Targeting interleukins to treat severe asthma

Expert Review of Respiratory Medicine

Volumn 6, Issue 4, 2012, Pages 423-439

  Gibeon, David ^a   Menzies Gow, Andrew N ^a  

^a ROYAL BROMPTON HOSPITAL   (United Kingdom)

Author keywords

cytokines; interleukins; monoclonal antibody; severe asthma; T lymphocytes

Indexed keywords

AIN 457; ALTRAKINCEPT; AMG 317; BENRALIZUMAB; CHEMOKINE RECEPTOR CCR3; CORTICOSTEROID; DACLIZUMAB; DEXAMETHASONE; ENOKIZUMAB; GAMMA INTERFERON; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; INTERLEUKIN 10; INTERLEUKIN 12; INTERLEUKIN 13; INTERLEUKIN 17F; INTERLEUKIN 21; INTERLEUKIN 22; INTERLEUKIN 28; INTERLEUKIN 4; INTERLEUKIN 5; INTERLEUKIN 6; INTERLEUKIN 8; INTERLEUKIN 9; LEBRIKIZUMAB; LYMPHOTOXIN; PASCOLIZUMAB; PITRAKINRA; RECOMBINANT INTERLEUKIN 1 RECEPTOR BLOCKING AGENT; RECOMBINANT INTERLEUKIN 12; RESLIZUMAB; SECUKINUMAB; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ALLERGIC ASTHMA; ASTHMA; BREAST CARCINOMA; BRONCHUS HYPERREACTIVITY; CD4+ T LYMPHOCYTE; CORTICOSTEROID THERAPY; CYTOKINE PRODUCTION; CYTOKINE RELEASE; DISEASE SEVERITY; DRUG FATALITY; DRUG SAFETY; DRUG WITHDRAWAL; FLU LIKE SYNDROME; HEART ARRHYTHMIA; HUMAN; IMMUNOCOMPETENT CELL; IMMUNOMODULATION; INFECTION; INFLAMMATION; INFLAMMATORY INFILTRATE; LIVER FUNCTION TEST; MORBIDITY; MORTALITY; MYELITIS; NONHUMAN; PATHOGENESIS; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); REGULATORY T LYMPHOCYTE; REVIEW; RHEUMATOID ARTHRITIS; SIDE EFFECT; T LYMPHOCYTE SUBPOPULATION; TH1 CELL; TH1 TH2 BALANCE; TH17 CELL; TH2 CELL; TH22 CELL; TH9 CELL; TREATMENT RESPONSE; VIRUS MENINGITIS;

EID: 84866372922     PISSN: 17476348     EISSN: 17476356     Source Type: Journal    
DOI: 10.1586/ers.12.38     Document Type: Review

References (223)

1. Meyer EH, DeKruyff RH, Umetsu DT. T cells and NKT cells in the pathogenesis of asthma. Annu. Rev. Med. 59, 281-292 (2008)
2. Romagnani S. T-cell subsets (Th1 versus Th2). Ann. Allergy Asthma Immunol. 85(1), 9-18; quiz 18, 21 (2000)
3. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu. Rev. Immunol. 27, 485-517 (2009)
4. Leung DY, Martin RJ, Szefler SJ et al. Dysregulation of interleukin 4, interleukin 5, and interferon γ gene expression in steroid-resistant asthma. J. Exp. Med. 181(1), 33-40 (1995)
5. Bentley AM, Hamid Q, Robinson DS et al. Prednisolone treatment in asthma. Reduction in the numbers of eosinophils, T cells, tryptase-only positive mast cells, and modulation of IL-4, IL-5, and interferon-γ cytokine gene expression within the bronchial mucosa. Am. J. Respir. Crit. Care Med. 153(2), 551-556 (1996)
6. Pelletier M, Maggi L, Micheletti A et al. Evidence for a cross-talk between human neutrophils and Th17 cells. Blood 115(2), 335-343 (2010)
7. Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28(4), 454-467 (2008)
8. Cosmi L, Liotta F, Maggi E, Romagnani S, Annunziato F. Th17 cells: New players in asthma pathogenesis. Allergy 66(8), 989-998 (2011)
9. Jabeen R, Kaplan MH. The symphony of the ninth: The development and function of Th9 cells. Curr. Opin. Immunol. 24(3), 303-307 (2012)
10. Eyerich S, Eyerich K, Cavani A, Schmidt- Weber C. IL-17 and IL-22: Siblings, not twins. Trends Immunol. 31(9), 354-361 (2010)
11. Johnson VJ, Yucesoy B, Luster MI. Prevention of IL-1 signaling attenuates airway hyperresponsiveness and inflammation in a murine model of toluene diisocyanate-induced asthma. J. Allergy Clin. Immunol. 116(4), 851-858 (2005)
12. Whelan R, Kim C, Chen M, Leiter J, Grunstein MM, Hakonarson H. Role and regulation of interleukin-1 molecules in pro-asthmatic sensitised airway smooth muscle. Eur. Respir. J. 24(4), 559-567 (2004)
13. Broide DH, Lotz M, Cuomo AJ, Coburn DA, Federman EC, Wasserman SI. Cytokines in symptomatic asthma airways. J. Allergy Clin. Immunol. 89(5), 958-967 (1992)
14. Nakae S, Komiyama Y, Yokoyama H et al. IL-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response. Int. Immunol. 15(4), 483-490 (2003)
15. Okada S, Inoue H, Yamauchi K et al. Potential role of interleukin-1 in allergeninduced late asthmatic reactions in guinea pigs: Suppressive effect of interleukin-1 receptor antagonist on late asthmatic reaction. J. Allergy Clin. Immunol. 95(6), 1236-1245 (1995)
16. Hallegua DS, Weisman MH. Potential therapeutic uses of interleukin 1 receptor antagonists in human diseases. Ann. Rheum. Dis. 61(11), 960-967 (2002)
17. Nelson BH. IL-2, regulatory T cells, and tolerance. J. Immunol. 172(7), 3983-3988 (2004)
18. Rand TH, Silberstein DS, Kornfeld H, Weller PF. Human eosinophils express functional interleukin 2 receptors. J. Clin. Invest. 88(3), 825-832 (1991)
19. Yamaguchi Y, Suda T, Shiozaki H et al. Role of IL-5 in IL-2-induced eosinophilia. In vivo and in vitro expression of IL-5 mRNA by IL-2. J. Immunol. 145(3), 873-877 (1990)
20. Atkins MB, Lotze MT, Dutcher JP et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985 and 1993. J. Clin. Oncol. 17(7), 2105-2116 (1999)
21. Haddad H, Rini BI. Current treatment considerations in metastatic renal cell carcinoma. Curr. Treat. Options Oncol. 13(2), 212-229 (2012)
22. Abrams D, Levy Y, Losso MH et al; The INSIGHT-ESPRIT Study Group; SILCAAT Scientific Committee. Interleukin-2 therapy in patients with HIV infection. N. Engl. J. Med. 361(16), 1548-1559 (2009)
23. Koreth J, Matsuoka K, Kim HT et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N. Engl. J. Med. 365(22), 2055-2066 (2011)
24. Morris JC, Waldmann TA. Advances in interleukin 2 receptor targeted treatment. Ann. Rheum. Dis. 59(SUPPL.1), i109-i114 (2000)
25. Barutca S, Meydan N, Barlak A. Prevention of interleukin-2-induced severe bronchospasm with salbutamol. J. Aerosol Med. 16(2), 183-184 (2003)
26. Suda T, Hashizume H, Aoshima Y et al. Management of interleukin-2-induced severe bronchoconstriction. Eur. Respir. J. 29(3), 612-613 (2007)
27. Park CS, Lee SM, Chung SW, Uh S, Kim HT, Kim YH. Interleukin-2 and soluble interleukin-2 receptor in bronchoalveolar lavage fluid from patients with bronchial asthma. Chest 106(2), 400-406 (1994)
28. Azzawi M, Bradley B, Jeffery PK et al. Identification of activated T lymphocytes and eosinophils in bronchial biopsies in stable atopic asthma. Am. Rev. Respir. Dis. 142(6 Pt 1), 1407-1413 (1990)
29. Antoniu SA. Daclizumab a novel corticosteroid-sparing therapy for asthma? Expert Opin. Investig. Drugs 18(3), 369-371 (2009)
30. Foss FM, Waldmann TA. Interleukin-2 receptor-directed therapies for cutaneous lymphomas. Hematol. Oncol. Clin. North Am. 17(6), 1449-1458 (2003
31. Waldmann TA. The IL-2/IL-2 receptor system: A target for rational immune intervention. Immunol. Today 14(6), 264-270 (1993)
32. Waldmann TA. Anti-Tac (daclizumab, Zenapax) in the treatment of leukemia, autoimmune diseases, and in the prevention of allograft rejection: A 25-year personal odyssey. J. Clin. Immunol. 27(1), 1-18 (2007)
33. McClellan M, Keller S, Zhao V et al. Daclizumab inhibits mitogen-stimulated Th1 and Th2 cytokine production from human PBMC. J. Allergy Clin. Immunol. 109(1), S24 (2002)
34. Busse WW, Israel E, Nelson HS et al.; Daclizumab Asthma Study Group. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: A randomized, controlled trial. Am. J. Respir. Crit. Care Med. 178(10), 1002-1008 (2008)
35. Takatsu K, Nakajima H. IL-5 and eosinophilia. Curr. Opin. Immunol. 20(3), 288-294 (2008)
36. Sakuishi K, Oki S, Araki M, Porcelli SA, Miyake S, Yamamura T. Invariant NKT cells biased for IL-5 production act as crucial regulators of inflammation. J. Immunol. 179(6), 3452-3462 (2007)
37. Warren HS, Kinnear BF, Phillips JH, Lanier LL. Production of IL-5 by human NK cells and regulation of IL-5 secretion by IL-4, IL-10, and IL-12. J. Immunol. 154(10), 5144-5152 (1995)
38. Yamada T, Sun Q, Zeibecoglou K et al. IL-3, IL-5, granulocyte-macrophage colony-stimulating factor receptor α-subunit, and common β-subunit expression by peripheral leukocytes and blood dendritic cells. J. Allergy Clin. Immunol. 101(5), 677-682 (1998)
39. Lopez AF, Sanderson CJ, Gamble JR, Campbell HD, Young IG, Vadas MA. Recombinant human interleukin 5 is a selective activator of human eosinophil function. J. Exp. Med. 167(1), 219-224 (1988)
40. Clutterbuck EJ, Hirst EM, Sanderson CJ. Human interleukin-5 (IL-5) regulates the production of eosinophils in human bone marrow cultures: Comparison and interaction with IL-1, IL-3, IL-6, and GMCSF. Blood 73(6), 1504-1512 (1989)
41. Kay AB. The role of eosinophils in the pathogenesis of asthma. Trends Mol. Med. 11(4), 148-152 (2005)
42. Bousquet J, Chanez P, Lacoste JY et al. Eosinophilic inflammation in asthma. N. Engl. J. Med. 323(15), 1033-1039 (1990)
43. Parvord ID, Martin N. Induced sputum in asthma:application in clinical practice. In: Non-Invasive Assessment of Airways Inflammation in Asthma and COPD. Loukides S, Kostikas K, Barnes PJ (Eds). PMP, Athens, 125-139 (2011)
44. Gibson PG, Fujimura M, Niimi A. Eosinophilic bronchitis: Clinical manifestations and implications for treatment. Thorax 57(2), 178-182 (2002)
45. Jatakanon A, Lim S, Barnes PJ. Changes in sputum eosinophils predict loss of asthma control. Am. J. Respir. Crit. Care Med. 161(1), 64-72 (2000)
46. Romagnoli M, Vachier I, Tarodo de la Fuente P et al. Eosinophilic inflammation in sputum of poorly controlled asthmatics. Eur. Respir. J. 20(6), 1370-1377 (2002)
47. Hastie AT, Moore WC, Meyers DA et al.; National Heart, Lung, and Blood Institute Severe Asthma Research Program. Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J. Allergy Clin. Immunol. 125(5), 1028- 1036.e13 (2010)
48. Green RH, Brightling CE, McKenna S et al. Asthma exacerbations and sputum eosinophil counts: A randomised controlled trial. Lancet 360(9347), 1715-1721 (2002)
49. Jayaram L, Pizzichini MM, Cook RJ et al. Determining asthma treatment by monitoring sputum cell counts: Effect on exacerbations. Eur. Respir. J. 27(3), 483-494 (2006)
50. Tanaka H, Kawada N, Yamada T, Kawada K, Takatsu K, Nagai H. Allergen-induced airway inflammation and bronchial responsiveness in interleukin-5 receptor α chain-deficient mice. Clin. Exp. Allergy 30(6), 874-881 (2000)
51. Takatsu K. Interleukin-5 and IL-5 receptor in health and diseases. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 87(8), 463-485 (2011)
52. Hamelmann E, Oshiba A, Loader J et al. Antiinterleukin-5 antibody prevents airway hyperresponsiveness in a murine model of airway sensitization. Am. J. Respir. Crit. Care Med. 155(3), 819-825 (1997)
53. Akutsu I, Kojima T, Kariyone A, Fukuda T, Makino S, Takatsu K. Antibody against interleukin-5 prevents antigen-induced eosinophil infiltration and bronchial hyperreactivity in the guinea pig airways. Immunol. Lett. 45(1-2), 109-116 (1995)
54. Mauser PJ, Pitman AM, Fernandez X et al. Effects of an antibody to interleukin-5 in a monkey model of asthma. Am. J. Respir. Crit. Care Med. 152(2), 467-472 (1995)
55. Hamid Q, Azzawi M, Ying S et al. Expression of mRNA for interleukin-5 in mucosal bronchial biopsies from asthma. J. Clin. Invest. 87(5), 1541-1546 (1991)
56. Humbert M, Corrigan CJ, Kimmitt P, Till SJ, Kay AB, Durham SR. Relationship between IL-4 and IL-5 mRNA expression and disease severity in atopic asthma. Am. J. Respir. Crit. Care Med. 156(3 Pt 1), 704-708 (1997)
57. Shi H, Qin S, Huang G et al. Infiltration of eosinophils into the asthmatic airways caused by interleukin 5. Am. J. Respir. Cell Mol. Biol. 16(3), 220-224 (1997)
58. Flood-Page P, Menzies-Gow A, Phipps S et al. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J. Clin. Invest. 112(7), 1029-1036 (2003)
59. 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. 167(2), 199-204 (2003)
60. Leckie MJ, ten Brinke A, Khan J et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356(9248), 2144-2148 (2000)
61. Kips JC, O'Connor BJ, Langley SJ et al. Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: A pilot study. Am. J. Respir. Crit. Care Med. 167(12), 1655-1659 (2003)
62. Flood-Page P, Swenson C, Faiferman I et al.; International Mepolizumab Study Group. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am. J. Respir. Crit. Care Med. 176(11), 1062-1071 (2007)
63. Nair P, Pizzichini MM, Kjarsgaard M et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N. Engl. J. Med. 360(10), 985-993 (2009)
64. Haldar P, Brightling CE, Hargadon B et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med. 360(10), 973-984 (2009)
65. Castro M, Mathur S, Hargreave F et al.; Res-5-0010 Study Group. Reslizumab for poorly controlled, eosinophilic asthma: A randomized, placebo-controlled study. Am. J. Respir. Crit. Care Med. 184(10), 1125-1132 (2011)
66. McCallister JW. Reslizumab and eosinophilic asthma: one step closer to phenotype-directed therapy? Am. J. Respir. Crit. Care Med. 184(10), 1096-1097 (2011)
67. Bateman ND, Shahi A, Feeley KM, Woolford TJ. Activated eosinophils in nasal polyps: A comparison of asthmatic and non-asthmatic patients. Clin. Otolaryngol. 30(3), 221-225 (2005)
68. Gevaert P, Lang-Loidolt D, Lackner A et al. Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps. J. Allergy Clin. Immunol. 118(5), 1133-1141 (2006)
69. Kolbeck R, Kozhich A, Koike M et al. MEDI-563, a humanized anti-IL-5 receptor α mAb with enhanced antibodydependent cell-mediated cytotoxicity function. J. Allergy Clin. Immunol. 125(6), 1344-1353.e2 (2010)
70. Busse WW, Katial R, Gossage D et al. Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti-IL-5 receptor α antibody, in a Phase I study of subjects with mild asthma. J. Allergy Clin. Immunol. 125(6), 1237-1244.e2 (2010)
71. Gossage D, Geba G, Gillen A et al. A multiple ascending subcutaneous (SC) dose study of MEDI-563, a humanized anti-IL-5Rα monoclonal antibody, in adult asthmatics. Annu. Cong. Eur. Resp. Soc. P1177 (2010)
72. Molfino NA, Gossage D, Kolbeck R, Parker JM, Geba GP. Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor. Clin. Exp. Allergy 42(5), 712-737 (2012)
73. Gauvreau GM, Pageau R, Seguin R et al. Dose-response effects of TPI ASM8 in asthmatics after allergen. Allergy 66(9), 1242-1248 (2011)
74. Caramori G, Adcock IM, Ito K. Targeting Th2 cells in asthmatic airways. Curr. Opin. Investig. Drugs 5(11), 1141-1147 (2004)
75. Ohara J, Paul WE. Receptors for B-cell stimulatory factor-1 expressed on cells of haematopoietic lineage. Nature 325(6104), 537-540 (1987)
76. Chung KF, Barnes PJ. Cytokines in asthma. Thorax 54(9), 825-857 (1999)
77. Miloux B, Laurent P, Bonnin O et al. Cloning of the human IL-13R α1 chain and reconstitution with the IL4R α of a functional IL-4/IL-13 receptor complex. FEBS Lett. 401(2-3), 163-166 (1997)
78. Ishizaka A, Sakiyama Y, Nakanishi M et al. The inductive effect of interleukin-4 on IgG4 and IgE synthesis in human peripheral blood lymphocytes. Clin. Exp. Immunol. 79(3), 392-396 (1990)
79. Punnonen J, Aversa G, Cocks BG et al. Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc. Natl Acad. Sci. USA 90(8), 3730-3734 (1993)
80. 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. 2(2), 66-70 (2001)
81. Li L, Xia Y, Nguyen A et al. Effects of Th2 cytokines on chemokine expression in the lung: IL-13 potently induces eotaxin expression by airway epithelial cells. J. Immunol. 162(5), 2477-2487 (1999)
82. 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. 17(3), 368-375 (1997)
83. Coyle AJ, Le Gros G, Bertrand C et al. Interleukin-4 is required for the induction of lung Th2 mucosal immunity. Am. J. Respir. Cell Mol. Biol. 13(1), 54-59 (1995)
84. Zhu Z, Homer RJ, Wang Z et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J. Clin. Invest. 103(6), 779-788 (1999)
85. Townley RG, Gendapodi PR, Qutna N, Evans J, Romero FA, Abel P. Effect of interleukin 13 on bronchial hyperresponsiveness and the bronchoprotective effect of β-adrenergic bronchodilators and corticosteroids. Ann. Allergy Asthma Immunol. 102(3), 190-197 (2009)
86. Webb DC, McKenzie AN, Koskinen AM, Yang M, Mattes J, Foster PS. Integrated signals between IL-13, IL-4, and IL-5 regulate airways hyperreactivity. J. Immunol. 165(1), 108-113 (2000)
87. Komai M, Tanaka H, Masuda T et al. Role of Th2 responses in the development of allergen-induced airway remodelling in a murine model of allergic asthma. Br. J. Pharmacol. 138(5), 912-920 (2003)
88. Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A. IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis. Nat. Med. 12(1), 99-106 (2006)
89. Bellini A, Marini MA, Bianchetti L, Barczyk M, Schmidt M, Mattoli S. Interleukin (IL)-4, IL-13, and IL-17A differentially affect the profibrotic and proinflammatory functions of fibrocytes from asthmatic patients. Mucosal Immunol. 5(2), 140-149 (2012)
90. Takayama G, Arima K, Kanaji T et al. Periostin: A novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J. Allergy Clin. Immunol. 118(1), 98-104 (2006)
91. Sidhu SS, Yuan S, Innes AL et al. Roles of epithelial cell-derived periostin in TGF-β activation, collagen production, and collagen gel elasticity in asthma. Proc. Natl Acad. Sci. USA 107(32), 14170-14175 (2010)
92. Corren J, Lemanske RF, Hanania NA et al. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365(12), 1088-1098 (2011)
93. Blease K, Jakubzick C, Westwick J, Lukacs N, Kunkel SL, Hogaboam CM. Therapeutic effect of IL-13 immunoneutralization during chronic experimental fungal asthma. J. Immunol. 166(8), 5219-5224 (2001)
94. Yang G, Volk A, Petley T et al. Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness, inflammation and airway remodeling. Cytokine 28(6), 224-232 (2004)
95. Yang G, Li L, Volk A et al. Therapeutic dosing with anti-interleukin-13 monoclonal antibody inhibits asthma progression in mice. J. Pharmacol. Exp. Ther. 313(1), 8-15 (2005)
96. Akimoto T, Numata F, Tamura M et al. Abrogation of bronchial eosinophilic inflammation and airway hyperreactivity in signal transducers and activators of transcription (STAT)6-deficient mice. J. Exp. Med. 187(9), 1537-1542 (1998)
97. Kuperman D, Schofield B, Wills-Karp M, Grusby MJ. Signal transducer and activator of transcription factor 6 (STAT6)-deficient mice are protected from antigen-induced airway hyperresponsiveness and mucus production. J. Exp. Med. 187(6), 939-948 (1998)
98. Gavett SH, O'Hearn DJ, Karp CL et al. Interleukin-4 receptor blockade prevents airway responses induced by antigen challenge in mice. Am. J. Physiol. 272(2 Pt 1), L253-L261 (1997)
99. McKenzie GJ, Fallon PG, Emson CL, Grencis RK, McKenzie AN. Simultaneous disruption of interleukin (IL)-4 and IL-13 defines individual roles in T helper cell type 2-mediated responses. J. Exp. Med. 189(10), 1565-1572 (1999)
100. Sato TA, Widmer MB, Finkelman FD et al. Recombinant soluble murine IL-4 receptor can inhibit or enhance IgE responses in vivo. J. Immunol. 150(7), 2717-2723 (1993)
101. Shi HZ, Deng JM, Xu H et al. Effect of inhaled interleukin-4 on airway hyperreactivity in asthmatics. Am. J. Respir. Crit. Care Med. 157(6 Pt 1), 1818-1821 (1998)
102. Hart TK, Blackburn MN, Brigham-Burke M et al. Preclinical efficacy and safety of pascolizumab (SB 240683): A humanized anti-interleukin-4 antibody with therapeutic potential in asthma. Clin. Exp. Immunol. 130(1), 93-100 (2002)
103. Long AA. Monoclonal antibodies and other biologic agents in the treatment of asthma. mAbs 1(3), 237-246 (2009)
104. Borish LC, Nelson HS, Lanz MJ et al. Interleukin-4 receptor in moderate atopic asthma. A Phase I/II randomized, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 160(6), 1816-1823 (1999)
105. Borish LC, Nelson HS, Corren J et al.; IL-4R Asthma Study Group. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J. Allergy Clin. Immunol. 107(6), 963-970 (2001)
106. Adcock IM, Caramori G, Chung KF. New targets for drug development in asthma. Lancet 372(9643), 1073-1087 (2008)
107. Andrews AL, Holloway JW, Holgate ST, Davies DE. IL-4 receptor α is an important modulator of IL-4 and IL-13 receptor binding: Implications for the development of therapeutic targets. J. Immunol. 176(12), 7456-7461 (2006)
108. Hershey GK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA. The association of atopy with a gain-of-function mutation in the α subunit of the interleukin-4 receptor. N. Engl. J. Med. 337(24), 1720-1725 (1997)
109. Wenzel SE, Balzar S, Ampleford E et al. IL4R α mutations are associated with asthma exacerbations and mast cell/IgE expression. Am. J. Respir. Crit. Care Med. 175(6), 570-576 (2007)
110. Corren J, Busse W, Meltzer EO et al. A randomized, controlled, Phase II study of AMG 317, an IL-4Rα antagonist, in patients with asthma. Am. J. Respir. Crit. Care Med. 181(8), 788-796 (2010)
111. Antoniu SA, Cojocaru I. Pitrakinra for asthma. Expert Opin. Biol. Ther. 10(11), 1609-1615 (2010)
112. Tomkinson A, Tepper J, Morton M et al. Inhaled vs subcutaneous effects of a dual IL-4/IL-13 antagonist in a monkey model of asthma. Allergy 65(1), 69-77 (2010)
113. Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two Phase IIa studies. Lancet 370(9596), 1422-1431 (2007)
114. Otulana BA, Wenzel SE, Ind PW et al. A Phase IIb study of inhaled pitrakinra, an IL-4/IL-13 antagonist, successfully identified responder subpopulations of patients with uncontrolled asthma. Am. J. Respir. Crit. Care Med. 183, A6179 (2011)
115. Doganci A, Eigenbrod T, Krug N et al. The IL-6R α chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo. J. Clin. Invest. 115(2), 313-325 (2005)
116. Kamimura D, Ishihara K, Hirano T. IL-6 signal transduction and its physiological roles: The signal orchestration model. Rev. Physiol. Biochem. Pharmacol. 149, 1-38 (2003)
117. Dienz O, Rincon M. The effects of IL-6 on CD4 T cell responses. Clin. Immunol. 130(1), 27-33 (2009)
118. Neveu WA, Allard JL, Raymond DM et al. Elevation of IL-6 in the allergic asthmatic airway is independent of inflammation but associates with loss of central airway function. Respir. Res. 11, 28 (2010)
119. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17-producing human T helper cells. Nat. Immunol. 8(9), 942-949 (2007)
120. Wang J, Homer RJ, Chen Q, Elias JA. Endogenous and exogenous IL-6 inhibit aeroallergen-induced Th2 inflammation. J. Immunol. 165(7), 4051-4061 (2000)
121. Dixon AE, Raymond DM, Suratt BT, Bourassa LM, Irvin CG. Lower airway disease in asthmatics with and without rhinitis. Lung 186(6), 361-368 (2008)
122. Govindaraju V, Michoud MC, Al-Chalabi M, Ferraro P, Powell WS, Martin JG. Interleukin-8: Novel roles in human airway smooth muscle cell contraction and migration. Am. J. Physiol. Cell Physiol. 291(5), C957-C965 (2006)
123. Gibson PG, Simpson JL, Saltos N. Heterogeneity of airway inflammation in persistent asthma: Evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest 119(5), 1329-1336 (2001)
124. Chanez P, Enander I, Jones I, Godard P, Bousquet J. Interleukin 8 in bronchoalveolar lavage of asthmatic and chronic bronchitis patients. Int. Arch. Allergy Immunol. 111(1), 83-88 (1996)
125. Shute JK, Vrugt B, Lindley IJ et al. Free and complexed interleukin-8 in blood and bronchial mucosa in asthma. Am. J. Respir. Crit. Care Med. 155(6), 1877-1883 (1997)
126. Mahler DA, Huang S, Tabrizi M, Bell GM. Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: A pilot study. Chest 126(3), 926-934 (2004)
127. Holz O, Khalilieh S, Ludwig-Sengpiel A et al. SCH527123, a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects. Eur. Respir. J. 35(3), 564-570 (2010)
128. Gaga M, Nair PK, Hargreave F et al. SCH527123, a novel treatment option for severe neutrophilic asthma. Am. J. Respir. Crit. Care Med. 181, A6763 (2010)
129. Uyttenhove C, Simpson RJ, Van Snick J. Functional and structural characterization of P40, a mouse glycoprotein with T-cell growth factor activity. Proc. Natl Acad. Sci. USA 85(18), 6934-6938 (1988)
130. Schmitt E, Germann T, Goedert S et al. IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-β and IL-4, and is inhibited by IFN-γ. J. Immunol. 153(9), 3989-3996 (1994)
131. Xing J, Wu Y, Ni B. Th9: A new player in asthma pathogenesis? J. Asthma 48(2), 115-125 (2011)
132. McLane MP, Haczku A, van de Rijn M et al. Interleukin-9 promotes allergeninduced eosinophilic inflammation and airway hyperresponsiveness in transgenic mice. Am. J. Respir. Cell Mol. Biol. 19(5), 713-720 (1998)
133. Levitt RC, McLane MP, MacDonald D et al. IL-9 pathway in asthma: New therapeutic targets for allergic inflammatory disorders. J. Allergy Clin. Immunol. 103(5 Pt 2), S485-S491 (1999)
134. Chang HC, Sehra S, Goswami R et al. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat. Immunol. 11(6), 527-534 (2010)
135. Jeanin P, Deineste Y, Lecoanet-Henchoz S et al. Interleukin-7 (IL-7) enhances class switching to IgE and IgG4 in the presence of T cells via IL-9 and sCD23. Blood 91(4), 1355-1361 (1998)
136. Louahed J, Toda M, Jen J et al. Interleukin-9 upregulates mucus expression in the airways. Am. J. Respir. Cell Mol. Biol. 22(6), 649-656 (2000)
137. Erpenbeck VJ, Hohlfeld JM, Volkmann B et al. Segmental allergen challenge in patients with atopic asthma leads to increased IL-9 expression in bronchoalveolar lavage fluid lymphocytes. J. Allergy Clin. Immunol. 111(6), 1319-1327 (2003)
138. Shimbara A, Christodoulopoulos P, Soussi-Gounni A et al. IL-9 and its receptor in allergic and nonallergic lung disease: Increased expression in asthma. J. Allergy Clin. Immunol. 105(1 Pt 1), 108-115 (2000)
139. White B, Leon F, White W, Robbie G. Two first-in-human, open-label, Phase I dose-escalation safety trials of MEDI-528, a monoclonal antibody against interleukin-9, in healthy adult volunteers. Clin. Ther. 31(4), 728-740 (2009)
140. Parker JM, Oh CK, LaForce C et al. Safety profile and clinical activity of multiple subcutaneous doses of MEDI-528, a humanized anti-interleukin-9 monoclonal antibody, in two randomized Phase 2a studies in subjects wtih asthma. BMC Pulm. Med. 28, 11-14 (2011)
141. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683-765 (2001)
142. Bogdan C, Vodovotz Y, Nathan C. Macrophage deactivation by interleukin 10. J. Exp. Med. 174(6), 1549-1555 (1991)
143. Williams LM, Ricchetti G, Sarma U, Smallie T, Foxwell BM. Interleukin-10 suppression of myeloid cell activation - a continuing puzzle. Immunology 113(3), 281-292 (2004)
144. Glocker EO, Kotlarz D, Klein C, Shah N, Grimbacher B. IL-10 and IL-10 receptor defects in humans. Ann. NY Acad. Sci. 1246, 102-107 (2011)
145. Jeannin P, Lecoanet S, Delneste Y, Gauchat JF, Bonnefoy JY. IgE versus IgG4 production can be differentially regulated by IL-10. J. Immunol. 160(7), 3555-3561 (1998)
146. Barrat FJ, Cua DJ, Boonstra A et al. In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J. Exp. Med. 195(5), 603-616 (2002)
147. O'Garra A, Barrat FJ, Castro AG, Vicari A, Hawrylowicz C. Strategies for use of IL-10 or its antagonists in human disease. Immunol. Rev. 223, 114-131 (2008)
148. Berkman N, John M, Roesems G, Jose PJ, Barnes PJ, Chung KF. Inhibition of macrophage inflammatory protein-1 α expression by IL-10. Differential sensitivities in human blood monocytes and alveolar macrophages. J. Immunol. 155(9), 4412-4418 (1995)
149. 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. 97(6), 1288-1296 (1996)
150. Hsu CY, Liu HE, Sheu FY et al. Synergistic therapeutic effects of combined adenovirusmediated interleukin-10 and interleukin-12 gene therapy on airway inflammation in asthmatic mice. J. Gene Med. 12(1), 11-21 (2010)
151. Grissell TV, Powell H, Shafren DR et al. Interleukin-10 gene expression in acute virus-induced asthma. Am. J. Respir. Crit. Care Med. 172(4), 433-439 (2005)
152. John M, Lim S, Seybold J et al. Inhaled corticosteroids increase interleukin-10 but reduce macrophage inflammatory protein-1α, granulocyte-macrophage colony-stimulating factor, and interferon-γ release from alveolar macrophages in asthma. Am. J. Respir. Crit. Care Med. 157(1), 256-262 (1998)
153. Karagiannidis C, Akdis M, Holopainen P et al. Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma. J. Allergy Clin. Immunol. 114(6), 1425-1433 (2004)
154. Till SJ, Francis JN, Nouri-Aria K, Durham SR. Mechanisms of immunotherapy. J. Allergy Clin. Immunol. 113(6), 1025-1034; quiz 1035 (2004)
155. Hawrylowicz C, Richards D, Loke TK, Corrigan C, Lee T. A defect in corticosteroid-induced IL-10 production in T lymphocytes from corticosteroidresistant asthmatic patients. J. Allergy Clin. Immunol. 109(2), 369-370 (2002)
156. Xystrakis E, Kusumakar S, Boswell S et al. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J. Clin. Invest. 116(1), 146-155 (2006)
157. Hasko G, Szabo C. IL-12 as a therapeutic target for pharmacological modulation in immune-mediated and inflammatory diseases: regulation of T helper 1/T helper 2 responses. Br. J. Pharmacol. 127(6), 1295-1304 (1999)
158. van der Pouw Kraan TC, Boeije LC, de Groot ER et al. Reduced production of IL-12 and IL-12-dependent IFN-γ release in patients with allergic asthma. J. Immunol. 158(11), 5560-5565 (1997)
159. Kiniwa M, Gately M, Gubler U, Chizzonite R, Fargeas C, Delespesse G. Recombinant interleukin-12 suppresses the synthesis of immunoglobulin E by interleukin-4 stimulated human lymphocytes. J. Clin. Invest. 90(1), 262-266 (1992)
160. Okano Y, Nakamura Y, Sano T, Azuma M, Sone S. Interleukin-12 inhibits production of interleukin-5 but not of granulocyte/ macrophage colony-stimulating factor by antigen-stimulated blood mononuclear cells in allergic bronchial asthmatics. Int. Arch. Allergy Immunol. 115(1), 83-90 (1998)
161. Bryan SA, O'Connor BJ, Matti S et al. Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356(9248), 2149-2153 (2000)
162. Leonard JP, Sherman ML, Fisher GL et al. Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-γ production. Blood 90(7), 2541-2548 (1997)
163. Leonard P, Sur S. Interleukin-12: Potential role in asthma therapy. BioDrugs 17(1), 1-7 (2003)
164. Pene J, Chevalier S, Preisser L et al. Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes. J. Immunol. 180(11), 7423-7430 (2008)
165. Barczyk A, Pierzchala W, Sozanska E. Interleukin-17 in sputum correlates with airway hyperresponsiveness to methacholine. Respir. Med. 97(6), 726-733 (2003)
166. Hashimoto T, Akiyama K, Kobayashi N, Mori A. Comparison of IL-17 production by helper T cells among atopic and nonatopic asthmatics and control subjects. Int. Arch. Allergy Immunol. 137(SUPPL.1), 51-54 (2005)
167. Molet S, Hamid Q, Davoine F et al. IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J. Allergy Clin. Immunol. 108(3), 430-438 (2001)
168. McKinley L, Alcorn JF, Peterson A et al. Th17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J. Immunol. 181(6), 4089-4097 (2008)
169. Al-Ramli W, Prefontaine D, Chouiali F et al. T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma. J. Allergy Clin. Immunol. 123(5), 1185-1187 (2009)
170. Nakae S, Komiyama Y, Nambu A et al. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17(3), 375-387 (2002)
171. Schnyder-Candrian S, Togbe D, Couillin I et al. Interleukin-17 is a negative regulator of established allergic asthma. J. Exp. Med. 203(12), 2715-2725 (2006)
172. Linden A. Role of interleukin-17 and the neutrophil in asthma. Int. Arch. Allergy Immunol. 126(3), 179-184 (2001)
173. Zijlstra GJ, Ten Hacken NH, Hoffmann RF, van Oosterhout AJ, Heijink IH. Interleukin-17A induces glucocorticoid insensitivity in human bronchial epithelial cells. Eur. Respir. J. 39(2), 439-445 (2012)
174. Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat. Immunol. 10(8), 857-863 (2009)
175. Commins S, Steinke JW, Borish L. The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29. J. Allergy Clin. Immunol. 121(5), 1108-1111 (2008)
176. Nakagome K, Imamura M, Kawahata K et al. High expression of IL-22 suppresses antigen-induced immune responses and eosinophilic airway inflammation via an IL-10-associated mechanism. J. Immunol. 187(10), 5077-5089 (2011)
177. Liang SC, Tan XY, Luxenberg DP et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203(10), 2271-2279 (2006)
178. Sonnenberg GF, Nair MG, Kirn TJ, Zaph C, Fouser LA, Artis D. Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A. J. Exp. Med. 207(6), 1293-1305 (2010)
179. Hurst SD, Muchamuel T, Gorman DM et al. New IL-17 family members promote Th1 or Th2 responses in the lung: In vivo function of the novel cytokine IL-25. J. Immunol. 169(1), 443-453 (2002)
180. Tamachi T, Maezawa Y, Ikeda K, Iwamoto I, Nakajima H. Interleukin 25 in allergic airway inflammation. Int. Arch. Allergy Immunol. 140(SUPPL.1), 59-62 (2006)
181. Tamachi T, Maezawa Y, Ikeda K et al. IL-25 enhances allergic airway inflammation by amplifying a TH2 cell-dependent pathway in mice. J. Allergy Clin. Immunol. 118(3), 606-614 (2006)
182. Ballantyne SJ, Barlow JL, Jolin HE et al. Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma. J. Allergy Clin. Immunol. 120(6), 1324-1331 (2007)
183. Schmitz J, Owyang A, Oldham E et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23(5), 479-490 (2005)
184. Luthi AU, Cullen SP, McNeela EA et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 31(1), 84-98 (2009)
185. Pecaric-Petkovic T, Didichenko SA, Kaempfer S, Spiegl N, Dahinden CA. Human basophils and eosinophils are the direct target leukocytes of the novel IL-1 family member IL-33. Blood 113(7), 1526-1534 (2009)
186. Smithgall MD, Comeau MR, Yoon BR, Kaufman D, Armitage R, Smith DE. IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells. Int. Immunol. 20(8), 1019-1030 (2008)
187. Neill DR, Wong SH, Bellosi A et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464(7293), 1367-1370 (2010)
188. Borish L, Steinke JW. Interleukin-33 in asthma: how big of a role does it play? Curr. Allergy Asthma Rep. 11(1), 7-11 (2011)
189. Komai-Koma M, Xu D, Li Y, McKenzie AN, McInnes IB, Liew FY. IL-33 is a chemoattractant for human Th2 cells. Eur. J. Immunol. 37(10), 2779-2786 (2007)
190. Coyle AJ, Lloyd C, Tian J et al. Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses. J. Exp. Med. 190(7), 895-902 (1999)
191. Drube S, Heink S, Walter S et al. The receptor tyrosine kinase c-Kit controls IL-33 receptor signaling in mast cells. Blood 115(19), 3899-3906 (2010)
192. Rank MA, Kobayashi T, Kozaki H, Bartemes KR, Squillace DL, Kita H. IL-33-activated dendritic cells induce an atypical TH2-type response. J. Allergy Clin. Immunol. 123(5), 1047-1054 (2009)
193. Kearley J, Buckland KF, Mathie SA, Lloyd CM. Resolution of allergic inflammation and airway hyperreactivity is dependent upon disruption of the T1/ST2-IL-33 pathway. Am. J. Respir. Crit. Care Med. 179(9), 772-781 (2009)
194. Chow JY, Wong CK, Cheung PF, Lam CW. Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel Th2 cytokine IL-33: Implications for allergic inflammation. Cell. Mol. Immunol. 7(1), 26-34 (2010)
195. Prefontaine D, Nadigel J, Chouiali F et al. Increased IL-33 expression by epithelial cells in bronchial asthma. J. Allergy Clin. Immunol. 125(3), 752-754 (2010)
196. Minshall E, Chakir J, Laviolette M et al. IL-11 expression is increased in severe asthma: Association with epithelial cells and eosinophils. J. Allergy Clin. Immunol. 105(2 Pt 1), 232-238 (2000)
197. Bierbaum S, Nickel R, Zitnik S et al. Confirmation of association of IL-15 with pediatric asthma and comparison of different controls. Allergy 61(5), 576-580 (2006)
198. Muro S, Taha R, Tsicopoulos A et al. Expression of IL-15 in inflammatory pulmonary diseases. J. Allergy Clin. Immunol. 108(6), 970-975 (2001)
199. Laza-Stanca V, Message SD, Edwards MR et al. The role of IL-15 deficiency in the pathogenesis of virus-induced asthma exacerbations. PLoS Pathog. 7(7), e1002114 (2011)
200. Deng JM, Shi HZ. Interleukin-16 in asthma. Chin. Med. J. 119(12), 1017-1025 (2006)
201. Laberge S, Ernst P, Ghaffar O et al. Increased expression of interleukin-16 in bronchial mucosa of subjects with atopic asthma. Am. J. Respir. Cell Mol. Biol. 17(2), 193-202 (1997)
202. de Bie JJ, Henricks PA, Cruikshank WW, Hofman G, Nijkamp FP, van Oosterhout AJ. Effect of interleukin-16-blocking peptide on parameters of allergic asthma in a murine model. Eur. J. Pharmacol. 383(2), 189-196 (1999)
203. Hessel EM, Cruikshank WW, Van Ark I et al. Involvement of IL-16 in the induction of airway hyper-responsiveness and up-regulation of IgE in a murine model of allergic asthma. J. Immunol. 160(6), 2998-3005 (1998)
204. Tanaka H, Miyazaki N, Oashi K et al. IL-18 might reflect disease activity in mild and moderate asthma exacerbation. J. Allergy Clin. Immunol. 107(2), 331-336 (2001)
205. Ma Y, Zhang B, Tang RK, Liu Y, Peng GG. Interleukin-18 promoter polymorphism and asthma risk: A metaanalysis. Mol. Biol. Rep. 39(2), 1371-1376 (2012)
206. Huang F, Wachi S, Thai P et al. Potentiation of IL-19 expression in airway epithelia by IL-17A and IL-4/IL-13: Important implications in asthma. J. Allergy Clin. Immunol. 121(6), 1415-1421, 1421.e1 (2008)
207. Liao SC, Cheng YC, Wang YC et al. IL-19 induced Th2 cytokines and was upregulated in asthma patients. J. Immunol. 173(11), 6712-6718 (2004)
208. Chatterjee R, Batra J, Ghosh B. A common exonic variant of interleukin21 confers susceptibility to atopic asthma. Int. Arch. Allergy Immunol. 148(2), 137-146 (2009)
209. Hiromura Y, Kishida T, Nakano H et al. IL-21 administration into the nostril alleviates murine allergic rhinitis. J. Immunol. 179(10), 7157-7165 (2007)
210. Frohlich A, Marsland BJ, Sonderegger I et al. IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo. Blood 109(5), 2023-2031 (2007)
211. Nakajima H, Hirose K. Role of IL-23 and Th17 cells in airway inflammation in asthma. Immune Netw. 10(1), 1-4 (2010)
212. Pflanz S, Timans JC, Cheung J et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells. Immunity 16(6), 779-790 (2002)
213. Chae SC, Li CS, Kim KM et al. Identification of polymorphisms in human interleukin-27 and their association with asthma in a Korean population. J. Hum. Genet. 52(4), 355-361 (2007)
214. Li JJ, Wang W, Baines KJ et al. IL-27/IFN-g induce MyD88-dependent steroid-resistant airway hyperresponsiveness by inhibiting glucocorticoid signaling in macrophages. J. Immunol. 185(7), 4401-4409 (2010)
215. Koltsida O, Hausding M, Stavropoulos A et al. IL-28A (IFN-g2) modulates lung DC function to promote Th1 immune skewing and suppress allergic airway disease. EMBO Mol. Med. 3(6), 348-361 (2011)
216. Wang J, Oberley-Deegan R, Wang S et al. Differentiated human alveolar type II cells secrete antiviral IL-29 (IFN-lambda 1) in response to influenza A infection. J. Immunol. 182(3), 1296-1304 (2009)
217. Contoli M, Message SD, Laza-Stanca V et al. Role of deficient type III interferonlambda production in asthma exacerbations. Nat. Med. 12(9), 1023-1026 (2006)
218. Lei Z, Liu G, Huang Q et al. SCF and IL-31 rather than IL-17 and BAFF are potential indicators in patients with allergic asthma. Allergy 63(3), 327-332 (2008)
219. Bilsborough J, Mudri S, Chadwick E, Harder B, Dillon SR. IL-31 receptor (IL-31RA) knockout mice exhibit elevated responsiveness to oncostatin M. J. Immunol. 185(10), 6023-6030 (2010)
220. Meyer N, Christoph J, Makrinioti H et al. Inhibition of angiogenesis by IL-32: Possible role in asthma. J. Allergy Clin. Immunol. 129(4), 964-973.e7 (2012)
221. Huang CH, Loo EX, Kuo IC et al. Airway inflammation and IgE production induced by dust mite allergen-specific memory/ effector Th2 cell line can be effectively attenuated by IL-35. J. Immunol. 187(1), 462-471 (2011)
222. Pavord ID, Haldar P, Bradding P et al. Mepolizumab in refractory eosinophilic asthma. Thorax 65(4), 370 (2010)
223. Gamble J, Stevenson M, McClean E, Heaney LG. The prevalence of nonadherence in difficult asthma. Am. J. Respir. Crit. Care Med. 180(9), 817-822 (2009)