Opin Mol Ther. 2008; 10 (1):10–20 ReviewPubMedGoogle Scholar
  114. 114.
    Kline JN, Krieg AM. Toll-like receptor 9 activation with CpG oligodeoxynucleotides for asthma therapy. Drug News Perspect. 2008;21 (8):–9Google Scholar
  115. 115.
    Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, Hargreave FE, O'Byrne PM. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009 Mar 5;360(10):985–93CrossRefPubMedGoogle Scholar
  116. 116.
    Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall RP, Bradding P, Green RH, Wardlaw AJ, Pavord ID. Mepolizumab and exacerbations of refractory eosino-philic asthma. N Engl J Med. 2009 Mar 5;360(10):973–84CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Leif Bjermer
    • 1
  • Zuzana Diamant
    • 2
  1. 1.Department of Respiratory Medicine and Allergology, Heart and Lund DivisionUniversity Hospital of LundSweden
  2. 2.Departments of Allergology and PulmonologyErasmus University Medical CenterRotterdamThe Netherlands

Personalised recommendations