The cytokine network in asthma and chronic obstructive pulmonary disease

Journal of Clinical Investigation

Volumn 118, Issue 11, 2008, Pages 3546-3556

  Barnes, Peter J ^a  

^a NATIONAL HEART AND LUNG INSTITUTE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA INTERFERON; ALTRAKINCEPT; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CCR5 ANTAGONIST; CHEMOKINE RECEPTOR CX3CR1; CYTOKINE; EPIDERMAL GROWTH FACTOR; ETANERCEPT; GAMMA INTERFERON; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; IMA 638; INTERLEUKIN 10; INTERLEUKIN 12; INTERLEUKIN 13; INTERLEUKIN 13 ANTIBODY; INTERLEUKIN 17; INTERLEUKIN 1BETA; INTERLEUKIN 25; INTERLEUKIN 4; INTERLEUKIN 5; INTERLEUKIN 6; INTERLEUKIN 9; LYMPHOKINE; MEDI 528; MEDI 563; MEPOLIZUMAB; MONOCYTE CHEMOTACTIC PROTEIN 1; NERVE GROWTH FACTOR; NEUROTROPHIN; PS 433540; QAX 576; TRANSCRIPTION FACTOR GATA 3; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; UNINDEXED DRUG; VASCULOTROPIN;

ASTHMA; CHRONIC INFLAMMATION; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL TRIAL; CYTOKINE RELEASE; DRUG EFFECT; DRUG EFFICACY; HUMAN; LOW DRUG DOSE; LYMPHOCYTE DIFFERENTIATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; TH1 CELL; TH2 CELL;

ASTHMA; CYTOKINES; HUMANS; MODELS, BIOLOGICAL; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE;

EID: 55849148482     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI36130     Document Type: Review

References (134)

1. Barnes, P.J. 2008. Immunology of asthma and chronic obstructive pulmonary disease. Nat. Rev. Immunol. 8:183-192.
2. Hogg, J.C., et al. 2004. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N. Engl. J. Med. 350:2645-2653.
3. Ho, I.C., and Pai, S.Y. 2007. GATA-3 - not just for Th2 cells anymore. Cell. Mol. Immunol. 4:15-29.
4. Caramori, G., et al. 2001. Expression of GATA family of transcription factors in T-cells, monocytes and bronchial biopsies. Eur. Respir. J. 18:466-473.
5. Maneechotesuwan, K., et al. 2007. Regulation of Th2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3. J. Immunol. 178:2491-2498.
6. Carriere, V., et al. 2007. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc. Natl.Acad. Sci. U. S. A. 104:282-287.
7. Komai-Koma, M., et al. 2007. IL-33 is a chemoattractant for human Th2 cells. Eur. J. Immunol. 37:2779-2786.
8. Barczyk, A., et al. 2006. Cytokine production by bronchoalveolar lavage T lymphocytes in chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 117:1484-1492.
9. Wills-Karp, M. 2004. Interleukin-13 in asthma pathogenesis. Immunol. Rev. 202:175-90.
10. Kuperman, D.A., et al. 2002. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat. Med. 8:885-889.
11. Zhu, Z., et al. 2004. Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science. 304:1678-1682.
12. Boutten, A., et al. 2004. Decreased expression of interleukin 13 in human lung emphysema. Thorax. 59:850-854.
13. Kroegel, C., Julius, P., Matthys, H., Virchow, J.C., Jr., and Luttmann, W. 1996. Endobronchial secretion of interleukin-13 following local allergen challenge in atopic asthma: relationship to interleukin-4 and eosinophil counts. Eur. Respir. J. 9:899-904.
14. Chupp, G.L., et al. 2007. A chitinase-like protein in the lung and circulation of patients with severe asthma. N. Engl. J. Med. 357:2016-2027.
15. Wenzel, S., Wilbraham, D., Fuller, R., Getz, E.B., and Longphre, M. 2007. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet. 370:1422-1431.
16. Stirling, R.G., van Rensen, E.L., Barnes, P.J., and Chung, K.F. 2001. Interleukin-5 induces CD34(+) eosinophil progenitor mobilization and eosinophil CCR3 expression in asthma. Am. J. Respir. Crit. Care Med. 164:1403-1409.
17. Flood-Page, P., et al. 2007. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am. J. Respir. Crit. Care Med. 176:1062-1071.
18. Flood-Page, P.T., Menzies-Gow, A.N., Kay, A.B., and Robinson, D.S. 2003. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airways. Am. J. Respir. Crit. Care Med. 167:199-204.
19. Zhou, Y., McLane, M., and Levitt, R.C. 2001. Interleukin-9 as a therapeutic target for asthma. Respir. Res. 2:80-84.
20. Steenwinckel, V., et al. 2007. IL-13 mediates in vivo IL-9 activities on lung epithelial cells but not on hematopoietic cells. J. Immunol. 178:3244-3251.
21. Finotto, S., et al. 2002. Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science. 295:336-338.
22. Hwang, E.S., Szabo, S.J., Schwartzberg, P.L., and Glimcher, L.H. 2005. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science. 307:430-433.
23. Usui, T., et al. 2006. T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. J. Exp. Med. 203:755-766.
24. Grumelli, S., et al. 2004. An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema. PLoS Med. 1:e8.
25. Kumar, R.K., Webb, D.C., Herbert, C., and Foster, P.S. 2006. Interferon-gamma as a possible target in chronic asthma. Inflamm. Allergy Drug Targets. 5:253-256.
26. Szabo, S.J., et al. 2002. Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science. 295:338-342.
27. Di Stefano, A., et al. 2004. STAT4 activation in smokers and patients with chronic obstructive pulmonary disease. Eur. Respir. J. 24:78-85.
28. Wark, P.A., et al. 2005. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J. Exp. Med. 201:937-947.
29. Contoli, M., et al. 2006. Role of deficient type III interferon-lambda production in asthma exacerbations. Nat. Med. 12:1023-1026.
30. Simon, H.U., Seelbach, H., Ehmann, R., and Schmitz, M. 2003. Clinical and immunological effects of low-dose IFN-alpha treatment in patients with corticosteroid-resistant asthma. Allergy. 58:1250-1255.
31. Trinchieri, G., Pflanz, S., and Kastelein, R.A. 2003. The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity. 19:641-644.
32. van der Pouw Kraan, T.C., et al. 1997. Reduced production of IL-12 and IL-12-dependent IFN-gamma release in patients with allergic asthma. J. Immunol. 158:5560-5565.
33. Bryan, S., et al. 2000. Effects of recombinant human interleukin-12 on eosinophils, airway hyperreactivity and the late asthmatic response. Lancet. 356:2149-2153.
34. Cooper, A.M., and Khader, S.A. 2007. IL-12p40: an inherently agonistic cytokine. Trends Immunol. 28:33-38.
35. Dinarello, C.A. 2007. Interleukin-18 and the pathogenesis of inflammatory diseases. Semin. Nephrol. 27:98-114.
36. Imaoka, H., et al. 2008. Interleukin-18 production and pulmonary function in COPD. Eur. Respir. J. 31:287-297.
37. Owaki, T., et al. 2005. A role for IL-27 in early regulation of Th1 differentiation. J. Immunol. 175:2191-2200.
38. Yoshimoto, T., Yoshimoto, T., Yasuda, K., Mizuguchi, J., and Nakanishi, K. 2007. IL-27 suppresses Th2 cell development and Th2 cytokines production from polarized Th2 cells: a novel therapeutic way for Th2-mediated allergic inflammation. J. Immunol. 179:4415-4423.
39. Manel, N., Unutmaz, D., and Littman, D.R. 2008. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat. Immunol. 9:641-649.
40. Volpe, E., et al. 2008. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat. Immunol. 9:650-657.
41. Bullens, D.M., et al. 2006. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx? Respir. Res. 7:135.
42. Pene, J., et al. 2008. Chronically inflamed human tissues are infiltrated by highly differentiated th17 lymphocytes. J. Immunol. 180:7423-7430.
43. Dragon, S., et al. 2007. IL-17 enhances IL-1beta-mediated CXCL-8 release from human airway smooth muscle cells. Am. J. Physiol. Lung Cell Mol. Physiol. 292:L1023-L1029.
44. Schmidt-Weber, C.B., Akdis, M., and Akdis, C.A. 2007. TH17 cells in the big picture of immunology. J. Allergy Clin. Immunol. 120:247-254.
45. Chen, Y., et al. 2003. Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. J. Biol.Chem. 278:17036-17043.
46. Nurieva, R., et al. 2007. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature. 448:480-483.
47. Fort, M.M., et al. 2001. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity. 15:985-995.
48. Wang, Y.H., et al. 2007. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J. Exp. Med. 204:1837-1847.
49. Ballantyne, S.J., et al. 2007. Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma. J. Allergy Clin. Immunol. 120:1324-1331.
50. Thomas, P.S., Yates, D.H., and Barnes, P.J. 1995. Tumor necrosis factor-α increases airway responsiveness and sputum neutrophils in normal human subjects. Am. J. Respir. Crit. Care Med. 152:76-80.
51. Kips, J.C., Tavernier, J.H., Joos, G.F., Peleman, R.A., and Pauwels, R.A. 1993. The potential role of tumor necrosis factor α in asthma. Clin. Exp. Allergy. 23:247-250.
52. Berry, M.A., et al. 2006. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N. Engl. J. Med. 354:697-708.
53. Erin, E.M., et al. 2006. The effects of a monoclonal antibody directed against tumour necrosis factor-alpha in asthma. Am. J. Respir. Crit. Care Med. 174:753-762.
54. Aaron, S.D., et al. 2001. Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 163:349-355.
55. Rennard, S.I., et al. 2007. The safety and efficacy of infliximab in moderate-to-severe chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 175:926-934.
56. Dentener, M.A., et al. 2008. Effect of infliximab on local and systemic inflammation in chronic obstructive pulmonary disease: a pilot study. Respiration. 76:275-282. doi:10.1159/000117386.
57. Rosenwasser, L.J. 1998. Biologic activities of IL-1 and its role in human disease. J. Allergy Clin. Immunol. 102:344-350.
58. Culpitt, S.V., et al. 2003. Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 167:24-31.
59. Erin, E.M., et al. 2008. Rapid anti-inflammatory effect of inhaled ciclesonide in asthma: a randomised, placebo-controlled study. Chest. Online publication ahead of print. doi:10.1378/chest.07-2575.
60. Bhowmik, A., Seemungal, T.A., Sapsford, R.J., and Wedzicha, J.A. 2000. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax 55:114-120.
61. Ying, S., et al. 2005. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J. Immunol. 174:8183-8190.
62. Allakhverdi, Z., et al. 2007. Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J. Exp. Med. 204:253-258.
63. Liu, Y.J., et al. 2007. TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annu. Rev. Immunol. 25:193-219.
64. Seshasayee, D., et al. 2007. In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammation. J. Clin. Invest. 117:3868-3878.
65. Gajewska, B.U., Wiley, R.E., and Jordana, M. 2003. GM-CSF and dendritic cells in allergic airway inflammation: basic mechanisms and prospects for therapeutic intervention. Curr. Drug Targets Inflamm. Allergy. 2:279-292.
66. Balbi, B., et al. 1997. Increased bronchoalveolar granulocytes and granulocyte/macrophage colony-stimulating factor during exacerbations of chronic bronchitis. Eur. Respir. J. 10:846-850.
67. Reber, L., Da Silva, C.A., and Frossard, N. 2006. Stem cell factor and its receptor c-Kit as targets for inflammatory diseases. Eur. J. Pharmacol. 533:327-340.
68. Berlin, A.A., Lincoln, P., Tomkinson, A., and Lukacs, N.W. 2004. Inhibition of stem cell factor reduces pulmonary cytokine levels during allergic airway responses. Clin. Exp. Immunol. 136:15-20.
69. Berlin, A.A., and Lukacs, N.W. 2005. Treatment of cockroach allergen asthma model with imatinib attenuates airway responses. Am. J. Respir. Crit. Care Med. 171:35-39.
70. Olsson, N., Rak, S., and Nilsson, G. 2000. Demonstration of mast cell chemotactic activity in bronchoalveolar lavage fluid collected from asthmatic patients before and during pollen season. J. Allergy Clin. Immunol. 105:455-461.
71. Freund-Michel, V., and Frossard, N. 2008. The nerve growth factor and its receptors in airway inflammatory diseases. Pharmacol. Ther. 117:52-76.
72. Nassenstein, C., Kutschker, J., Tumes, D., and Braun, A. 2006. Neuro-immune interaction in allergic asthma: role of neurotrophins. Biochem. Soc. Trans. 34:591-593.
73. Wan, Y.Y., and Flavell, R.A. 2007. Regulatory T cells, transforming growth factor-beta, and immune suppression. Proc. Am. Thorac. Soc. 4:271-276.
74. Minshall, E.M., et al. 1997. Eosinophil-associated TGF-beta1 mRNA expression and airways fibrosis in bronchial asthma. Am. J. Respir.Cell Mol. Biol. 17:326-333.
75. Balzar, S., et al. 2005. Increased TGF-beta2 in severe asthma with eosinophilia. J. Allergy Clin. Immunol. 115:110-117.
76. de Boer, W.I., et al. 1998. Transforming growth factor beta1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 158:1951-1957.
77. Takizawa, H., et al. 2001. Increased expression of transforming growth factor-beta1 in small airway epithelium from tobacco smokers and patients with chronic obstructive pulmonary disease (COPD). Am. J. Respir. Crit. Care Med. 163:1476-1483.
78. Wang, I.M., et al. 2008. Gene expression profiling in patients with chronic obstructive pulmonary disease and lung cancer. Am. J. Respir. Crit. Care Med. 177:402-411.
79. Ning, W., et al. 2004. Comprehensive gene expression profiles reveal pathways related to the pathogenesis of chronic obstructive pulmonary disease. Proc. Natl. Acad. Sci. U. S. A. 101:14895-14900.
80. Shao, M.X., and Nadel, J.A. 2005. Neutrophil elastase induces MUC5AC mucin production in human airway epithelial cells via a cascade involving protein kinase C, reactive oxygen species, and TNF-alpha-converting enzyme. J. Immunol. 175:4009-4016.
81. Takeyama, K., Fahy, J.V., and Nadel, J.A. 2001. Relationship of epidermal growth factor receptors to goblet cell production in human bronchi. Am. J. Respir. Crit. Care Med. 163:511-516.
82. de Boer, W.I., et al. 2006. Expression of epidermal growth factors and their receptors in the bronchial epithelium of subjects with chronic obstructive pulmonary disease. Am. J. Clin. Pathol. 125:184-192.
83. Siddiqui, S., et al. 2007. Vascular remodeling is a feature of asthma and nonasthmatic eosinophilic bronchitis. J. Allergy Clin. Immunol. 120:813-819.
84. Feltis, B.N., et al. 2006. Increased vascular endothelial growth factor and receptors: relationship to angiogenesis in asthma. Am. J. Respir.Crit. Care Med. 173:1201-1207.
85. Kanazawa, H., Asai, K., Hirata, K., and Yoshikawa, J. 2003. Possible effects of vascular endothelial growth factor in the pathogenesis of chronic obstructive pulmonary disease. Am. J. Med. 114:354-358.
86. Kasahara, Y., et al. 2000. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J. Clin. Invest. 106:1311-1319.
87. Lukacs, N.W., Hogaboam, C.M., and Kunkel, S.L. 2005. Chemokines and their receptors in chronic pulmonary disease. Curr. Drug Targets Inflamm. Allergy. 4:313-317.
88. Donnelly, L.E., and Barnes, P.J. 2006. Chemokine receptors as therapeutic targets in chronic obstructive pulmonary disease. Trends Pharmacol. Sci. 27:546-553.
89. de Boer, W.I., et al. 2000. Monocyte chemoattractant protein 1, interleukin 8, and chronic airways inflammation in COPD. J. Pathol. 190:619-626.
90. Traves, S.L., Culpitt, S., Russell, R.E.K., Barnes, P.J., and Donnelly, L.E. 2002. Elevated levels of the chemokines GRO-α and MCP-1 in sputum samples from COPD patients. Thorax. 57:590-595.
91. Ying, S., et al. 1999. Eosinophil chemotactic chemokines (eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein-3 (MCP-3), and MCP-4), and C-C chemokine receptor 3 expression in bronchial biopsies from atopic and nonatopic (Intrinsic) asthmatics. J. Immunol. 163:6321-6329.
92. Dorman, S.C., et al. 2005. Progenitor egress from the bone marrow after allergen challenge: role of stromal cell-derived factor 1alpha and eotaxin. J. Allergy Clin. Immunol. 115:501-507.
93. Ravensberg, A.J., et al. 2005. Eotaxin-2 and eotaxin-3 expression is associated with persistent eosinophilic bronchial inflammation in patients with asthma after allergen challenge. J. Allergy Clin. Immunol. 115:779-785.
94. Bocchino, V., et al. 2002. Eotaxin and CCR3 are up-regulated in exacerbations of chronic bronchitis. Allergy. 57:17-22.
95. Pilette, C., Francis, J.N., Till, S.J., and Durham, S.R. 2004. CCR4 ligands are up-regulated in the airways of atopic asthmatics after segmental allergen challenge. Eur. Respir. J. 23:876-884.
96. Di Stefano, A., et al. 2001. Decreased T lymphocyte infiltration in bronchial biopsies of subjects with severe chronic obstructive pulmonary disease. Clin. Exp. Allergy. 31:893-902.
97. Costa, C., et al. 2008. CXCR3 and CCR5 chemokines in the induced sputum from patients with COPD. Chest. 133:26-33.
98. Zhu, J., et al. 2001. Exacerbations of Bronchitis: bronchial eosinophilia and gene expression for interleukin-4, interleukin-5, and eosinophil chemoattractants. Am. J. Respir. Crit. Care Med. 164:109-116.
99. Berkman, N., et al. 1996. Expression of RANTES mRNA and protein in airways of patients with mild asthma. Am. J. Respir. Crit. Care Med. 154:1804-1811.
100. Qiu, Y., et al. 2003. Biopsy neutrophilia, chemokine and receptor gene expression in severe exacerbations of COPD. Am. J. Respir. Crit. Care Med. 168:968-975.
101. Hay, D.W.P., and Sarau, H.M. 2001. Interleukin-8 receptor antagonists in pulmonary diseases. Curr. Opin. Pharmacol. 1:242-247.
102. Jatakanon, A., et al. 1999. Neutrophilic inflammation in severe persistent asthma. Am. J. Respir. Crit. Care Med. 160:1532-1539.
103. Norzila, M.Z., Fakes, K., Henry, R.L., Simpson, J., and Gibson, P.G. 2000. Interleukin-8 secretion and neutrophil recruitment accompanies induced sputum eosinophil activation in children with acute asthma. Am. J. Respir. Crit. Care Med. 161:769-774.
104. Saetta, M., et al. 2002. Increased expression of the chemokine receptor CXCR3 and its ligand CXCL10 in peripheral airways of smokers with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 165:1404-1409.
105. Brightling, C.E., et al. 2005. The CXCL10/CXCR3 axis mediates human lung mast cell migration to asthmatic airway smooth muscle. Am. J. Respir. Crit. Care Med. 171:1103-1108.
106. Thomas, S.Y., Banerji, A., Medoff, B.D., Lilly, C.M., and Luster, A.D. 2007. Multiple chemokine receptors, including CCR6 and CXCR3, regulate antigen-induced T cell homing to the human asthmatic airway. J. Immunol. 179:1901-1912.
107. Xanthou, G., Duchesnes, C.E., Williams, T.J., and Pease, J.E. 2003. CCR3 functional responses are regulated by both CXCR3 and its ligands CXCL9, CXCL10 and CXCL11. Eur. J. Immunol. 33:2241-2250.
108. Lukacs, N.W., Berlin, A., Schols, D., Skerlj, R.T., and Bridger, G.J. 2002. AMD3100, a CxCR4 antagonist, attenuates allergic lung inflammation and airway hyperreactivity. Am. J. Pathol. 160:1353-1360.
109. Sukkar, M.B., et al. 2004. Fractalkine/CX3CL1 production by human airway smooth muscle cells: induction by IFN-gamma and TNF-alpha and regulation by TGF-beta and corticosteroids. Am. J. Physiol. Lung Cell Mol. Physiol. 287:L1230-L1240.
110. El Shazly, A., et al. 2006. Fraktalkine produced by airway smooth muscle cells contributes to mast cell recruitment in asthma. J. Immunol. 176:1860-1868.
111. Rimaniol, A.C., et al. 2003. The CX3C chemokine fractalkine in allergic asthma and rhinitis. J. Allergy Clin. Immunol. 112:1139-1146.
112. Pretolani, M., and Goldman, M. 1997. IL-10: a potential therapy for allergic inflammation? Immunol. Today. 18:277-280.
113. John, M., et al. 1998. Inhaled corticosteroids increase IL-10 but reduce MIP-1α, GM-CSF and IFN-g release from alveolar macrophages in asthma. Am. J. Respir. Crit. Care Med. 157:256-262.
114. Hawrylowicz, C.M. 2005. Regulatory T cells and IL-10 in allergic inflammation. J. Exp. Med. 202:1459-1463.
115. Bohle, B., et al. 2007. Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specific T-cell tolerance, and immune deviation. J. Allergy Clin. Immunol. 120:707-713.
116. Takanashi, S., et al. 1999. Interleukin-10 level in sputum is reduced in bronchial asthma, COPD and in smokers. Eur. Respir. J. 14:309-314.
117. Barnes, P.J. 2003. Cytokine-directed therapies for the treatment of chronic airway diseases. Cytokine Growth Factor Rev. 14:511-522.
118. Gauvreau, G.M., et al. 2008. Antisense therapy against CCR3 and the common beta chain attenuates allergen-induced eosinophilic responses. Am. J. Respir. Crit. Care Med. 177:952-958.
119. Barnes, P.J. 2006. How corticosteroids control inflammation. Br. J. Pharmacol. 148:245-254.
120. Rolfe, F.G., Valentine, J.E., and Sewell, W.A. 1997. Cyclosporin A and FK506 reduce interleukin-5 mRNA abundance by inhibiting gene transcription. Am. J. Respir. Cell Mol. Biol. 17:243-250.
121. Chung, K.F. 2006. Phosphodiesterase inhibitors in airways disease. Eur. J. Pharmacol. 533:110-117.
122. Barnes, P.J. 2006. Novel signal transduction modulators for the treatment of airway diseases. Pharmacol. Ther. 109:238-245.
123. Birrell, M.A., et al. 2006. IkappaB kinase-2-independent and -dependent inflammation in airway disease models: relevance of IKK-2 inhibition to the clinic. Mol. Pharmacol. 69:1791-1800.
124. Smith, S.J., et al. 2006. Inhibitory effect of p38 mitogen-activated protein kinase inhibitors on cytokine release from human macrophages. Br. J. Pharmacol. 149:393-404.
125. Medicherla, S., et al. 2007. p38? selective MAP kinase inhibitor, SD-282, reduces inflammation in a sub-chronic model of tobacco smoke-induced airway inf lammation. J. Pharmacol. Exp.Ther. 324:921-929.
126. Gram, H., and Di Padova, F.E. 2008. Antibodies to human IL-1 beta. European Patent EP1313769, filed August 20, 2001, and issued May 21, 2008. http://www.freepatentsonline.com/EP1313769.html.
127. Moseley, B., et al. 1998. Use of interleukin-4 receptors to inhibit biological responses mediated by interleukin-4. US Patent 5767065, filed June 6, 1995, and issued June 16, 1998. http://www.patentstorm.us/patents/5767065/ claims.html.
128. Hart, T.K., et al. 2002. Preclinical efficacy and safety of pascolizumab (SB 240683): a humanized anti-interleukin-4 antibody with therapeutic potential in asthma. Clin. Exp. Immunol. 130:93-100.
129. Wilkinson, M. 2007 July 24. MedImmune's antibody gives hope to asthma sufferers. DrugResearcher.com. http://www.drugresearcher.com/news/ng.asp?id= 78451.
130. Roche. 2005 November 17. Actemra monotherapy significantly slows down damage to joints in patients with early aggressive rheumatoid arthritis. Roche media news. http://www.roche.com/med-cor-2005-11-17.
131. PR Newswire. 2007 August 19. Phase 2a multi-dose study initiated by MedImmune in patients with asthma to further expand anti-interleukin-9 program. Bio-Medicine.org. http://www.bio-medicine.org/medicine-technology-1/Phase-2a- Multi-Dose-Study-Initiated-by-MedImmune-in-Patients-With-Asthma-to-Further- Expand-Anti-Interleukin-9-Program-95-1/.
132. MedImmune. CAT-354. http://www.cambridgeantibody.com/home/products/ cambridge_derived_products/cat354.
133. Henderson, L., Weintraub, B., and Martin, C. 2002. Abgenix cancels development of its anti-IL8 monoclonal antibody. Btech Investor, Inc. http://www.bioportfolio.com/news/btech_051502_1.htm.
134. Sharpless, A.P. 2007 September 25. Pharmacopeia earns milestone payment from Schering-Plough on initiation of Phase 1 clinical trials of novel therapeutic candidate [press release]. Princeton, New Jersey, USA. http://www.pharmacopeia.com/wt/page/press/pr_1190725994.