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Targeting cytokines to treat asthma and chronic obstructive pulmonary disease

Abstract

Cytokines play a key role in orchestrating and perpetuating the chronic airway inflammation in asthma and chronic obstructive pulmonary disease (COPD), making them attractive targets for treating these disorders. Asthma and some cases of COPD are mainly driven by type 2 immune responses, which comprise increased airway eosinophils, T helper 2 (TH2) cells and group 2 innate lymphoid cells (ILC2s) and the secretion of IL-4, IL-5 and IL-13. Clinical trials of antibodies that block these interleukins have shown reduced acute exacerbations and oral corticosteroid use and improvements in lung function and symptoms in selected patients. More recent approaches that block upstream cytokines, such as thymic stromal lymphopoietin (TSLP), show promise in improving patient outcome. Importantly, the clinical trials in cytokine blockade have highlighted the crucial importance of patient selection for the successful use of these expensive therapies and the need for biomarkers to better predict drug responses.

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Fig. 1: Targeting type 2 cytokines in airway disease.
Fig. 2: Targeting non-type 2 immunity in airway disease.

References

  1. 1.

    Barnes, P. J. et al. Chronic obstructive pulmonary disease. Nat. Rev. Primers 1, 15076 (2015).

    Article  Google Scholar 

  2. 2.

    Postma, D. S. & Rabe, K. F. The asthma-COPD overlap syndrome. N. Engl. J. Med. 373, 1241–1249 (2015).

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Barnes, P. J. Asthma-COPD overlap. Chest 149, 7–8 (2016).

    PubMed  Article  Google Scholar 

  4. 4.

    Price, D., Fletcher, M. & van der Molen, T. Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ Prim. Care Respir. Med. 24, 14009 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Gross, N. J. & Barnes, P. J. New therapies for asthma and chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 195, 159–166 (2017).

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Chung, K. F. Targeting the interleukin pathway in the treatment of asthma. Lancet 386, 1086–1096 (2015).

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Lefaudeux, D. et al. U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics. J. Allergy Clin. Immunol. 139, 1797–1807 (2017).

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Barnes, P. J. Cellular and molecular mechanisms of asthma and COPD. Clin. Sci. 131, 1541–1558 (2017).

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Ebbo, M., Crinier, A., Vely, F. & Vivier, E. Innate lymphoid cells: major players in inflammatory diseases. Nat. Rev. Immunol. 17, 665–678 (2017).

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Barnes, P. J. Pathophysiology of allergic inflammation. Immunol. Rev. 242, 31–50 (2011).

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Hogg, J. C. et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N. Engl. J. Med. 350, 2645–2653 (2004).

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Brusselle, G. G., Joos, G. F. & Bracke, K. R. New insights into the immunology of chronic obstructive pulmonary disease. Lancet 378, 1015–1026 (2011).

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    McDonough, J. E. et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N. Engl. J. Med. 365, 1567–1575 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. 14.

    Galban, C. J. et al. Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression. Nat. Med. 18, 1711–1715 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. 15.

    Lange, P. et al. Lung-function trajectories leading to chronic obstructive pulmonary disease. N. Engl. J. Med. 373, 111–122 (2015).

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Barnes, P. J. Mechanisms of development of multimorbidity in the elderly. Eur. Respir. J. 45, 790–806 (2015).

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Barnes, P. J. Glucocorticosteroids. Handb. Exp. Pharmacol. 237, 93–115 (2017).

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Barnes, P. J. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 131, 636–645 (2013).

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Ito, K. et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N. Engl. J. Med. 352, 1967–1976 (2005).

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Hew, M. et al. Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. Am. J. Respir. Crit. Care Med. 174, 134–141 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  21. 21.

    Molfino, N. A., Gossage, D., Kolbeck, R., Parker, J. M. & Geba, G. P. Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor. Clin. Exp. Allergy 42, 712–737 (2012).

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    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 is the first study of an anti-IL-5 antibody in patients with asthma and shows a marked reduction in blood and sputum eosinophils.

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Flood-Page, P. et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am. J. Respir. Crit. Care Med. 176, 1062–1071 (2007).

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Haldar, P. et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med. 360, 973–984 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. 25.

    Nair, P. et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N. Engl. J. Med. 360, 985–993 (2009).

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Pavord, I. D. et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 380, 651–659 (2012). This is a large study of an anti-IL-5 antibody in patients with severe eosinophilic asthma that shows an ~50% reduction in acute exacerbations.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Bel, E. H. et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N. Engl. J. Med. 371, 1189–1197 (2014).

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Ortega, H. G. et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N. Engl. J. Med. 371, 1198–1207 (2014).

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Powell, C., Milan, S. J., Dwan, K., Bax, L. & Walters, N. Mepolizumab versus placebo for asthma. Cochrane Database Syst. Rev. 7, CD010834 (2015).

    Google Scholar 

  30. 30.

    Chupp, G. L. et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir. Med. 5, 390–400 (2017).

    PubMed  Article  Google Scholar 

  31. 31.

    Wechsler, M. E. et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N. Engl. J. Med. 376, 1921–1932 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. 32.

    Kim, S., Marigowda, G., Oren, E., Israel, E. & Wechsler, M. E. Mepolizumab as a steroid-sparing treatment option in patients with Churg-Strauss syndrome. J. Allergy Clin. Immunol. 125, 1336–1343 (2010).

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Castro, M. et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am. J. Respir. Crit. Care Med. 184, 1125–1132 (2011).

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Castro, M. et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir. Med. 3, 355–366 (2015).

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Bjermer, L. et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest 150, 789–798 (2016).

    PubMed  Article  Google Scholar 

  36. 36.

    Brusselle, G., Germinaro, M., Weiss, S. & Zangrilli, J. Reslizumab in patients with inadequately controlled late-onset asthma and elevated blood eosinophils. Pulm. Pharmacol. Ther. 43, 39–45 (2017).

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Corren, J., Weinstein, S., Janka, L., Zangrilli, J. & Garin, M. Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest 150, 799–810 (2016).

    PubMed  Article  Google Scholar 

  38. 38.

    Ghazi, A., Trikha, A. & Calhoun, W. J. Benralizumab—a humanized mAb to IL-5Ralpha with enhanced antibody-dependent cell-mediated cytotoxicity — a novel approach for the treatment of asthma. Expert Opin. Biol. Ther. 12, 113–118 (2012).

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Kolbeck, R. et al. MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J. Allergy Clin. Immunol. 125, 1344–1353 (2010). This paper explains the mechanism of action of benralizumab, an IL-5Rα-specific antibody that induces cytotoxicity.

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Castro, M. et al. Benralizumab, an anti-interleukin 5 receptor alpha monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir. Med. 2, 879–890 (2014).

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Khorasanizadeh, M., Eskian, M., Assa’ad, A. H., Camargo, C. A. Jr & Rezaei, N. Efficacy and safety of benralizumab, a monoclonal antibody against IL-5Rα, in uncontrolled eosinophilic asthma. Int. Rev. Immunol. 35, 294–311 (2016).

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Bleecker, E. R. et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet 388, 2115–2127 (2016).

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    FitzGerald, J. M. et al. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 388, 2128–2141 (2016).

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Nair, P. et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N. Engl. J. Med. 376, 2448–2458 (2017).

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Ferguson, G. T. et al. Benralizumab for patients with mild to moderate, persistent asthma (BISE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir. Med. 5, 568–576 (2017).

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Nowak, R. M. et al. A randomized trial of benralizumab, an antiinterleukin 5 receptor alpha monoclonal antibody, after acute asthma. Am. J. Emerg. Med. 33, 14–20 (2015).

    PubMed  Article  Google Scholar 

  47. 47.

    Brightling, C. E. et al. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir. Med. 2, 891–901 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  48. 48.

    Dasgupta, A. et al. A pilot randomised clinical trial of mepolizumab in COPD with eosinophilic bronchitis. Eur. Respir. J. 49, 1602486 (2017).

    PubMed  Article  Google Scholar 

  49. 49.

    Pavord, I. D. et al. Mepolizumab for eosinophilic chronic obstructive pulmonary disease. N. Engl. J. Med. 377, 1613–1629 (2017). Reference 48 and 49 are two large studies of an anti-IL-5 therapy in patients with COPD that show a small reduction in exacerbations in patients with elevated blood eosinophils.

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Leung, E., Al Efraij, K. & FitzGerald, J. M. The safety of mepolizumab for the treatment of asthma. Expert Opin. Drug Safety 16, 397–404 (2017).

    Article  CAS  Google Scholar 

  51. 51.

    Lugogo, N. et al. Long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma: a multi-center, open-label, phase IIIb study. Clin. Ther. 38, 2058–2070.e1 (2016).

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Cabon, Y. et al. Comparison of anti-interleukin-5 therapies in patients with severe asthma: global and indirect meta-analyses of randomized placebo-controlled trials. Clin. Exp. Allergy 47, 129–138 (2017). This is a meta-analysis of published studies of anti-IL-5 antibody treatment of severe asthma.

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Larose, M. C. et al. Correlation between CCL26 production by human bronchial epithelial cells and airway eosinophils: Involvement in patients with severe eosinophilic asthma. J. Allergy Clin. Immunol. 136, 904–913 (2015).

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Kasaian, M. T. & Miller, D. K. IL-13 as a therapeutic target for respiratory disease. Biochem. Pharmacol. 76, 147–155 (2008).

    PubMed  Article  CAS  Google Scholar 

  55. 55.

    Antoniu, S. A. Pitrakinra, a dual IL-4/IL-13 antagonist for the potential treatment of asthma and eczema. Curr. Opin. Invest. Drugs 11, 1286–1294 (2010).

    CAS  Google Scholar 

  56. 56.

    Chiba, Y., Todoroki, M., Nishida, Y., Tanabe, M. & Misawa, M. A novel STAT6 inhibitor AS1517499 ameliorates antigen-induced bronchial hypercontractility in mice. Am. J. Respir. Cell Mol. Biol. 41, 516–524 (2009).

    PubMed  Article  CAS  Google Scholar 

  57. 57.

    Izuhara, K. et al. Roles of periostin in respiratory disorders. Am. J. Respir. Crit. Care Med. 19, 949–956 (2016).

    Article  CAS  Google Scholar 

  58. 58.

    Corren, J. et al. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365, 1088–1098 (2011).

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    Hanania, N. A. et al. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax 70, 748–756 (2015). References 58 and 59 are two large studies of an anti-IL-13 antibody that demonstrate little clinical benefit in patients with severe type 2 asthma.

    PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Piper, E. et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur. Respir. J. 41, 330–338 (2013).

    PubMed  Article  CAS  Google Scholar 

  61. 61.

    Brightling, C. E. et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet. Resp. Med. 3, 692–701 (2015).

    Article  CAS  Google Scholar 

  62. 62.

    Wenzel, S. et al. Dupilumab in persistent asthma with elevated eosinophil levels. N. Engl. J. Med. 368, 2455–2466 (2013).

    PubMed  Article  CAS  Google Scholar 

  63. 63.

    Wenzel, S. et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting beta2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 388, 31–44 (2016). This is a large clinical trial of an anti-IL-4Rα antibody in patients with moderate to severe asthma, which shows marked improvement of symptoms and lung function and reduced exacerbations, even in patients without elevated blood eosinophils.

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Blauvelt, A. et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet 389, 2287–2303 (2017).

    PubMed  Article  CAS  Google Scholar 

  65. 65.

    Kraft, M. & Worm, M. Dupilumab in the treatment of moderate-to-severe atopic dermatitis. Expert Rev. Clin. Immunol. 13, 301–310 (2017).

    PubMed  Article  CAS  Google Scholar 

  66. 66.

    Bachert, C. et al. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA 315, 469–479 (2016).

    PubMed  Article  CAS  Google Scholar 

  67. 67.

    Mitchell, P. D. & O’Byrne, P. M. Epithelial-derived cytokines in asthma. Chest 151, 1338–1344 (2017).

    PubMed  Article  Google Scholar 

  68. 68.

    Ying, S. et al. Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease. J. Immunol. 181, 2790–2798 (2008).

    PubMed  Article  CAS  Google Scholar 

  69. 69.

    Gauvreau, G. M. et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N. Engl. J. Med. 370, 2102–2110 (2014).

    PubMed  Article  CAS  Google Scholar 

  70. 70.

    Corren, J. et al. Tezepelumab in adults with uncontrolled asthma. N. Engl. J. Med. 377, 936–946 (2017). This large study shows good efficacy of an anti-TSLP antibody in patients with severe asthma, with improvement in symptoms and lung function and reduced exacerbations, blood eosinophils and FeNO.

    PubMed  Article  CAS  Google Scholar 

  71. 71.

    Nagarkar, D. R. et al. Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis. J. Allergy Clin. Immunol. 132, 593–600 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. 72.

    Verstraete, K. et al. Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma. Nat. Commun. 8, 14937 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  73. 73.

    Xu, M. & Dong, C. IL-25 in allergic inflammation. Immunol. Rev. 278, 185–191 (2017).

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Mitchell, P. D. & O’Byrne, P. M. Biologics and the lung: TSLP and other epithelial cell-derived cytokines in asthma. Pharmacol. Ther. 169, 104–112 (2017).

    PubMed  Article  CAS  Google Scholar 

  75. 75.

    Cheng, D. et al. Epithelial interleukin-25 is a key mediator in Th2-high, corticosteroid-responsive asthma. Am. J. Respir. Crit. Care Med. 190, 639–648 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. 76.

    Christianson, C. A. et al. Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33. J. Allergy Clin. Immunol. 136, 59–68 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. 77.

    Kubo, M. Innate and adaptive type 2 immunity in lung allergic inflammation. Immunol. Rev. 278, 162–172 (2017).

    PubMed  Article  CAS  Google Scholar 

  78. 78.

    Prefontaine, D. et al. Increased IL-33 expression by epithelial cells in bronchial asthma. J. Allergy Clin. Immunol. 125, 752–754 (2010).

    PubMed  Article  CAS  Google Scholar 

  79. 79.

    Qiu, C. et al. Anti-interleukin-33 inhibits cigarette smoke-induced lung inflammation in mice. Immunology 138, 76–82 (2013).

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Xia, J. et al. Increased IL-33 expression in chronic obstructive pulmonary disease. Am. J. Physiol. Lung Cell Mol. Physiol. 308, L619–L627 (2015).

    PubMed  Article  CAS  Google Scholar 

  81. 81.

    Vlahos, R., Bozinovski, S., Hamilton, J. A. & Anderson, G. P. Therapeutic potential of treating chronic obstructive pulmonary disease (COPD) by neutralising granulocyte macrophage-colony stimulating factor (GM-CSF). Pharmacol. Ther. 112, 106–115 (2006).

    PubMed  Article  CAS  Google Scholar 

  82. 82.

    Molfino, N. A. et al. Phase 2, randomised placebo-controlled trial to evaluate the efficacy and safety of an anti-GM-CSF antibody (KB003) in patients with inadequately controlled asthma. BMJ Open 6, e007709 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Barnes, P. J. Role of GATA-3 in allergic diseases. Curr. Mol. Med. 8, 330–334 (2008).

    PubMed  Article  CAS  Google Scholar 

  84. 84.

    Finotto, S. et al. Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression. J. Exp. Med. 193, 1247–1260 (2001).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  85. 85.

    Maneechotesuwan, K. et al. Suppression of GATA-3 nuclear import and phosphorylation: a novel mechanism of corticosteroid action in allergic disease. PLoS Med. 6, e1000076 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  86. 86.

    Krug, N. et al. Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N. Engl. J. Med. 372, 1987–1995 (2015). This study shows that an inhaled GATA3-blocking DNAzyme modestly reduces the response to inhaled allergen in patients with mild asthma.

    PubMed  Article  Google Scholar 

  87. 87.

    Berry, M. A. et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N. Engl. J. Med. 354, 697–708 (2006).

    PubMed  Article  CAS  Google Scholar 

  88. 88.

    Howarth, P. H. et al. Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 60, 1012–1018 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  89. 89.

    Erin, E. M. et al. The effects of a monoclonal antibody directed against tumour necrosis factor-alpha in asthma. Am. J. Respir. Crit. Care Med. 174, 753–762 (2006).

    PubMed  Article  CAS  Google Scholar 

  90. 90.

    Wenzel, S. E. et al. A randomized, double-blind, placebo-controlled study of TNF-α blockade in severe persistent asthma. Am. J. Respir. Crit. Care Med. 179, 549–558 (2009). This large study demonstrates a lack of effect and side effects of anti-TNF therapy in patients with severe asthma.

    PubMed  Article  CAS  Google Scholar 

  91. 91.

    Rennard, S. I. et al. The safety and efficacy of infliximab in moderate to severe chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 175, 926–934 (2007). This study shows a lack of clinical effect and serious side effects with an anti-TNF therapy in patients with severe COPD.

    PubMed  Article  CAS  Google Scholar 

  92. 92.

    Suissa, S., Ernst, P. & Hudson, M. TNF-alpha antagonists and the prevention of hospitalisation for chronic obstructive pulmonary disease. Pulm. Pharmacol. Ther. 21, 234–238 (2008).

    PubMed  Article  CAS  Google Scholar 

  93. 93.

    Dentener, M. A. et al. Effect of infliximab on local and systemic inflammation in chronic obstructive pulmonary disease: a pilot study. Respiration 76, 275–282 (2008).

    PubMed  Article  CAS  Google Scholar 

  94. 94.

    Al-Ramli, W. et al. T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma. J. Allergy Clin. Immunol. 123, 1185–1187 (2009).

    PubMed  Article  CAS  Google Scholar 

  95. 95.

    Ricciardolo, F. L. M. et al. Identification of IL-17F/frequent exacerbator endotype in asthma. J. Allergy Clin. Immunol. 140, 395–406 (2017).

    PubMed  Article  CAS  Google Scholar 

  96. 96.

    Alcorn, J. F., Crowe, C. R. & Kolls, J. K. TH17 cells in asthma and COPD. Annu. Rev. Physiol. 72, 495–516 (2010).

    PubMed  Article  CAS  Google Scholar 

  97. 97.

    Di Stefano, A. et al. Th17-related cytokine expression is increased in the bronchial mucosa of stable COPD patients. Clin. Exp. Immunol 157, 316–324 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Maneechotesuwan, K., Kasetsinsombat, K., Wongkajornsilp, A. & Barnes, P. J. Decreased indoleamine 2,3-dioxygenase activity and IL-10/IL-17 A ratio in patients with COPD. Thorax 68, 330–337 (2013).

    PubMed  Article  Google Scholar 

  99. 99.

    Shen, N., Wang, J., Zhao, M., Pei, F. & He, B. Anti-interleukin-17 antibodies attenuate airway inflammation in tobacco-smoke-exposed mice. Inhal. Toxicol. 23, 212–218 (2011).

    PubMed  Article  CAS  Google Scholar 

  100. 100.

    McKinley, L. et al. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J. Immunol. 181, 4089–4097 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  101. 101.

    Busse, W. W. et al. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am. J. Respir. Crit. Care Med. 188, 1294–1302 (2013). This study shows a lack of clinical effect of an anti-IL-17R antibody in patients with severe asthma.

    PubMed  Article  CAS  Google Scholar 

  102. 102.

    Eich, A. et al. A randomized, placebo-controlled phase 2 trial of CNTO 6785 in chronic obstructive pulmonary disease. COPD 14, 476–483 (2017).

    PubMed  Article  Google Scholar 

  103. 103.

    Duvallet, E., Semerano, L., Assier, E., Falgarone, G. & Boissier, M. C. Interleukin-23: a key cytokine in inflammatory diseases. Ann. Med. 43, 503–511 (2011).

    PubMed  Article  CAS  Google Scholar 

  104. 104.

    Fujii, U. et al. IL-23 is essential for the development of elastase-induced pulmonary inflammation and emphysema. Am. J. Respir. Cell. Mol. Biol. 55, 697–707 (2016).

    PubMed  Article  CAS  Google Scholar 

  105. 105.

    Benson, J. M. et al. Therapeutic targeting of the IL-12/23 pathways: generation and characterization of ustekinumab. Nat. Biotechnol. 29, 615–624 (2011).

    PubMed  Article  CAS  Google Scholar 

  106. 106.

    Papp, K. A. et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N. Engl. J. Med. 376, 1551–1560 (2017).

    PubMed  Article  CAS  Google Scholar 

  107. 107.

    US National Library of Medicine. ClincalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02443298 (2018).

  108. 108.

    Sousa, A. R., Lane, S. J., Nakhosteen, J. A., Lee, T. H. & Poston, R. N. Expression of interleukin-1 beta (IL-1β) and interleukin-1 receptor antagonist (IL-1ra) on asthmatic bronchial epithelium. Am. J. Respir. Crit. Care Med. 154, 1061–1066 (1996).

    PubMed  Article  CAS  Google Scholar 

  109. 109.

    Kim, R. Y. et al. Inflammasomes in COPD and neutrophilic asthma. Thorax 70, 1199–1201 (2015).

    PubMed  Article  Google Scholar 

  110. 110.

    Di Stefano, A. et al. Innate immunity but not NLRP3 inflammasome activation correlates with severity of stable COPD. Thorax 69, 516–524 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Rogliani, P., Calzetta, L., Ora, J. & Matera, M. G. Canakinumab for the treatment of chronic obstructive pulmonary disease. Pulm Pharmacol. Ther. 31, 15–27 (2015).

    PubMed  Article  CAS  Google Scholar 

  112. 112.

    Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    PubMed  Article  CAS  Google Scholar 

  113. 113.

    Novick, D., Kim, S., Kaplanski, G. & Dinarello, C. A. Interleukin-18, more than a Th1 cytokine. Semin. Immunol. 25, 439–448 (2013).

    PubMed  Article  CAS  Google Scholar 

  114. 114.

    Rovina, N. et al. Interleukin-18 in induced sputum: association with lung function in chronic obstructive pulmonary disease. Respir. Med. 103, 1056–1062 (2009).

    PubMed  Article  Google Scholar 

  115. 115.

    Dima, E. et al. Implication of interleukin (IL)-18 in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cytokine 74, 313–317 (2015).

    PubMed  Article  CAS  Google Scholar 

  116. 116.

    Briend, E. et al. IL-18 associated with lung lymphoid aggregates drives IFNgamma production in severe COPD. Respir. Res. 18, 159 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Mistry, P. et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of single-dose antiinterleukin- 18 mAb GSK1070806 in healthy and obese subjects. Int. J. Clin. Pharmacol. Ther. 52, 867–879 (2014).

    PubMed  Article  CAS  Google Scholar 

  118. 118.

    Grubek-Jaworska, H. et al. IL-6 and IL-13 in induced sputum of COPD and asthma patients: correlation with respiratory tests. Respiration 84, 101–107 (2012).

    PubMed  Article  CAS  Google Scholar 

  119. 119.

    Nishimoto, N. & Kishimoto, T. Inhibition of IL-6 for the treatment of inflammatory diseases. Curr. Opin. Pharmacol. 4, 386–391 (2004).

    PubMed  Article  CAS  Google Scholar 

  120. 120.

    Paul-Pletzer, K. Tocilizumab: blockade of interleukin-6 signaling pathway as a therapeutic strategy for inflammatory disorders. Drugs Today 42, 559–576 (2006).

    PubMed  Article  CAS  Google Scholar 

  121. 121.

    Donnelly, L. E. & Barnes, P. J. Chemokine receptors as therapeutic targets in chronic obstructive pulmonary disease. Trends Pharmacol. Sci. 27, 546–553 (2006).

    PubMed  Article  CAS  Google Scholar 

  122. 122.

    Erin, E. M., Williams, T. J., Barnes, P. J. & Hansel, T. T. Eotaxin receptor (CCR3) antagonism in asthma and allergic disease. Curr. Drug Targets. Inflamm. Allergy 1, 201–214 (2002).

    PubMed  Article  CAS  Google Scholar 

  123. 123.

    Das, A. M. et al. Selective inhibition of eosinophil influx into the lung by small molecule CC chemokine receptor 3 antagonists in mouse models of allergic inflammation. J. Pharmacol. Exp. Ther. 318, 411–417 (2006).

    PubMed  Article  CAS  Google Scholar 

  124. 124.

    Ying, S. et al. Eosinophil chemotactic chemokines (eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein-3 (MCP-3), and MCP-4), and C-C chemokine receptor 3 expression in bronchial biopsies from atopic and nonatopic (Intrinsic) asthmatics. J. Immunol. 163, 6321–6329 (1999).

    PubMed  CAS  Google Scholar 

  125. 125.

    Pease, J. E. & Horuk, R. Recent progress in the development of antagonists to the chemokine receptors CCR3 and CCR4. Expert Opin. Drug Discov. 9, 467–483 (2014).

    PubMed  Article  CAS  Google Scholar 

  126. 126.

    Sabroe, I. et al. A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry. J. Biol. Chem. 275, 25985–25992 (2000).

    PubMed  Article  CAS  Google Scholar 

  127. 127.

    Gauvreau, G. M. et al. Antisense therapy against CCR3 and the common beta chain attenuates allergen-induced eosinophilic responses. Am. J. Respir. Crit. Care Med. 177, 952–958 (2008).

    PubMed  Article  CAS  Google Scholar 

  128. 128.

    Donnelly, L. E. & Barnes, P. J. Chemokine receptor CXCR2 antagonism to prevent airway inflammation. Drugs Future 36, 465–472 (2011).

    Article  CAS  Google Scholar 

  129. 129.

    Traves, S. L., Culpitt, S., Russell, R. E. K., Barnes, P. J. & Donnelly, L. E. Elevated levels of the chemokines GRO-α and MCP-1 in sputum samples from COPD patients. Thorax 57, 590–595 (2002).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  130. 130.

    Jatakanon, A. et al. Neutrophilic inflammation in severe persistent asthma. Am. J. Respir. Crit. Care Med. 160, 1532–1539 (1999).

    PubMed  Article  CAS  Google Scholar 

  131. 131.

    Holz, O. et al. SCH527123, a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects. Eur. Respir. J. 35, 564–570 (2010).

    PubMed  Article  CAS  Google Scholar 

  132. 132.

    Leaker, B. R., Barnes, P. J. & O’Connor, B. Inhibition of LPS-induced airway neutrophilic inflammation in healthy volunteers with an oral CXCR2 antagonist. Respir. Res. 14, 137 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  133. 133.

    Lazaar, A. L. et al. SB-656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans. Br. J. Clin. Pharmacol 72, 282–293 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  134. 134.

    Rennard, S. I. et al. CXCR2 antagonist MK-7123- a phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 191, 1001–1011 (2015). This large study shows an overall lack of clinical benefit of an oral CXCR2 antagonist in patients with COPD.

    PubMed  Article  CAS  Google Scholar 

  135. 135.

    Nair, P. et al. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. Clin. Exp. Allergy 42, 1097–1103 (2012). This study shows a lack of clinical benefit of a CXCR2 antagonist in severe neutrophilic asthma.

    PubMed  Article  CAS  Google Scholar 

  136. 136.

    O’Byrne, P. M. et al. Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial. Lancet Respir. Med. 4, 797–806 (2016).

    PubMed  Article  CAS  Google Scholar 

  137. 137.

    Busch-Petersen, J. et al. Danirixin: a Reversible and Selective Antagonist of the CXC Chemokine Receptor 2. J. Pharmacol. Exp. Ther. 362, 338–346 (2017).

    PubMed  Article  CAS  Google Scholar 

  138. 138.

    Kirsten, A. M. et al. The safety and tolerability of oral AZD5069, a selective CXCR2 antagonist, in patients with moderate-to-severe COPD. Pulm Pharmacol. Ther. 31, 36–41 (2015).

    PubMed  Article  CAS  Google Scholar 

  139. 139.

    Costa, C. et al. CXCR3 and CCR5 chemokines in the induced sputum from patients with COPD. Chest 133, 26–33 (2008).

    PubMed  Article  CAS  Google Scholar 

  140. 140.

    Pilette, C., Francis, J. N., Till, S. J. & Durham, S. R. CCR4 ligands are up-regulated in the airways of atopic asthmatics after segmental allergen challenge. Eur. Respir. J. 23, 876–884 (2004).

    PubMed  Article  CAS  Google Scholar 

  141. 141.

    Costa, C. et al. Enhanced monocyte migration to CXCR3 and CCR5 chemokines in COPD. Eur. Respir. J. 47, 1093–1102 (2016).

    PubMed  Article  CAS  Google Scholar 

  142. 142.

    Kerstjens, H. A., Bjermer, L., Eriksson, L., Dahlstrom, K. & Vestbo, J. Tolerability and efficacy of inhaled AZD4818, a CCR1 antagonist, in moderate to severe COPD patients. Respir. Med. 104, 1297–1303 (2010).

    PubMed  Article  Google Scholar 

  143. 143.

    Woollard, S. M. & Kanmogne, G. D. Maraviroc: a review of its use in HIV infection and beyond. Drug Design Dev. Ther. 9, 5447–5468 (2015).

    CAS  Google Scholar 

  144. 144.

    Vijayanand, P. et al. Chemokine receptor 4 plays a key role in T cell recruitment into the airways of asthmatic patients. J. Immunol. 184, 4568–4574 (2010).

    PubMed  Article  CAS  Google Scholar 

  145. 145.

    Cahn, A. et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study. BMC Pharmacol. Toxicol. 14, 14 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  146. 146.

    ten Brinke, A., Zwinderman, A. H., Sterk, P. J., Rabe, K. F. & Bel, E. H. “Refractory” eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids. Am. J. Respir. Crit. Care Med. 170, 601–605 (2004).

    PubMed  Article  Google Scholar 

  147. 147.

    Pavord, I. D. et al. Blood eosinophils and inhaled corticosteroid/long-acting beta-2 agonist efficacy in COPD. Thorax 71, 118–125 (2016).

    PubMed  Article  Google Scholar 

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Acknowledgements

P.J.B. holds a National Institute for Health Research Senior Investigator Award.

Competing interests

P.J.B. has served on Scientific Advisory Boards of AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Glenmark, Johnson & Johnson, Napp, Novartis, Pfizer, ProSonix, RespiVert, Teva and Zambon and has received research funding from AstraZeneca, Boehringer-Ingelheim, Chiesi, Novartis and Takeda.

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Nature Reviews Immunology thanks Sally Wenzel and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Glossary

U-BIOPRED

Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes is a European project investigating mechanisms of severe asthma.

Type 2 immunity

A type of immunity that provides protection against parasitic infections but is also activated in allergic diseases such as asthma. It is orchestrated by T helper 2 (TH2) cells and group 2 innate lymphoid cells (ILC2s) through the secretion of IL-4, IL-5, IL-9 and IL-13, which are regulated by the transcription factor GATA3. Type 2 inflammation is characterized by eosinophils, mast cells and alternatively activated macrophages. Upstream cytokines from epithelial cells that regulate TH2 cells and ILC2s include the alarmins IL-25, IL-33 and thymic stromal lymphopoietin (TSLP).

T helper 2 (TH2) cells

A subset of CD4+ T helper cells that has an important role in humoral immunity and in allergic responses. TH2 cells express the transcription factors GATA3 and signal transducer and activator of transcription 6 (STAT6) and produce cytokines such as IL-4, IL-5, IL-9 and IL-13, which regulate IgE synthesis, eosinophil proliferation, mast cell proliferation and airway hyperresponsiveness, respectively.

Innate lymphoid cells

Immune cells that do not express antigen specific B or T cell receptors. Three main subtypes are recognized depending on the transcription factors expressed and the pattern of cytokines they release.

Airway hyperresponsiveness

Increased airway narrowing in response to various external stimuli that is a physiological characteristic of patients with asthma.

Type 1 immunity

A type of immunity that provides protection against microbial infections and is orchestrated by T helper 1 cells, cytotoxic T cells and group 1 innate lymphoid cells and the transcription factor T-bet, which regulates the secretion of IFNγ. Type 1 immunity is associated with increased pro-inflammatory macrophage activation.

Type 3 immunity

A type of immunity that is directed against microorganisms, in particular fungi, and orchestrated by T helper 17 cells and group 3 innate lymphoid cells, which express RORγt and secrete IL-17 and IL-22, leading to neutrophilic inflammation.

TH17 cells

A subset of CD4+ T helper cells that express the transcription factor RORγt and secrete IL-17A, IL-17F and IL-22. They are involved in neutrophilic inflammatory responses and are important in responses to bacteria and viruses, as well as autoimmune diseases.

GATA3

A transcription factor expressed predominantly by T helper 2 cells and group 2 innate lymphoid cells that is important for their differentiation and secretion of characteristic type 2 cytokines (IL-4, IL-5, IL-9 and IL-13).

Forced expired volume in 1 second

(FEV1). A measure of airflow. Decreases in FEV1 reflect airway obstruction in asthma and chronic obstructive pulmonary disease and are a measure of disease severity.

Fractional exhaled nitric oxide

(FeNO). The fractional content in exhaled breath of nitric oxide gas, which is a non-invasive biomarker of type 2 inflammation.

Alarmin

A type of molecule that is released from damaged cells and activates the immune system. In airway disease, alarmins released from airway epithelial cells include IL-25, IL-33 and thymic stromal lymphopoietin (TSLP), which activate type 2 immunity.

NLRP3 inflammasome

Intracellular multiprotein complex containing NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), which leads to activation of caspase 1 and the generation of IL-1β and IL-18 from precursors. It is a component of the innate immune system and activated by several inflammatory signals.

Muckle–Wells syndrome

Rare autosomal dominant disease that causes periodic fever and is associated with NLRP3 inflammasome activation and increased production of IL-1β.

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Barnes, P.J. Targeting cytokines to treat asthma and chronic obstructive pulmonary disease. Nat Rev Immunol 18, 454–466 (2018). https://doi.org/10.1038/s41577-018-0006-6

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