Table of Contents Author Guidelines Submit a Manuscript
Clinical and Developmental Immunology
Volume 2013 (2013), Article ID 609395, 9 pages
http://dx.doi.org/10.1155/2013/609395
Review Article

Th17-Associated Cytokines as a Therapeutic Target for Steroid-Insensitive Asthma

Division of Clinical Medicine, Department of Respiratory Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan

Received 15 March 2013; Accepted 5 December 2013

Academic Editor: Enric Esplugues

Copyright © 2013 Yuko Morishima et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. “Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions,” American Journal of Respiratory and Critical Care Medicine, vol. 162, no. 6, pp. 2341–2351, 2000. View at Scopus
  2. L. C. Borish, H. S. Nelson, J. Corren et al., “Efficacy of soluble IL-4 receptor for the treatment of adults with asthma,” Journal of Allergy and Clinical Immunology, vol. 107, no. 6, pp. 963–970, 2001. View at Publisher · View at Google Scholar · View at Scopus
  3. S. Wenzel, D. Wilbraham, R. Fuller, E. B. Getz, and M. Longphre, “Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies,” The Lancet, vol. 370, no. 9596, pp. 1422–1431, 2007. View at Publisher · View at Google Scholar · View at Scopus
  4. P. Haldar, C. E. Brightling, B. Hargadon et al., “Mepolizumab and exacerbations of refractory eosinophilic asthma,” The New England Journal of Medicine, vol. 360, no. 10, pp. 973–984, 2009. View at Publisher · View at Google Scholar · View at Scopus
  5. M. Castro, S. Mathur, F. Hargreave et al., “Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study,” American Journal of Respiratory and Critical Care Medicine, vol. 184, no. 10, pp. 1125–1132, 2011. View at Publisher · View at Google Scholar · View at Scopus
  6. J. Corren, R. F. Lemanske, N. A. Hanania et al., “Lebrikizumab treatment in adults with asthma,” The New England Journal of Medicine, vol. 365, no. 12, pp. 1088–1098, 2011. View at Publisher · View at Google Scholar · View at Scopus
  7. P. Flood-Page, C. Swenson, I. Faiferman et al., “A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma,” American Journal of Respiratory and Critical Care Medicine, vol. 176, no. 11, pp. 1062–1071, 2007. View at Publisher · View at Google Scholar · View at Scopus
  8. G. Pelaia, A. Vatrella, and R. Maselli, “The potential of biologics for the treatment of asthma,” Nature Reviews, vol. 11, no. 12, pp. 958–972, 2012. View at Google Scholar
  9. S. E. Wenzel, S. J. Szefler, D. Y. M. Leung, S. I. Sloan, M. D. Rex, and R. J. Martin, “Bronchoscopic evaluation of severe asthma: persistent inflammation associated with high dose glucocorticoids,” American Journal of Respiratory and Critical Care Medicine, vol. 156, no. 3 I, pp. 737–743, 1997. View at Google Scholar · View at Scopus
  10. A. Jatakanon, C. Uasuf, W. Maziak, S. Lim, K. F. Chung, and P. J. Barnes, “Neutrophilic inflammation in severe persistent asthma,” American Journal of Respiratory and Critical Care Medicine, vol. 160, no. 5 I, pp. 1532–1539, 1999. View at Google Scholar · View at Scopus
  11. “The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma,” European Respiratory Journal, vol. 22, no. 3, pp. 470–477, 2003. View at Publisher · View at Google Scholar · View at Scopus
  12. A. T. Hastie, W. C. Moore, D. A. Meyers et al., “Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes,” Journal of Allergy and Clinical Immunology, vol. 125, no. 5, pp. 1028–1036, 2010. View at Publisher · View at Google Scholar · View at Scopus
  13. R. H. Green, C. E. Brightling, G. Woltmann, D. Parker, A. J. Wardlaw, and I. D. Pavord, “Analysis of induced sputum in adults with asthma: Identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids,” Thorax, vol. 57, no. 10, pp. 875–879, 2002. View at Publisher · View at Google Scholar · View at Scopus
  14. P. W. Hellings, A. Kasran, Z. Liu et al., “Interleukin-17 orchestrates the granulocyte influx into airways after allergen inhalation in a mouse model of allergic asthma,” American Journal of Respiratory Cell and Molecular Biology, vol. 28, no. 1, pp. 42–50, 2003. View at Publisher · View at Google Scholar · View at Scopus
  15. D. M. A. Bullens, E. Truyen, L. Coteur et al., “IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx?” Respiratory Research, vol. 7, article 135, 2006. View at Publisher · View at Google Scholar · View at Scopus
  16. W. Al-Ramli, D. Préfontaine, F. Chouiali et al., “TH17-associated cytokines (IL-17A and IL-17F) in severe asthma,” Journal of Allergy and Clinical Immunology, vol. 123, no. 5, pp. 1185–1187, 2009. View at Publisher · View at Google Scholar · View at Scopus
  17. I. Agache, C. Ciobanu, C. Agache, and M. Anghel, “Increased serum IL-17 is an independent risk factor for severe asthma,” Respiratory Medicine, vol. 104, no. 8, pp. 1131–1137, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. L. E. Harrington, R. D. Hatton, P. R. Mangan et al., “Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages,” Nature Immunology, vol. 6, no. 11, pp. 1123–1132, 2005. View at Publisher · View at Google Scholar · View at Scopus
  19. H. Park, Z. Li, X. O. Yang et al., “A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17,” Nature Immunology, vol. 6, no. 11, pp. 1133–1141, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. I. I. Ivanov, B. S. McKenzie, L. Zhou et al., “The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells,” Cell, vol. 126, no. 6, pp. 1121–1133, 2006. View at Publisher · View at Google Scholar · View at Scopus
  21. L. Zhou, I. I. Ivanov, R. Spolski et al., “IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways,” Nature Immunology, vol. 8, no. 9, pp. 967–974, 2007. View at Publisher · View at Google Scholar · View at Scopus
  22. R. Nurieva, X. O. Yang, G. Martinez et al., “Essential autocrine regulation by IL-21 in the generation of inflammatory T cells,” Nature, vol. 448, no. 7152, pp. 480–483, 2007. View at Publisher · View at Google Scholar · View at Scopus
  23. H. Ogura, M. Murakami, Y. Okuyama et al., “Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction,” Immunity, vol. 29, no. 4, pp. 628–636, 2008. View at Publisher · View at Google Scholar · View at Scopus
  24. Y. Chung, S. H. Chang, G. J. Martinez et al., “Critical regulation of early Th17 cell differentiation by interleukin-1 signaling,” Immunity, vol. 30, no. 4, pp. 576–587, 2009. View at Publisher · View at Google Scholar · View at Scopus
  25. S. Iwamoto, S. Iwai, K. Tsujiyama et al., “TNF-α drives human CD14+ monocytes to differentiate into CD70+ dendritic cells evoking Th1 and Th17 responses,” Journal of Immunology, vol. 179, no. 3, pp. 1449–1457, 2007. View at Google Scholar · View at Scopus
  26. E. V. Acosta-Rodriguez, G. Napolitani, A. Lanzavecchia, and F. Sallusto, “Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17-producing human T helper cells,” Nature Immunology, vol. 8, no. 9, pp. 942–949, 2007. View at Publisher · View at Google Scholar · View at Scopus
  27. N. J. Wilson, K. Boniface, J. R. Chan et al., “Development, cytokine profile and function of human interleukin 17-producing helper T cells,” Nature Immunology, vol. 8, no. 9, pp. 950–957, 2007. View at Publisher · View at Google Scholar · View at Scopus
  28. K. Ghoreschi, A. Laurence, X. Yang et al., “Generation of pathogenic TH 17 cells in the absence of TGF-β 2 signalling,” Nature, vol. 467, no. 7318, pp. 967–971, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. L. Yang, D. E. Anderson, C. Baecher-Allan et al., “IL-21 and TGF-β are required for differentiation of human T H17 cells,” Nature, vol. 454, no. 7202, pp. 350–352, 2008. View at Publisher · View at Google Scholar · View at Scopus
  30. N. Manel, D. Unutmaz, and D. R. Littman, “The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt,” Nature Immunology, vol. 9, no. 6, pp. 641–649, 2008. View at Publisher · View at Google Scholar · View at Scopus
  31. E. Volpe, N. Servant, R. Zollinger et al., “A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses,” Nature Immunology, vol. 9, no. 6, pp. 650–657, 2008. View at Publisher · View at Google Scholar · View at Scopus
  32. T. J. Harris, J. F. Grosso, H. Yen et al., “An in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity,” Journal of Immunology, vol. 179, no. 7, pp. 4313–4317, 2007. View at Google Scholar · View at Scopus
  33. W. Elyaman, E. M. Bradshaw, C. Uyttenhove et al., “IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 31, pp. 12885–12890, 2009. View at Publisher · View at Google Scholar · View at Scopus
  34. V. Lazarevic and L. H. Glimcher, “T-bet in disease,” Nature Immunology, vol. 12, no. 7, pp. 597–606, 2011. View at Publisher · View at Google Scholar · View at Scopus
  35. L. Zhou, J. E. Lopes, M. M. W. Chong et al., “TGF-Β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function,” Nature, vol. 453, no. 7192, pp. 236–240, 2008. View at Publisher · View at Google Scholar · View at Scopus
  36. T. Korn, E. Bettelli, M. Oukka, and V. K. Kuchroo, “IL-17 and Th17 cells,” Annual Review of Immunology, vol. 27, pp. 485–517, 2009. View at Publisher · View at Google Scholar · View at Scopus
  37. J. F. Wright, Y. Guo, A. Quazi et al., “Identification of an interleukin 17F/17A heterodimer in activated human CD4+ T cells,” The Journal of Biological Chemistry, vol. 282, no. 18, pp. 13447–13455, 2007. View at Publisher · View at Google Scholar · View at Scopus
  38. Y. Iwakura, H. Ishigame, S. Saijo, and S. Nakae, “Functional specialization of interleukin-17 family members,” Immunity, vol. 34, no. 2, pp. 149–162, 2011. View at Publisher · View at Google Scholar · View at Scopus
  39. K. Ota, M. Kawaguchi, F. Kokubu et al., “Potential involvement of IL-17F in asthma,” Clinical and Developmental Immunology. In press.
  40. A. Barczyk, W. Pierzcha, and E. Sozañska, “Interleukin-17 in sputum correlates with airway hyperresponsiveness to methacholine,” Respiratory Medicine, vol. 97, no. 6, pp. 726–733, 2003. View at Publisher · View at Google Scholar · View at Scopus
  41. S. Molet, Q. Hamid, F. Davoine et al., “IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines,” Journal of Allergy and Clinical Immunology, vol. 108, no. 3, pp. 430–438, 2001. View at Publisher · View at Google Scholar · View at Scopus
  42. C. Doe, M. Bafadhel, S. Siddiqui et al., “Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD,” Chest, vol. 138, no. 5, pp. 1140–1147, 2010. View at Publisher · View at Google Scholar · View at Scopus
  43. J. Chakir, J. Shannon, S. Molet et al., “Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-β, IL-11, IL-17, and type I and type III collagen expression,” Journal of Allergy and Clinical Immunology, vol. 111, no. 6, pp. 1293–1298, 2003. View at Publisher · View at Google Scholar · View at Scopus
  44. A. Vazquez-Tello, A. Semlali, J. Chakir et al., “Induction of glucocorticoid receptor-β expression in epithelial cells of asthmatic airways by T-helper type 17 cytokines,” Clinical and Experimental Allergy, vol. 40, no. 9, pp. 1312–1322, 2010. View at Publisher · View at Google Scholar · View at Scopus
  45. Y. Zhao, J. Yang, Y. Gao, and W. Guo, “Th17 immunity in patients with allergic asthma,” International Archives of Allergy and Immunology, vol. 151, no. 4, pp. 297–307, 2010. View at Publisher · View at Google Scholar · View at Scopus
  46. A. Hamzaoui, H. Maalmi, A. Berraïes, H. Abid, J. Ammar, and K. Hamzaoui, “Transcriptional characteristics of CD4+ T cells in young asthmatic children: RORC and FOXP3 axis,” Journal of Inflammation Research, vol. 4, no. 1, pp. 139–146, 2011. View at Google Scholar · View at Scopus
  47. G. D. Albano, C. Di Sano, A. Bonanno et al., “Th17 immunity in children with allergic asthma and rhinitis: a pharmacological approach,” PLoS ONE, vol. 8, no. 4, Article ID e58892, 2013. View at Google Scholar
  48. J. W. Chien, C. Y. Lin, K. D. Yang, C. H. Lin, J. K. Kao, and Y. G. Tsai, “Increased IL-17A secreting CD4+ T cells, serum IL-17 levels and exhaled nitric oxide are correlated with childhood asthma severity,” Clinical and Experimental Allergy, vol. 43, no. 9, pp. 1018–1026, 2013. View at Google Scholar
  49. L. Roussel, F. Houle, C. Chan et al., “IL-17 promotes p38 MAPK-dependent endothelial activation enhancing neutrophil recruitment to sites of inflammation,” Journal of Immunology, vol. 184, no. 8, pp. 4531–4537, 2010. View at Publisher · View at Google Scholar · View at Scopus
  50. S. C. Liang, A. J. Long, F. Bennett et al., “An IL-17F/A heterodimer protein is produced by mouse Th17 cells and induces airway neutrophil recruitment,” Journal of Immunology, vol. 179, no. 11, pp. 7791–7799, 2007. View at Google Scholar · View at Scopus
  51. H. Hoshino, J. Lötvall, B. Skoogh, and A. Lindén, “Neutrophil recruitment by interleukin-17 into rat airways in vivo: role of tachykinins,” American Journal of Respiratory and Critical Care Medicine, vol. 159, no. 5 I, pp. 1423–1428, 1999. View at Google Scholar · View at Scopus
  52. M. Laan, Z. Cui, H. Hoshino et al., “Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways,” Journal of Immunology, vol. 162, no. 4, pp. 2347–2352, 1999. View at Google Scholar · View at Scopus
  53. H. Ishigame, S. Kakuta, T. Nagai et al., “Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses,” Immunity, vol. 30, no. 1, pp. 108–119, 2009. View at Publisher · View at Google Scholar · View at Scopus
  54. S. Nakae, H. Suto, G. J. Berry, and S. J. Galli, “Mast cell-derived TNF can promote Th17 cell-dependent neutrophil recruitment in ovalbumin-challenged OTII mice,” Blood, vol. 109, no. 9, pp. 3640–3648, 2007. View at Publisher · View at Google Scholar · View at Scopus
  55. L. McKinley, J. F. Alcorn, A. Peterson et al., “TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice,” Journal of Immunology, vol. 181, no. 6, pp. 4089–4097, 2008. View at Google Scholar · View at Scopus
  56. S. Lajoie, I. P. Lewkowich, Y. Suzuki et al., “Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma,” Nature Immunology, vol. 11, no. 10, pp. 928–935, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. S. Ano, Y. Morishima, Y. Ishii et al., “Transcription factors GATA-3 and RORγt are important for determining the phenotype of allergic airway inflammation in a murine model of asthma,” Journal of Immunology, vol. 190, no. 3, pp. 1056–1065, 2013. View at Google Scholar
  58. R. He, M. K. Oyoshi, H. Jin, and R. S. Geha, “Epicutaneous antigen exposure induces a Th17 response that drives airway inflammation after inhalation challenge,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 40, pp. 15817–15822, 2007. View at Publisher · View at Google Scholar · View at Scopus
  59. R. H. Wilson, G. S. Whitehead, H. Nakano, M. E. Free, J. K. Kolls, and D. N. Cook, “Allergic sensitization through the airway primes Th17-dependent neutrophilia and airway hyperresponsiveness,” American Journal of Respiratory and Critical Care Medicine, vol. 180, no. 8, pp. 720–730, 2009. View at Publisher · View at Google Scholar · View at Scopus
  60. Q. Wang, H. Li, Z. Zhang, Y. Yao, and J. Zhou, “Prolonged ovalbumin challenge facilitates Th17 polarization in sensitized mice,” Inflammation Research, vol. 59, no. 7, pp. 561–569, 2010. View at Publisher · View at Google Scholar · View at Scopus
  61. Q. Wang, H. Li, Y. Yao, D. Xia, and J. Zhou, “The overexpression of heparin-binding epidermal growth factor is responsible for Th17-induced airway remodeling in an experimental asthma model,” Journal of Immunology, vol. 185, no. 2, pp. 834–841, 2010. View at Publisher · View at Google Scholar · View at Scopus
  62. A. S. Saffar, H. Ashdown, and A. S. Gounni, “The molecular mechanisms of glucocorticoids-mediated neutrophil survival,” Current Drug Targets, vol. 12, no. 4, pp. 556–562, 2011. View at Publisher · View at Google Scholar · View at Scopus
  63. G. Cox, “Glucocorticoid treatment inhibits apoptosis in human neutrophils: separation of survival and activation outcomes,” Journal of Immunology, vol. 154, no. 9, pp. 4719–4725, 1995. View at Google Scholar · View at Scopus
  64. G. J. Zijlstra, N. H. T. ten Hacken, R. F. Hoffmann, A. J. M. van Oosterhout, and I. H. Heijink, “Interleukin-17A induces glucocorticoid insensitivity in human bronchial epithelial cells,” European Respiratory Journal, vol. 39, no. 2, pp. 439–445, 2012. View at Publisher · View at Google Scholar · View at Scopus
  65. Y. Chang, L. Al-Alwan, P. Risse et al., “TH17 cytokines induce human airway smooth muscle cell migration,” Journal of Allergy and Clinical Immunology, vol. 127, no. 4, pp. 1046–1053, 2011. View at Publisher · View at Google Scholar · View at Scopus
  66. Y. Chang, L. Al-Alwan, P. A. Risse et al., “Th17-associated cytokines promote human airway smooth muscle cell proliferation,” The FASEB Journal, vol. 26, no. 12, pp. 5152–5160, 2012. View at Google Scholar
  67. Y. Chen, P. Thai, Y. Zhao, Y. Ho, M. M. DeSouza, and R. Wu, “Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop,” The Journal of Biological Chemistry, vol. 278, no. 19, pp. 17036–17043, 2003. View at Publisher · View at Google Scholar · View at Scopus
  68. S. Al-Muhsen, S. Letuve, A. Vazquez-Tello et al., “Th17 cytokines induce pro-fibrotic cytokines release from human eosinophils,” Respiratory Research, vol. 14, p. 34, 2013. View at Google Scholar
  69. D. C. Newcomb, M. G. Boswell, W. Zhou et al., “Human TH17 cells express a functional IL-13 receptor and IL-13 attenuates IL-17A production,” Journal of Allergy and Clinical Immunology, vol. 127, no. 4, pp. 1006–1013, 2010. View at Google Scholar · View at Scopus
  70. S. Schnyder-Candrian, D. Togbe, I. Couillin et al., “Interleukin-17 is a negative regulator of established allergic asthma,” Journal of Experimental Medicine, vol. 203, no. 12, pp. 2715–2725, 2006. View at Publisher · View at Google Scholar · View at Scopus
  71. M. S. Rahman, A. Yamasaki, J. Yang, L. Shan, A. J. Halayko, and A. S. Gounni, “IL-17A induces eotaxin-1/CC chemokine ligand 11 expression in human airway smooth muscle cells: role of MAPK (Erk1/2, JNK, and p38) pathways,” Journal of Immunology, vol. 177, no. 6, pp. 4064–4071, 2006. View at Google Scholar · View at Scopus
  72. A. Saleh, L. Shan, A. J. Halayko, S. Kung, and A. S. Gounni, “Critical role for STAT3 in IL-17A-mediated CCL11 expression in human airway smooth muscle cells,” Journal of Immunology, vol. 182, no. 6, pp. 3357–3365, 2009. View at Publisher · View at Google Scholar · View at Scopus
  73. S. E. Wenzel, L. B. Schwartz, E. L. Langmack et al., “Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics,” American Journal of Respiratory and Critical Care Medicine, vol. 160, no. 3, pp. 1001–1008, 1999. View at Google Scholar · View at Scopus
  74. S. F. Seys, M. Grabowski, W. Adriaensen et al., “Sputum cytokine mapping reveals an “IL-5, IL-17A, IL-25-high” pattern associated with poorly controlled asthma,” Clinical and Experimental Allergy, vol. 43, no. 9, pp. 1009–1017, 2013. View at Google Scholar
  75. P. Miossec and J. K. Kolls, “Targeting IL-17 and TH17 cells in chronic inflammation,” Nature Reviews, vol. 11, no. 10, pp. 763–776, 2012. View at Google Scholar
  76. P. Rich, B. Sigurgeirsson, D. Thaci et al., “Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study,” The British Journal of Dermatology, vol. 168, no. 2, pp. 402–411, 2013. View at Google Scholar
  77. C. Leonardi, R. Matheson, C. Zachariae et al., “Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis,” The New England Journal of Medicine, vol. 366, no. 13, pp. 1190–1199, 2012. View at Google Scholar · View at Scopus
  78. I. B. McInnes, J. Sieper, J. Braun et al., “Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial,” Annals of the Rheumatic Diseases, 2013. View at Publisher · View at Google Scholar
  79. M. C. Genovese, P. Durez, H. B. Richards et al., “Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study,” Annals of the Rheumatic Diseases, vol. 72, no. 6, pp. 863–869, 2013. View at Google Scholar
  80. A. D. Dick, I. Tugal-Tutkun, S. Foster et al., “Secukinumab in the treatment of noninfectious uveitis: results of three randomized, controlled clinical trials,” Ophthalmology, vol. 120, no. 4, pp. 777–787, 2013. View at Google Scholar
  81. D. Baeten, X. Baraliakos, J. Braun et al., “Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial,” The Lancet, vol. 382, no. 9906, pp. 1705–1713, 2013. View at Google Scholar
  82. W. Hueber, B. E. Sands, S. Lewitzky et al., “Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial,” Gut, vol. 61, no. 12, pp. 1693–1700, 2012. View at Google Scholar
  83. K. A. Papp, C. Leonardi, A. Menter et al., “Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis,” The New England Journal of Medicine, vol. 366, no. 13, pp. 1181–1189, 2012. View at Publisher · View at Google Scholar · View at Scopus
  84. K. B. Gordon, A. B. Kimball, D. Chau et al., “Impact of brodalumab treatment on psoriasis symptoms and health-related quality of life: use of a novel patient-reported outcome measure, the Psoriasis Symptom Inventory,” The British Journal of Dermatology, 2013. View at Publisher · View at Google Scholar
  85. W. W. Busse, S. Holgate, E. Kerwin et al., “Randomized, double-blind, placebo-controlled study of brodalumab, a humananti-IL-17 receptor monoclonal antibody, in moderate to severe asthma,” American Journal of Respiratory and Critical Care Medicine, vol. 188, no. 11, pp. 1294–1302, 2013. View at Google Scholar
  86. I. B. McInnes, A. Kavanaugh, A. B. Gottlieb et al., “Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial,” The Lancet, vol. 382, no. 9894, pp. 780–789, 2013. View at Google Scholar
  87. W. J. Sandborn, C. Gasink, L. L. Gao et al., “Ustekinumab induction and maintenance therapy in refractory Crohn's disease,” The New England Journal of Medicine, vol. 367, no. 16, pp. 1519–1528, 2012. View at Google Scholar
  88. N. Nishimoto and T. Kishimoto, “Interleukin 6: from bench to bedside,” Nature Clinical Practice Rheumatology, vol. 2, no. 11, pp. 619–626, 2006. View at Publisher · View at Google Scholar · View at Scopus
  89. R. A. Linker, F. Lühder, K. Kallen et al., “IL-6 transsignalling modulates the early effector phase of EAE and targets the blood-brain barrier,” Journal of Neuroimmunology, vol. 205, no. 1-2, pp. 64–72, 2008. View at Publisher · View at Google Scholar · View at Scopus
  90. A. Yokoyama, N. Kohno, S. Fujino et al., “Circulating interleukin-6 levels in patients with bronchial asthma,” American Journal of Respiratory and Critical Care Medicine, vol. 151, no. 5, pp. 1354–1358, 1995. View at Google Scholar · View at Scopus
  91. D. H. Broide, M. Lotz, A. J. Cuomo, D. A. Coburn, E. C. Federman, and S. I. Wasserman, “Cytokines in symptomatic asthma airways,” Journal of Allergy and Clinical Immunology, vol. 89, no. 5, pp. 958–967, 1992. View at Publisher · View at Google Scholar · View at Scopus
  92. A. Doganci, T. Eigenbrod, N. Krug et al., “The IL-6R alpha chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo,” The Journal of Clinical Investigation, vol. 115, no. 2, pp. 313–325, 2005. View at Google Scholar
  93. M. A. R. Ferreira, M. C. Matheson, D. L. Duffy et al., “Identification of IL6R and chromosome 11q13.5 as risk loci for asthma,” The Lancet, vol. 378, no. 9795, pp. 1006–1014, 2011. View at Publisher · View at Google Scholar · View at Scopus
  94. T. Tanaka, M. Narazaki, and T. Kishimoto, “Therapeutic targeting of the interleukin-6 receptor,” Annual Review of Pharmacology and Toxicology, vol. 52, pp. 199–219, 2012. View at Publisher · View at Google Scholar · View at Scopus