Skip to main content
SpringerLink
Log in

Specific Therapies for Asthma Endotypes: A New Twist in Drug Development

  • Chapter
  • First Online:
Allergy Prevention and Exacerbation

Part of the book series: Birkhäuser Advances in Infectious Diseases ((BAID))

  • 537 Accesses

Abstract

Asthma is a heterogeneous disease mainly affecting the lower airways and hallmarked by a chronic lung tissue inflammation that is strongly influenced by environmental and immunological factors. In a subgroup of asthmatics, respiratory infections are associated with the development of chronic disease and more frequent inflammatory exacerbations. Nevertheless, patients suffering from different asthma subgroups are treated with mainly non-specific and symptom-related using anti-inflammatory drugs and bronchodilators. Therefore, it is of great importance to define molecular patterns of asthma and allergy as basis for endotype definitions, rather than using clinical disease phenotypes. In addition, a number of factors can contribute to poor responses, while underlying patho-biological differences are increasingly recognized to play a role. These factors include novel biomarkers as well as well-known pathways but also consideration of the influence of the airway microbiome. With respect to this, specific drugs are developed targeting cellular components (e.g. eosinophils, neutrophils, Th9 cells) or specific mediators (e.g. IgE, FceR, IL5, TSLP) but also key regulators such as GATA3. In addition, also viral-induced asthma is attracting notice and development of anti-viral therapy strategies are promoted.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ACQ:

Asthma control questionnaire

BHR:

Bronchial hyperresponsiveness

CCL:

CC-chemokine ligand

CD:

Cluster of differentiation

CLCA1:

Calcium-activated chloride channel protein 1

FcεRI:

High-affinity IgE receptor I

FDA:

US Food and Drug Administration

FeNO:

Fraction of exhaled nitric oxide

FEV1:

Volume of air expelled in the first second of a forced expiration

huMAb:

Humanized monoclonal antibody

ICS:

Inhaled corticosteroids

Ig:

Immunoglobulin

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

LABA:

Long acting beta2 agonist

LPS:

Lipopolysaccharide

mAb:

Monoclonal antibody

OCS:

Oral corticosteroid

POSTN:

Periostin

RSV:

Respiratory syncytial virus

Th:

T helper

TSLP:

Thymic stromal lymphopoietin

References

  • Aho VT, Pereira PA, Haahtela T, Pawankar R, Auvinen P, Koskinen K (2015) The microbiome of the human lower airways: a next generation sequencing perspective. World Allergy Organ J 8(1):23. https://doi.org/10.1186/s40413-015-0074-z

    Article  PubMed  CAS  Google Scholar 

  • Allakhverdi Z, Comeau MR, Jessup HK, Yoon BR, Brewer A, Chartier S, Paquette N, Ziegler SF, Sarfati M, Delespesse G (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(2):253–258. https://doi.org/10.1084/jem.20062211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Amelink M, de Groot JC, de Nijs SB, Lutter R, Zwinderman AH, Sterk PJ, ten Brinke A, Bel EH (2013) Severe adult-onset asthma: a distinct phenotype. J Allergy Clin Immunol 132(2):336–341. https://doi.org/10.1016/j.jaci.2013.04.052

    Article  PubMed  Google Scholar 

  • Anderson GP (2008) Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet 372(9643):1107–1119. https://doi.org/10.1016/S0140-6736(08)61452-X

    Article  PubMed  Google Scholar 

  • Antoniu SA (2010) MEDI-528, an anti-IL-9 humanized antibody for the treatment of asthma. Curr Opin Mol Ther 12(2):233–239

    CAS  PubMed  Google Scholar 

  • Aron JL, Akbari O (2017) Regulatory T cells and type 2 innate lymphoid cell dependent asthma. Allergy 72(8):1148–1155. https://doi.org/10.1111/all.13139

    Article  CAS  PubMed  Google Scholar 

  • Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, Ortega HG, Pavord ID, Investigators S (2014) Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 371(13):1189–1197. https://doi.org/10.1056/NEJMoa1403291

    Article  PubMed  CAS  Google Scholar 

  • Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, Green RH, Bradding P, Brightling CE, Wardlaw AJ, Pavord ID (2006) Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 354(7):697–708. https://doi.org/10.1056/NEJMoa050580

    Article  CAS  PubMed  Google Scholar 

  • Billington CK, Penn RB, Hall IP (2016) beta2 agonists. Handb Exp Pharmacol 237:23–40. https://doi.org/10.1007/164_2016_64

    Article  Google Scholar 

  • De Boever EH, Ashman C, Cahn AP, Locantore NW, Overend P, Pouliquen IJ, Serone AP, Wright TJ, Jenkins MM, Panesar IS, Thiagarajah SS, Wenzel SE (2014) Efficacy and safety of an anti-IL-13 mAb in patients with severe asthma: a randomized trial. J Allergy Clin Immunol 133(4):989–996. doi:https://doi.org/10.1016/j.jaci.2014.01.002

  • Borish LC, Nelson HS, Lanz MJ, Claussen L, Whitmore JB, Agosti JM, Garrison L (1999) 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. https://doi.org/10.1164/ajrccm.160.6.9808146

    Article  CAS  PubMed  Google Scholar 

  • Borish LC, Nelson HS, Corren J, Bensch G, Busse WW, Whitmore JB, Agosti JM, IL-4R Asthma Study Group (2001) Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol 107(6):963–970. https://doi.org/10.1067/mai.2001.115624

    Article  CAS  PubMed  Google Scholar 

  • Boulet LP, Chapman KR, Cote J, Kalra S, Bhagat R, Swystun VA, Laviolette M, Cleland LD, Deschesnes F, Su JQ, DeVault A, Fick RB Jr, Cockcroft DW (1997) Inhibitory effects of an anti-IgE antibody E25 on allergen-induced early asthmatic response. Am J Respir Crit Care Med 155(6):1835–1840. https://doi.org/10.1164/ajrccm.155.6.9196083

    Article  CAS  PubMed  Google Scholar 

  • Braman SS (2006) The global burden of asthma. Chest 130(1 Suppl):4S–12S. https://doi.org/10.1378/chest.130.1_suppl.4S

    Article  PubMed  Google Scholar 

  • Brown HM (1958) Treatment of chronic asthma with prednisolone; significance of eosinophils in the sputum. Lancet 2(7059):1245–1247

    Article  CAS  PubMed  Google Scholar 

  • Brusselle G, Kips J, Joos G, Bluethmann H, Pauwels R (1995) Allergen-induced airway inflammation and bronchial responsiveness in wild-type and interleukin-4-deficient mice. Am J Respir Cell Mol Biol 12(3):254–259. https://doi.org/10.1165/ajrcmb.12.3.7873190

    Article  CAS  PubMed  Google Scholar 

  • Busse W, Corren J, Lanier BQ, McAlary M, Fowler-Taylor A, Cioppa GD, van As A, Gupta N (2001) Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 108(2):184–190. https://doi.org/10.1067/mai.2001.117880

    Article  CAS  PubMed  Google Scholar 

  • Busse WW, Israel E, Nelson HS, Baker JW, Charous BL, Young DY, Vexler V, Shames RS, Daclizumab Asthma Study Group (2008) 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. https://doi.org/10.1164/rccm.200708-1200OC

    Article  CAS  PubMed  Google Scholar 

  • Busse WW, Morgan WJ, Gergen PJ, Mitchell HE, Gern JE, Liu AH, Gruchalla RS, Kattan M, Teach SJ, Pongracic JA, Chmiel JF, Steinbach SF, Calatroni A, Togias A, Thompson KM, Szefler SJ, Sorkness CA (2011) Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med 364(11):1005–1015. https://doi.org/10.1056/NEJMoa1009705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Busse WW, Holgate S, Kerwin E, Chon Y, Feng J, Lin J, Lin SL (2013) Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med 188(11):1294–1302. https://doi.org/10.1164/rccm.201212-2318OC

    Article  CAS  PubMed  Google Scholar 

  • Castro M, Mathur S, Hargreave F, Boulet LP, Xie F, Young J, Wilkins HJ, Henkel T, Nair P, Res-5-0010 Study Group (2011) Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med 184(10):1125–1132. https://doi.org/10.1164/rccm.201103-0396OC

    Article  CAS  PubMed  Google Scholar 

  • Castro M, Wenzel SE, Bleecker ER, Pizzichini E, Kuna P, Busse WW, Gossage DL, Ward CK, Wu Y, Wang B, Khatry DB, van der Merwe R, Kolbeck R, Molfino NA, Raible DG (2014) Benralizumab, an anti-interleukin 5 receptor alpha monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med 2(11):879–890. https://doi.org/10.1016/S2213-2600(14)70201-2

    Article  CAS  PubMed  Google Scholar 

  • Chibana K, Trudeau JB, Mustovich AT, Hu H, Zhao J, Balzar S, Chu HW, Wenzel SE (2008) IL-13 induced increases in nitrite levels are primarily driven by increases in inducible nitric oxide synthase as compared with effects on arginases in human primary bronchial epithelial cells. Clin Exp Allergy 38(6):936–946. https://doi.org/10.1111/j.1365-2222.2008.02969.x

    Article  CAS  PubMed  Google Scholar 

  • Clutterbuck EJ, Hirst EM, Sanderson CJ (1989) 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

    CAS  PubMed  Google Scholar 

  • Corren J, Busse W, Meltzer EO, Mansfield L, Bensch G, Fahrenholz J, Wenzel SE, Chon Y, Dunn M, Weng HH, Lin SL (2010) A randomized, controlled, phase 2 study of AMG 317, an IL-4Ralpha antagonist, in patients with asthma. Am J Respir Crit Care Med 181(8):788–796. https://doi.org/10.1164/rccm.200909-1448OC

    Article  CAS  PubMed  Google Scholar 

  • Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, Harris JM, Scheerens H, Wu LC, Su Z, Mosesova S, Eisner MD, Bohen SP, Matthews JG (2011a) Lebrikizumab treatment in adults with asthma. N Engl J Med 365(12):1088–1098. https://doi.org/10.1056/NEJMoa1106469

    Article  CAS  PubMed  Google Scholar 

  • Corren J, Wood RA, Patel D, Zhu J, Yegin A, Dhillon G, Fish JE (2011b) Effects of omalizumab on changes in pulmonary function induced by controlled cat room challenge. J Allergy Clin Immunol 127(2):398–405. https://doi.org/10.1016/j.jaci.2010.09.043

    Article  CAS  PubMed  Google Scholar 

  • Depner M, Ege MJ, Cox MJ, Dwyer S, Walker AW, Birzele LT, Genuneit J, Horak E, Braun-Fahrlander C, Danielewicz H, Maier RM, Moffatt MF, Cookson WO, Heederik D, von Mutius E, Legatzki A (2017) Bacterial microbiota of the upper respiratory tract and childhood asthma. J Allergy Clin Immunol 139(3):826–834. e813. https://doi.org/10.1016/j.jaci.2016.05.050

    Article  PubMed  Google Scholar 

  • Dixon AE, Pratley RE, Forgione PM, Kaminsky DA, Whittaker-Leclair LA, Griffes LA, Garudathri J, Raymond D, Poynter ME, Bunn JY, Irvin CG (2011) Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation. J Allergy Clin Immunol 128(3):508–515.e501–502. doi:https://doi.org/10.1016/j.jaci.2011.06.009

  • Dweik RA, Sorkness RL, Wenzel S, Hammel J, Curran-Everett D, Comhair SA, Bleecker E, Busse W, Calhoun WJ, Castro M, Chung KF, Israel E, Jarjour N, Moore W, Peters S, Teague G, Gaston B, Erzurum SC, National Heart, Lung, and Blood Institute Severe Asthma Research Program (2010) Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit Care Med 181(10):1033–1041. https://doi.org/10.1164/rccm.200905-0695OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Erin EM, Leaker BR, Nicholson GC, Tan AJ, Green LM, Neighbour H, Zacharasiewicz AS, Turner J, Barnathan ES, Kon OM, Barnes PJ, Hansel TT (2006) The effects of a monoclonal antibody directed against tumor necrosis factor-alpha in asthma. Am J Respir Crit Care Med 174(7):753–762. https://doi.org/10.1164/rccm.200601-072OC

    Article  CAS  PubMed  Google Scholar 

  • Fahy JV, Fleming HE, Wong HH, Liu JT, Su JQ, Reimann J, Fick RB Jr, Boushey HA (1997) The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am J Respir Crit Care Med 155(6):1828–1834. https://doi.org/10.1164/ajrccm.155.6.9196082

    Article  CAS  PubMed  Google Scholar 

  • FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, Ferguson GT, Busse WW, Barker P, Sproule S, Gilmartin G, Werkstrom V, Aurivillius M, Goldman M, CALIMA Study Investigators (2016) Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 388(10056):2128–2141. https://doi.org/10.1016/S0140-6736(16)31322-8

    Article  CAS  PubMed  Google Scholar 

  • Fitzpatrick AM, Teague WG, Meyers DA, Peters SP, Li X, Li H, Wenzel SE, Aujla S, Castro M, Bacharier LB, Gaston BM, Bleecker ER, Moore WC, National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program (2011) Heterogeneity of severe asthma in childhood: confirmation by cluster analysis of children in the National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program. J Allergy Clin Immunol 127(2):382–389.e381–313. doi:https://doi.org/10.1016/j.jaci.2010.11.015

  • Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS (2003) 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. https://doi.org/10.1164/rccm.200208-789OC

    Article  PubMed  Google Scholar 

  • Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, Robinson D, Wenzel S, Busse W, Hansel TT, Barnes NC, International Mepolizumab Study Group (2007) 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. https://doi.org/10.1164/rccm.200701-085OC

    Article  CAS  PubMed  Google Scholar 

  • Galli SJ, Tsai M (2012) IgE and mast cells in allergic disease. Nat Med 18(5):693–704. https://doi.org/10.1038/nm.2755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gauvreau GM, Boulet LP, Cockcroft DW, Fitzgerald JM, Carlsten C, Davis BE, Deschesnes F, Duong M, Durn BL, Howie KJ, Hui L, Kasaian MT, Killian KJ, Strinich TX, Watson RM, Nathalie Y, Zhou S, Raible D, O’Byrne PM (2011) Effects of interleukin-13 blockade on allergen-induced airway responses in mild atopic asthma. Am J Respir Crit Care Med 183(8):1007–1014. https://doi.org/10.1164/rccm.201008-1210OC

    Article  CAS  PubMed  Google Scholar 

  • Gauvreau GM, Boulet LP, Cockcroft DW, FitzGerald JM, Mayers I, Carlsten C, Laviolette M, Killian KJ, Davis BE, Larche M, Kipling C, Dua B, Mosesova S, Putnam W, Zheng Y, Scheerens H, McClintock D, Matthews JG, O’Byrne PM (2014a) OX40L blockade and allergen-induced airway responses in subjects with mild asthma. Clin Exp Allergy 44(1):29–37. https://doi.org/10.1111/cea.12235

    Article  CAS  PubMed  Google Scholar 

  • Gauvreau GM, O’Byrne PM, Boulet LP, Wang Y, Cockcroft D, Bigler J, FitzGerald JM, Boedigheimer M, Davis BE, Dias C, Gorski KS, Smith L, Bautista E, Comeau MR, Leigh R, Parnes JR (2014b) Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med 370(22):2102–2110. https://doi.org/10.1056/NEJMoa1402895

    Article  PubMed  CAS  Google Scholar 

  • Gauvreau GM, Arm JP, Boulet LP, Leigh R, Cockcroft DW, Davis BE, Mayers I, FitzGerald JM, Dahlen B, Killian KJ, Laviolette M, Carlsten C, Lazarinis N, Watson RM, Milot J, Swystun V, Bowen M, Hui L, Lantz AS, Meiser K, Maahs S, Lowe PJ, Skerjanec A, Drollmann A, O’Byrne PM (2016) Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early asthmatic responses. J Allergy Clin Immunol 138(4):1051–1059. https://doi.org/10.1016/j.jaci.2016.02.027

    Article  CAS  PubMed  Google Scholar 

  • Grunig G, Warnock M, Wakil AE, Venkayya R, Brombacher F, Rennick DM, Sheppard D, Mohrs M, Donaldson DD, Locksley RM, Corry DB (1998) Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282(5397):2261–2263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, Wardlaw AJ, Green RH (2008) Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 178(3):218–224. https://doi.org/10.1164/rccm.200711-1754OC

    Article  PubMed  PubMed Central  Google Scholar 

  • Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall RP, Bradding P, Green RH, Wardlaw AJ, Pavord ID (2009) Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 360(10):973–984. https://doi.org/10.1056/NEJMoa0808991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanania NA, Alpan O, Hamilos DL, Condemi JJ, Reyes-Rivera I, Zhu J, Rosen KE, Eisner MD, Wong DA, Busse W (2011) Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med 154(9):573–582. https://doi.org/10.7326/0003-4819-154-9-201105030-00002

    Article  PubMed  Google Scholar 

  • Hanania NA, Wenzel S, Rosen K, Hsieh HJ, Mosesova S, Choy DF, Lal P, Arron JR, Harris JM, Busse W (2013) Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med 187(8):804–811. https://doi.org/10.1164/rccm.201208-1414OC

    Article  CAS  PubMed  Google Scholar 

  • Hanania NA, Korenblat P, Chapman KR, Bateman ED, Kopecky P, Paggiaro P, Yokoyama A, Olsson J, Gray S, Holweg CT, Eisner M, Asare C, Fischer SK, Peng K, Putnam WS, Matthews JG (2016) Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir Med 4(10):781–796. https://doi.org/10.1016/S2213-2600(16)30265-X

    Article  CAS  PubMed  Google Scholar 

  • Harris JM, Maciuca R, Bradley MS, Cabanski CR, Scheerens H, Lim J, Cai F, Kishnani M, Liao XC, Samineni D, Zhu R, Cochran C, Soong W, Diaz JD, Perin P, Tsukayama M, Dimov D, Agache I, Kelsen SG (2016) A randomized trial of the efficacy and safety of quilizumab in adults with inadequately controlled allergic asthma. Respir Res 17:29. https://doi.org/10.1186/s12931-016-0347-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hastie AT, Moore WC, Meyers DA, Vestal PL, Li H, Peters SP, Bleecker ER, National Heart, Lung, Blood Institute Severe Asthma Research Program (2010) Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J Allergy Clin Immunol 125(5):1028–1036. e1013. https://doi.org/10.1016/j.jaci.2010.02.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holgate ST, Chuchalin AG, Hebert J, Lotvall J, Persson GB, Chung KF, Bousquet J, Kerstjens HA, Fox H, Thirlwell J, Cioppa GD, Omalizumab 011 International Study Group (2004) Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma. Clin Exp Allergy 34(4):632–638. https://doi.org/10.1111/j.1365-2222.2004.1916.x

    Article  CAS  PubMed  Google Scholar 

  • Homburg U, Renz H, Timmer W, Hohlfeld JM, Seitz F, Luer K, Mayer A, Wacker A, Schmidt O, Kuhlmann J, Turowska A, Roller J, Kutz K, Schluter G, Krug N, Garn H (2015) Safety and tolerability of a novel inhaled GATA3 mRNA targeting DNAzyme in patients with TH2-driven asthma. J Allergy Clin Immunol 136(3):797–800. https://doi.org/10.1016/j.jaci.2015.02.018

    Article  CAS  PubMed  Google Scholar 

  • Hooper LV, Littman DR, Macpherson AJ (2012) Interactions between the microbiota and the immune system. Science 336(6086):1268–1273. https://doi.org/10.1126/science.1223490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Howarth PH, Babu KS, Arshad HS, Lau L, Buckley M, McConnell W, Beckett P, Al Ali M, Chauhan A, Wilson SJ, Reynolds A, Davies DE, Holgate ST (2005) Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 60(12):1012–1018. https://doi.org/10.1136/thx.2005.045260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Humbert M, Beasley R, Ayres J, Slavin R, Hebert J, Bousquet J, Beeh KM, Ramos S, Canonica GW, Hedgecock S, Fox H, Blogg M, Surrey K (2005) Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 60(3):309–316. https://doi.org/10.1111/j.1398-9995.2004.00772.x

    Article  CAS  PubMed  Google Scholar 

  • Iida S, Misaka H, Inoue M, Shibata M, Nakano R, Yamane-Ohnuki N, Wakitani M, Yano K, Shitara K, Satoh M (2006) Nonfucosylated therapeutic IgG1 antibody can evade the inhibitory effect of serum immunoglobulin G on antibody-dependent cellular cytotoxicity through its high binding to FcgammaRIIIa. Clin Cancer Res 12(9):2879–2887. https://doi.org/10.1158/1078-0432.CCR-05-2619

    Article  CAS  PubMed  Google Scholar 

  • Jatakanon A, Uasuf C, Maziak W, Lim S, Chung KF, Barnes PJ (1999) Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med 160(5 Pt 1):1532–1539. https://doi.org/10.1164/ajrccm.160.5.9806170

    Article  CAS  PubMed  Google Scholar 

  • Jia G, Erickson RW, Choy DF, Mosesova S, Wu LC, Solberg OD, Shikotra A, Carter R, Audusseau S, Hamid Q, Bradding P, Fahy JV, Woodruff PG, Harris JM, Arron JR, Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma Study Group (2012) Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol 130 (3):647-654.e610. doi:https://doi.org/10.1016/j.jaci.2012.06.025

  • Kips JC, Tavernier J, Pauwels RA (1992) Tumor necrosis factor causes bronchial hyperresponsiveness in rats. Am Rev Respir Dis 145(2 Pt 1):332–336. https://doi.org/10.1164/ajrccm/145.2_Pt_1.332

    Article  CAS  PubMed  Google Scholar 

  • Kolbeck R, Kozhich A, Koike M, Peng L, Andersson CK, Damschroder MM, Reed JL, Woods R, Dall’acqua WW, Stephens GL, Erjefalt JS, Bjermer L, Humbles AA, Gossage D, Wu H, Kiener PA, Spitalny GL, Mackay CR, Molfino NA, Coyle AJ (2010) MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol 125(6):1344–1353. e1342. https://doi.org/10.1016/j.jaci.2010.04.004

    Article  CAS  PubMed  Google Scholar 

  • Kolwijck E, van de Veerdonk FL (2014) The potential impact of the pulmonary microbiome on immunopathogenesis of Aspergillus-related lung disease. Eur J Immunol 44(11):3156–3165. https://doi.org/10.1002/eji.201344404

    Article  CAS  PubMed  Google Scholar 

  • Krug N, Hohlfeld JM, Kirsten AM, Kornmann O, Beeh KM, Kappeler D, Korn S, Ignatenko S, Timmer W, Rogon C, Zeitvogel J, Zhang N, Bille J, Homburg U, Turowska A, Bachert C, Werfel T, Buhl R, Renz J, Garn H, Renz H (2015) Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N Engl J Med 372(21):1987–1995. https://doi.org/10.1056/NEJMoa1411776

    Article  PubMed  Google Scholar 

  • Lanier B, Bridges T, Kulus M, Taylor AF, Berhane I, Vidaurre CF (2009) Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. J Allergy Clin Immunol 124(6):1210–1216. https://doi.org/10.1016/j.jaci.2009.09.021

    Article  CAS  PubMed  Google Scholar 

  • Laviolette M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R, Katial R, Busse WW, Wenzel S, Wu Y, Datta V, Kolbeck R, Molfino NA (2013) Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol 132 (5):1086-1096.e1085. doi:https://doi.org/10.1016/j.jaci.2013.05.020

  • Leckie MJ, ten Brinke A, Khan J, Diamant Z, O’Connor BJ, Walls CM, Mathur AK, Cowley HC, Chung KF, Djukanovic R, Hansel TT, Holgate ST, Sterk PJ, Barnes PJ (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356(9248):2144–2148

    Article  CAS  PubMed  Google Scholar 

  • Leung E, Al Efraij K, FitzGerald JM (2017) The safety of mepolizumab for the treatment of asthma. Expert Opin Drug Saf:1–8. https://doi.org/10.1080/14740338.2017.1286327

  • Lin TH, Cheng CC, Su HH, Huang NC, Chen JJ, Kang HY, Chang TH (2016) Lipopolysaccharide attenuates induction of proallergic cytokines, thymic stromal lymphopoietin, and interleukin 33 in respiratory epithelial cells stimulated with PolyI:C and human parechovirus. Front Immunol 7:440. https://doi.org/10.3389/fimmu.2016.00440

    PubMed  PubMed Central  Google Scholar 

  • Lotvall J, Akdis CA, Bacharier LB, Bjermer L, Casale TB, Custovic A, Lemanske RF Jr, Wardlaw AJ, Wenzel SE, Greenberger PA (2011) Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 127(2):355–360. https://doi.org/10.1016/j.jaci.2010.11.037

    Article  PubMed  Google Scholar 

  • Mansbach JM, Hasegawa K, Henke DM, Ajami NJ, Petrosino JF, Shaw CA, Piedra PA, Sullivan AF, Espinola JA, Camargo CA, Jr (2016) Respiratory syncytial virus and rhinovirus severe bronchiolitis are associated with distinct nasopharyngeal microbiota. J Allergy Clin Immunol 137 (6):1909-1913.e1904. doi:https://doi.org/10.1016/j.jaci.2016.01.036

  • Marsland BJ (2013) Influences of the microbiome on the early origins of allergic asthma. Ann Am Thorac Soc 10(Suppl):S165–S169. https://doi.org/10.1513/AnnalsATS.201305-118AW

    Article  PubMed  Google Scholar 

  • Marsland BJ, Gollwitzer ES (2014) Host-microorganism interactions in lung diseases. Nat Rev Immunol 14(12):827–835. https://doi.org/10.1038/nri3769

    Article  CAS  PubMed  Google Scholar 

  • Martinez-Gonzalez I, Steer CA, Takei F (2015) Lung ILC2s link innate and adaptive responses in allergic inflammation. Trends Immunol 36(3):189–195. https://doi.org/10.1016/j.it.2015.01.005

    Article  CAS  PubMed  Google Scholar 

  • Massoud AH, Charbonnier LM, Lopez D, Pellegrini M, Phipatanakul W, Chatila TA (2016) An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells. Nat Med 22(9):1013–1022. https://doi.org/10.1038/nm.4147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McGrath KW, Icitovic N, Boushey HA, Lazarus SC, Sutherland ER, Chinchilli VM, Fahy JV, Asthma Clinical Research Network of the National Heart, Lung, Blood Institute (2012) A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med 185(6):612–619. https://doi.org/10.1164/rccm.201109-1640OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Milgrom H, Fick RB Jr, Su JQ, Reimann JD, Bush RK, Watrous ML, Metzger WJ (1999) Treatment of allergic asthma with monoclonal anti-IgE antibody. rhuMAb-E25 Study Group. N Engl J Med 341(26):1966–1973. https://doi.org/10.1056/NEJM199912233412603

    Article  CAS  PubMed  Google Scholar 

  • Milgrom H, Berger W, Nayak A, Gupta N, Pollard S, McAlary M, Taylor AF, Rohane P (2001) Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics 108(2):E36

    Article  CAS  PubMed  Google Scholar 

  • Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel SE (2004) Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol 113(1):101–108. https://doi.org/10.1016/j.jaci.2003.10.041

    Article  PubMed  Google Scholar 

  • Mochizuki H, Kusuda S, Okada K, Yoshihara S, Furuya H, Simoes EA (2017) Palivizumab prophylaxis in preterm infants and subsequent recurrent wheezing: 6 year follow up study. Am J Respir Crit Care Med 196(1):–29, 38. https://doi.org/10.1164/rccm.201609-1812OC

  • Modena BD, Tedrow JR, Milosevic J, Bleecker ER, Meyers DA, Wu W, Bar-Joseph Z, Erzurum SC, Gaston BM, Busse WW, Jarjour NN, Kaminski N, Wenzel SE (2014) Gene expression in relation to exhaled nitric oxide identifies novel asthma phenotypes with unique biomolecular pathways. Am J Respir Crit Care Med 190(12):1363–1372. https://doi.org/10.1164/rccm.201406-1099OC

    Article  PubMed  PubMed Central  Google Scholar 

  • Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, D’Agostino R Jr, Castro M, Curran-Everett D, Fitzpatrick AM, Gaston B, Jarjour NN, Sorkness R, Calhoun WJ, Chung KF, Comhair SA, Dweik RA, Israel E, Peters SP, Busse WW, Erzurum SC, Bleecker ER, National Heart, Lung, Blood Institute’s Severe Asthma Research Program (2010) Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 181(4):315–323. https://doi.org/10.1164/rccm.200906-0896OC

    Article  PubMed  Google Scholar 

  • Moore WC, Hastie AT, Li X, Li H, Busse WW, Jarjour NN, Wenzel SE, Peters SP, Meyers DA, Bleecker ER, National Heart, Lung, and Blood Institute’s Severe Asthma Research Program (2014) Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol 133(6):1557–1563.e1555. https://doi.org/10.1016/j.jaci.2013.10.011

    Article  PubMed  Google Scholar 

  • Morjaria JB, Chauhan AJ, Babu KS, Polosa R, Davies DE, Holgate ST (2008) The role of a soluble TNFalpha receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax 63(7):584–591. https://doi.org/10.1136/thx.2007.086314

    Article  CAS  PubMed  Google Scholar 

  • Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, Hargreave FE, O’Byrne PM (2009) Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 360(10):985–993. https://doi.org/10.1056/NEJMoa0805435

    Article  CAS  PubMed  Google Scholar 

  • Nair P, Gaga M, Zervas E, Alagha K, Hargreave FE, O’Byrne PM, Stryszak P, Gann L, Sadeh J, Chanez P, Study Investigators (2012) Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. Clin Exp Allergy 42(7):1097–1103. https://doi.org/10.1111/j.1365-2222.2012.04014.x

    Article  CAS  PubMed  Google Scholar 

  • National Asthma Education and Prevention Program (2007) Expert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma-summary report 2007. J Allergy Clin Immunol 120(5 Suppl):S94–138. https://doi.org/10.1016/j.jaci.2007.09.043

    Google Scholar 

  • Ober C, Yao TC (2011) The genetics of asthma and allergic disease: a 21st century perspective. Immunol Rev 242(1):10–30. https://doi.org/10.1111/j.1600-065X.2011.01029.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oh CK, Leigh R, McLaurin KK, Kim K, Hultquist M, Molfino NA (2013) A randomized, controlled trial to evaluate the effect of an anti-interleukin-9 monoclonal antibody in adults with uncontrolled asthma. Respir Res 14:93. https://doi.org/10.1186/1465-9921-14-93

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ortega HG, Yancey SW, Mayer B, Gunsoy NB, Keene ON, Bleecker ER, Brightling CE, Pavord ID (2016) Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med 4(7):549–556. https://doi.org/10.1016/S2213-2600(16)30031-5

    Article  CAS  PubMed  Google Scholar 

  • Parker JM, Oh CK, LaForce C, Miller SD, Pearlman DS, Le C, Robbie GJ, White WI, White B, Molfino NA, MEDI-528 Clinical Trials Group (2011) 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 with asthma. BMC Pulm Med 11:14. https://doi.org/10.1186/1471-2466-11-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pavord ID, Brightling CE, Woltmann G, Wardlaw AJ (1999) Non-eosinophilic corticosteroid unresponsive asthma. Lancet 353(9171):2213–2214. https://doi.org/10.1016/S0140-6736(99)01813-9

    Article  CAS  PubMed  Google Scholar 

  • Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, Ortega H, Chanez P (2012) Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 380(9842):651–659. https://doi.org/10.1016/S0140-6736(12)60988-X

    Article  CAS  PubMed  Google Scholar 

  • Piper E, Brightling C, Niven R, Oh C, Faggioni R, Poon K, She D, Kell C, May RD, Geba GP, Molfino NA (2013) A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J 41(2):330–338. https://doi.org/10.1183/09031936.00223411

    Article  CAS  PubMed  Google Scholar 

  • Prazma CM, Wenzel S, Barnes N, Douglass JA, Hartley BF, Ortega H (2014) Characterisation of an OCS-dependent severe asthma population treated with mepolizumab. Thorax 69(12):1141–1142. https://doi.org/10.1136/thoraxjnl-2014-205581

    Article  CAS  PubMed  Google Scholar 

  • Queen C, Schneider WP, Selick HE, Payne PW, Landolfi NF, Duncan JF, Avdalovic NM, Levitt M, Junghans RP, Waldmann TA (1989) A humanized antibody that binds to the interleukin 2 receptor. Proc Natl Acad Sci USA 86(24):10029–10033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rickel EA, Siegel LA, Yoon BR, Rottman JB, Kugler DG, Swart DA, Anders PM, Tocker JE, Comeau MR, Budelsky AL (2008) Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities. J Immunol 181(6):4299–4310

    Article  CAS  PubMed  Google Scholar 

  • Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley AM, Corrigan C, Durham SR, Kay AB (1992) Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med 326(5):298–304. https://doi.org/10.1056/NEJM199201303260504

    Article  CAS  PubMed  Google Scholar 

  • Schmidt-Weber CB, Akdis M, Akdis CA (2007) TH17 cells in the big picture of immunology. J Allergy Clin Immunol 120(2):247–254. https://doi.org/10.1016/j.jaci.2007.06.039

    Article  CAS  PubMed  Google Scholar 

  • Schmitt E, Germann T, Goedert S, Hoehn P, Huels C, Koelsch S, KĂĽhn R, MĂĽller W, Palm N, RĂĽde E (1994) IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma. J Immunol 153(9):3989–3996

    CAS  PubMed  Google Scholar 

  • Segal LN, Blaser MJ (2014) A brave new world: the lung microbiota in an era of change. Ann Am Thorac Soc 11(Suppl 1):S21–S27. https://doi.org/10.1513/AnnalsATS.201306-189MG

    Article  PubMed  PubMed Central  Google Scholar 

  • Sel S, Wegmann M, Dicke T, Sel S, Henke W, Yildirim AO, Renz H, Garn H (2008) Effective prevention and therapy of experimental allergic asthma using a GATA-3-specific DNAzyme. J Allergy Clin Immunol 121(4):910–916.e915. https://doi.org/10.1016/j.jaci.2007.12.1175

    Article  CAS  PubMed  Google Scholar 

  • Sheehan WJ, Mauger DT, Paul IM, Moy JN, Boehmer SJ, Szefler SJ, Fitzpatrick AM, Jackson DJ, Bacharier LB, Cabana MD, Covar R, Holguin F, Lemanske RF Jr, Martinez FD, Pongracic JA, Beigelman A, Baxi SN, Benson M, Blake K, Chmiel JF, Daines CL, Daines MO, Gaffin JM, Gentile DA, Gower WA, Israel E, Kumar HV, Lang JE, Lazarus SC, Lima JJ, Ly N, Marbin J, Morgan WJ, Myers RE, Olin JT, Peters SP, Raissy HH, Robison RG, Ross K, Sorkness CA, Thyne SM, Wechsler ME, Phipatanakul W, AsthmaNet NN (2016) Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma. N Engl J Med 375(7):619–630. https://doi.org/10.1056/NEJMoa1515990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shook BC, Lin K (2017) Recent advances in developing antiviral therapies for respiratory syncytial virus. Top Curr Chem 375(2):40. https://doi.org/10.1007/s41061-017-0129-4

    Article  CAS  Google Scholar 

  • Slager RE, Hawkins GA, Ampleford EJ, Bowden A, Stevens LE, Morton MT, Tomkinson A, Wenzel SE, Longphre M, Bleecker ER, Meyers DA (2010) IL-4 receptor alpha polymorphisms are predictors of a pharmacogenetic response to a novel IL-4/IL-13 antagonist. J Allergy Clin Immunol 126(4):875–878. https://doi.org/10.1016/j.jaci.2010.08.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slager RE, Otulana BA, Hawkins GA, Yen YP, Peters SP, Wenzel SE, Meyers DA, Bleecker ER (2012) IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti-IL-4 receptor alpha antagonist. J Allergy Clin Immunol 130(2):516–522.e514. https://doi.org/10.1016/j.jaci.2012.03.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Soler M, Matz J, Townley R, Buhl R, O’Brien J, Fox H, Thirlwell J, Gupta N, Della Cioppa G (2001) The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 18(2):254–261

    Article  CAS  PubMed  Google Scholar 

  • Tan WC (2005) Viruses in asthma exacerbations. Curr Opin Pulm Med 11(1):21–26

    PubMed  Google Scholar 

  • Tan LD, Bratt JM, Godor D, Louie S, Kenyon NJ (2016) Benralizumab: a unique IL-5 inhibitor for severe asthma. J Asthma Allergy 9:71–81. https://doi.org/10.2147/JAA.S78049

    Article  PubMed  PubMed Central  Google Scholar 

  • Teo SM, Mok D, Pham K, Kusel M, Serralha M, Troy N, Holt BJ, Hales BJ, Walker ML, Hollams E, Bochkov YA, Grindle K, Johnston SL, Gern JE, Sly PD, Holt PG, Holt KE, Inouye M (2015) The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe 17(5):704–715. https://doi.org/10.1016/j.chom.2015.03.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tomosada Y, Chiba E, Zelaya H, Takahashi T, Tsukida K, Kitazawa H, Alvarez S, Villena J (2013) Nasally administered Lactobacillus rhamnosus strains differentially modulate respiratory antiviral immune responses and induce protection against respiratory syncytial virus infection. BMC Immunol 14:40. https://doi.org/10.1186/1471-2172-14-40

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • van Rensen EL, Evertse CE, van Schadewijk WA, van Wijngaarden S, Ayre G, Mauad T, Hiemstra PS, Sterk PJ, Rabe KF (2009) Eosinophils in bronchial mucosa of asthmatics after allergen challenge: effect of anti-IgE treatment. Allergy 64(1):72–80. https://doi.org/10.1111/j.1398-9995.2008.01881.x

    Article  PubMed  Google Scholar 

  • Vignola AM, Humbert M, Bousquet J, Boulet LP, Hedgecock S, Blogg M, Fox H, Surrey K (2004) Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with concomitant allergic asthma and persistent allergic rhinitis: SOLAR. Allergy 59(7):709–717. https://doi.org/10.1111/j.1398-9995.2004.00550.x

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Misumi I, Gu AD, Curtis TA, Su L, Whitmire JK, Wan YY (2013) GATA-3 controls the maintenance and proliferation of T cells downstream of TCR and cytokine signaling. Nat Immunol 14(7):714–722. https://doi.org/10.1038/ni.2623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wenzel SE (2006) Asthma: defining of the persistent adult phenotypes. Lancet 368(9537):804–813. https://doi.org/10.1016/S0140-6736(06)69290-8

    Article  CAS  PubMed  Google Scholar 

  • Wenzel SE (2013) Complex phenotypes in asthma: current definitions. Pulm Pharmacol Ther 26(6):710–715. https://doi.org/10.1016/j.pupt.2013.07.003

    Article  CAS  PubMed  Google Scholar 

  • Wenzel SE, Szefler SJ, Leung DY, Sloan SI, Rex MD, Martin RJ (1997) Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 156(3 Pt 1):737–743. https://doi.org/10.1164/ajrccm.156.3.9610046

    Article  CAS  PubMed  Google Scholar 

  • Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB, Gibbs RL, Chu HW (1999) Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 160(3):1001–1008. https://doi.org/10.1164/ajrccm.160.3.9812110

    Article  CAS  PubMed  Google Scholar 

  • Wenzel S, Wilbraham D, Fuller R, Getz EB, 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(9596):1422–1431. https://doi.org/10.1016/S0140-6736(07)61600-6

    Article  CAS  PubMed  Google Scholar 

  • Wenzel SE, Barnes PJ, Bleecker ER, Bousquet J, Busse W, Dahlen SE, Holgate ST, Meyers DA, Rabe KF, Antczak A, Baker J, Horvath I, Mark Z, Bernstein D, Kerwin E, Schlenker-Herceg R, Lo KH, Watt R, Barnathan ES, Chanez P, Investigators TA (2009) A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med 179(7):549–558. https://doi.org/10.1164/rccm.200809-1512OC

    Article  CAS  PubMed  Google Scholar 

  • Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, Wang L, Kirkesseli S, Rocklin R, Bock B, Hamilton J, Ming JE, Radin A, Stahl N, Yancopoulos GD, Graham N, Pirozzi G (2013) Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 368(26):2455–2466. https://doi.org/10.1056/NEJMoa1304048

    Article  CAS  PubMed  Google Scholar 

  • Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, Pirozzi G, Sutherland ER, Evans RR, Joish VN, Eckert L, Graham NM, Stahl N, Yancopoulos GD, Louis-Tisserand M, Teper A (2016) Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting beta2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 388(10039):31–44. https://doi.org/10.1016/S0140-6736(16)30307-5

    Article  CAS  PubMed  Google Scholar 

  • White B, Leon F, White W, Robbie G (2009) 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. https://doi.org/10.1016/j.clinthera.2009.04.019

    Article  CAS  PubMed  Google Scholar 

  • Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, Donaldson DD (1998) Interleukin-13: central mediator of allergic asthma. Science 282(5397):2258–2261

    Article  CAS  PubMed  Google Scholar 

  • Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S, Ellwanger A, Sidhu SS, Dao-Pick TP, Pantoja C, Erle DJ, Yamamoto KR, Fahy JV (2007) Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci USA 104(40):15858–15863. https://doi.org/10.1073/pnas.0707413104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, Koth LL, Arron JR, Fahy JV (2009) T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 180(5):388–395. https://doi.org/10.1164/rccm.200903-0392OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu W, Bleecker E, Moore W, Busse WW, Castro M, Chung KF, Calhoun WJ, Erzurum S, Gaston B, Israel E, Curran-Everett D, Wenzel SE (2014) Unsupervised phenotyping of Severe Asthma Research Program participants using expanded lung data. J Allergy Clin Immunol 133(5):1280–1288. https://doi.org/10.1016/j.jaci.2013.11.042

    Article  PubMed  PubMed Central  Google Scholar 

  • Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, Oliver P, Huang W, Zhang P, Zhang J, Shellito JE, Bagby GJ, Nelson S, Charrier K, Peschon JJ, Kolls JK (2001) Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med 194(4):519–527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ying S, O’Connor B, Ratoff J, Meng Q, Mallett K, Cousins D, Robinson D, Zhang G, Zhao J, Lee TH, Corrigan C (2005) Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol 174(12):8183–8190

    Article  CAS  PubMed  Google Scholar 

  • Ying S, O’Connor B, Ratoff J, Meng Q, Fang C, Cousins D, Zhang G, Gu S, Gao Z, Shamji B, Edwards MJ, Lee TH, Corrigan CJ (2008) Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease. J Immunol 181(4):2790–2798

    Article  CAS  PubMed  Google Scholar 

  • Zhu J (2015) T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production. Cytokine 75(1):14–24. https://doi.org/10.1016/j.cyto.2015.05.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zissler UM, Chaker AM, Effner R, Ulrich M, Guerth F, Piontek G, Dietz K, Regn M, Knapp B, Theis FJ, Heine H, Suttner K, Schmidt-Weber CB (2016a) Interleukin-4 and interferon-gamma orchestrate an epithelial polarization in the airways. Mucosal Immunol 9(4):917–926. https://doi.org/10.1038/mi.2015.110

    Article  CAS  PubMed  Google Scholar 

  • Zissler UM, Esser-von Bieren J, Jakwerth CA, Chaker AM, Schmidt-Weber CB (2016b) Current and future biomarkers in allergic asthma. Allergy 71(4):475–494. https://doi.org/10.1111/all.12828

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center of Allergy & Environment (ZAUM), Technical University of Munich, Munich, Germany

    Ulrich M. Zissler

  2. Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany

    Ulrich M. Zissler

  3. German Center for Lung Research (DZL), CPC-M, Munich, Germany

    Ulrich M. Zissler

Authors
  1. Ulrich M. Zissler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ulrich M. Zissler .

Editor information

Editors and Affiliations

  1. ZAUM, Technical University of Munich, Munich, Germany

    Carsten B. Schmidt-Weber

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Zissler, U.M. (2017). Specific Therapies for Asthma Endotypes: A New Twist in Drug Development. In: Schmidt-Weber, C. (eds) Allergy Prevention and Exacerbation. Birkhäuser Advances in Infectious Diseases. Springer, Cham. https://doi.org/10.1007/978-3-319-69968-4_11

Download citation

Publish with us

Policies and ethics

Search

Navigation