Steroid-insensitive asthma is an infrequent but problematic airway disease that presents with persistent symptoms, airflow limitation, or recurrent exacerbations even when treated with steroid-based therapies. Because of unsatisfactory results obtained from currently available therapies for steroid-insensitive asthma, a better understanding of its pathogenesis and the development of new targeted molecular therapies are warranted. Recent studies indicated that levels of interleukin (IL)-17 are increased and both eosinophils and neutrophils infiltrate the airways of severe asthmatics. IL-17 is a proinflammatory cytokine mainly secreted from helper T (Th) 17 cells and is important for the induction of neutrophil recruitment and migration at sites of inflammation. This review focuses on the pathogenetic role of Th17 cells and their associated cytokines in steroid-insensitive asthma and discusses the prospects of novel therapeutic options targeting the Th17 signaling pathway. 1. Introduction Asthma is a very common disease that affects many people, men and women, young and old, worldwide. Although asthma is mostly well controlled by conventional therapies including inhaled corticosteroids, about 5–10% of asthma patients have a severe phenotype described as “fatal or near-fatal asthma,” “severe asthma,” “steroid-dependent asthma,” “steroid-insensitive asthma,” “difficult to control asthma,” “poorly controlled asthma,” “brittle asthma,” or “irreversible asthma” [1]. The causes of these conditions are complex and most likely heterogeneous. Some can be explained by insufficient or inadequate treatment, while others explained by airway inflammation that is resistant to conventional treatment. Continuous exposure to aggravating factors and/or associated comorbid conditions may exert a deleterious influence on asthma control, but a certain type of airway inflammation may also contribute to standard therapy unresponsiveness. As such, the pathogenesis of uncontrollable asthma, especially steroid-insensitive asthma, has been a long-standing interest among researchers attempting to establish a novel strategy for the treatment of patients with persistent symptoms, irreversible airflow obstruction, or frequent exacerbations even under adequate treatment. The current consensus on asthma is that the main underlying pathology is chronic airway inflammation in which inflammatory cells, such as eosinophils and helper T (Th) 2 lymphocytes, play a role. The Th1/Th2 paradigm has offered important insights into the pathogenesis of asthma, and there is no doubt that this classical
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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[34]
V. Lazarevic and L. H. Glimcher, “T-bet in disease,” Nature Immunology, vol. 12, no. 7, pp. 597–606, 2011.
[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.
[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.
[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.
[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.
[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. Soza？ska, “Interleukin-17 in sputum correlates with airway hyperresponsiveness to methacholine,” Respiratory Medicine, vol. 97, no. 6, pp. 726–733, 2003.
[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.
[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.
[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.
[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.
[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.
[46]
A. Hamzaoui, H. Maalmi, A. Berra？es, 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.
[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.
[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.
[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.
[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.
[51]
H. Hoshino, J. L？tvall, 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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[88]
N. Nishimoto and T. Kishimoto, “Interleukin 6: from bench to bedside,” Nature Clinical Practice Rheumatology, vol. 2, no. 11, pp. 619–626, 2006.
[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.
[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.
[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.
[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.
[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.
[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.
