{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T23:45:09Z","timestamp":1792453509043,"version":"4.5.0"},"reference-count":110,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T00:00:00Z","timestamp":1714608000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Ministry of Education, Culture, Sports, Science and Technology","award":["15K09228"],"award-info":[{"award-number":["15K09228"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Bronchial asthma is characterized by airway inflammation, airway hyperresponsiveness, and reversible airway obstruction. Eosinophils contribute to the pathogenesis of airway disease mainly by releasing eosinophil-specific granules, lipid mediators, superoxide anions, and their DNA. Type-2 cytokines such as interleukin (IL)-4 and IL-13 also play roles in the development of bronchial asthma. Among these cytokines, IL-4 is involved in T-cell differentiation, B-cell activation, B-cell differentiation into plasma cells, and the production of immunoglobulin E. Although IL-13 has similar effects to IL-4, IL-13 mainly affects structural cells, such as epithelial cells, smooth muscle cells, and fibroblasts. IL-13 induces the differentiation of goblet cells that produce mucus and induces the airway remodeling, including smooth muscle hypertrophy. IL-4 and IL-13 do not directly activate the effector functions of eosinophils; however, they can induce eosinophilic airway inflammation by upregulating the expression of vascular cell adhesion molecule-1 (for adhesion) and CC chemokine receptor 3 ligands (for migration). Dupilumab, a human anti-IL-4 receptor \u03b1 monoclonal antibody that inhibits IL-4 and IL-13 signaling, decreases asthma exacerbations and mucus plugs and increases lung function in moderate to severe asthma. In addition, dupilumab is effective for chronic rhinosinusitis with nasal polyps and for atopic dermatitis, and IL-4\/IL-13 blocking is expected to suppress allergen sensitization, including transcutaneous sensitization and atopic march.<\/jats:p>","DOI":"10.3390\/biom14050546","type":"journal-article","created":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T03:57:56Z","timestamp":1714622276000},"page":"546","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":90,"title":["The Possible Roles of IL-4\/IL-13 in the Development of Eosinophil-Predominant Severe Asthma"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3138-1451","authenticated-orcid":false,"given":"Kazuyuki","family":"Nakagome","sequence":"first","affiliation":[{"name":"Department of Respiratory Medicine, Saitama Medical University, Saitama 350-0495, Japan"},{"name":"Allergy Center, Saitama Medical University, Saitama 350-0495, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Nagata","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Saitama Medical University, Saitama 350-0495, Japan"},{"name":"Allergy Center, Saitama Medical University, Saitama 350-0495, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2003393","DOI":"10.1183\/13993003.03393-2020","article-title":"Understanding the key issues in the treatment of uncontrolled persistent asthma with type 2 inflammation","volume":"58","author":"Busse","year":"2021","journal-title":"Eur. Respir. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1067\/mai.2000.105712","article-title":"Mechanisms of eosinophil-associated inflammation","volume":"105","author":"Gleich","year":"2000","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/j.immuni.2019.03.018","article-title":"The Cytokines of Asthma","volume":"50","author":"Lambrecht","year":"2019","journal-title":"Immunity"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/imr.12706","article-title":"ILC2 The group 2 innate lymphoid cell (ILC2) regulatory network and its underlying mechanisms","volume":"286","author":"Kabata","year":"2018","journal-title":"Immunol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.jaci.2022.06.012","article-title":"Modulation of IL-4\/IL-13 cytokine signaling in the context of allergic disease","volume":"150","author":"Shankar","year":"2022","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1084\/jem.184.2.473","article-title":"Differentiation and stability of T helper 1 and 2 cells derived from naive human neonatal CD4+ T cells, analyzed at the single-cell level","volume":"184","author":"Sornasse","year":"1996","journal-title":"J. Exp. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"117228","DOI":"10.1016\/j.jep.2023.117228","article-title":"Efficacy of Trigonella foenum-graecum Linn\u00e9 in an animal model of particulate matter-induced asthma exacerbation","volume":"319","author":"Kim","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e14018","DOI":"10.1111\/pai.14018","article-title":"Broncho-Vaxom bacterial lysate prevents asthma via acetate enhancement in mouse model","volume":"34","author":"Lee","year":"2023","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/j.cell.2021.02.016","article-title":"The basic immunology of asthma","volume":"184","author":"Hammad","year":"2021","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1084\/jem.20031368","article-title":"Interleukin 18 acts on memory T helper cells type 1 to induce airway inflammation and hyperresponsiveness in a naive host mouse","volume":"199","author":"Sugimoto","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/ni.2020","article-title":"The transcription factor E4BP4 regulates the production of IL-10 and IL-13 in CD4+ T cells","volume":"12","author":"Motomura","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/nature08636","article-title":"Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells","volume":"463","author":"Moro","year":"2010","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jaci.2015.05.037","article-title":"Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia","volume":"137","author":"Smith","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1164\/ajrccm.161.1.9802048","article-title":"The relationship between airways inflammation and asthma severity","volume":"161","author":"Louis","year":"2000","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1016\/S0140-6736(02)11679-5","article-title":"Asthma exacerbations and sputum eosinophil counts: A randomised controlled trial","volume":"360","author":"Green","year":"2002","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/S2213-2600(15)00367-7","article-title":"Blood eosinophil count and prospective annual asthma disease burden: A UK cohort study","volume":"3","author":"Price","year":"2015","journal-title":"Lancet Respir. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/j.alit.2018.04.003","article-title":"Implication of fraction of exhaled nitric oxide and blood eosinophil count in severe asthma","volume":"67S","author":"Soma","year":"2018","journal-title":"Allergol. Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1164\/ajrccm\/137.1.62","article-title":"Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Relationship to bronchial hyperreactivity","volume":"137","author":"Wardlaw","year":"1988","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"eaar8477","DOI":"10.1126\/scitranslmed.aar8477","article-title":"Eosinophils increase airway sensory nerve density in mice and in human asthma","volume":"10","author":"Drake","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1126\/science.1100283","article-title":"A critical role for eosinophils in allergic airways remodeling","volume":"305","author":"Humbles","year":"2004","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Yasukawa, A., Hosoki, K., Toda, M., Miyake, Y., Matsushima, Y., Matsumoto, T., Boveda-Ruiz, D., Gil-Bernabe, P., Nagao, M., and Sugimoto, M. (2013). Eosinophils promote epithelial to mesenchymal transition of bronchial epithelial cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0064281"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"284","DOI":"10.4049\/jimmunol.179.1.284","article-title":"IL-5-induced hypereosinophilia suppresses the antigen-induced immune response via a TGF-beta-dependent mechanism","volume":"179","author":"Nakagome","year":"2007","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1056\/NEJMoa0805435","article-title":"Mepolizumab for prednisone-dependent asthma with sputum eosinophilia","volume":"360","author":"Nair","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1164\/rccm.201611-2234OC","article-title":"Mepolizumab Attenuates Airway Eosinophil Numbers, but Not Their Functional Phenotype, in Asthma","volume":"196","author":"Kelly","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"836635","DOI":"10.3389\/fphar.2022.836635","article-title":"Treatment Resistance in Severe Asthma Patients With a Combination of High Fraction of Exhaled Nitric Oxide and Low Blood Eosinophil Counts","volume":"13","author":"Hoshino","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2220","DOI":"10.3389\/fimmu.2018.02220","article-title":"Involvement and Possible Role of Eosinophils in Asthma Exacerbation","volume":"9","author":"Nakagome","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.anl.2011.01.011","article-title":"Pathogenesis of airway inflammation in bronchial asthma","volume":"38","author":"Nakagome","year":"2011","journal-title":"Auris. Nasus. Larynx."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1165\/ajrcmb.14.1.8534490","article-title":"Role of interleukin-4 and vascular cell adhesion molecule-1 in selective eosinophil migration into the airways in allergic asthma","volume":"14","author":"Fukuda","year":"1996","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1159\/000053844","article-title":"Eosinophil transmigration across VCAM-1-expressing endothelial cells is upregulated by antigen-stimulated mononuclear cells","volume":"125","author":"Nagata","year":"2001","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1159\/000494623","article-title":"Elevated Periostin Concentrations in the Bronchoalveolar Lavage Fluid of Patients with Eosinophilic Pneumonia","volume":"178","author":"Nakagome","year":"2019","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"143","DOI":"10.2332\/allergolint.13-RAI-0663","article-title":"Periostin in allergic inflammation","volume":"63","author":"Izuhara","year":"2014","journal-title":"Allergol. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1016\/j.jaci.2016.05.020","article-title":"Periostin upregulates the effector functions of eosinophils","volume":"138","author":"Noguchi","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1165\/ajrcmb.19.1.3001","article-title":"Granulocyte macrophage colony-stimulating factor augments ICAM-1 and VCAM-1 activation of eosinophil function","volume":"19","author":"Nagata","year":"1998","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6452","DOI":"10.4049\/jimmunol.169.11.6452","article-title":"Decreased expression of membrane IL-5 receptor alpha on human eosinophils: I. Loss of membrane IL-5 receptor alpha on airway eosinophils and increased soluble IL-5 receptor alpha in the airway after allergen challenge","volume":"169","author":"Liu","year":"2002","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1067\/mai.2002.122841","article-title":"Leukotriene D4 upregulates eosinophil adhesion via the cysteinyl leukotriene 1 receptor","volume":"109","author":"Nagata","year":"2002","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/S1081-1206(10)61269-0","article-title":"Leukotriene D4 and eosinophil transendothelial migration, superoxide generation, and degranulation via beta2 integrin","volume":"93","author":"Saito","year":"2004","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/j.jaci.2014.06.024","article-title":"Enhanced innate type 2 immune response in peripheral blood from patients with asthma","volume":"134","author":"Bartemes","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1165\/rcmb.2016-0099OC","article-title":"IL-13+ Type 2 Innate Lymphoid Cells Correlate with Asthma Control Status and Treatment Response","volume":"55","author":"Jia","year":"2016","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1016\/j.rmed.2015.09.016","article-title":"Type 2 innate lymphoid cells: A novel biomarker of eosinophilic airway inflammation in patients with mild to moderate asthma","volume":"109","author":"Liu","year":"2015","journal-title":"Respir. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.1038\/ncomms3675","article-title":"Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation","volume":"4","author":"Kabata","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.jaci.2017.03.032","article-title":"Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: The role of thymic stromal lymphopoietin","volume":"141","author":"Liu","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.jaci.2022.10.028","article-title":"Eosinophil depletion with benralizumab is associated with attenuated mannitol airway hyperresponsiveness in severe uncontrolled eosinophilic asthma","volume":"151","author":"Chan","year":"2023","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.anai.2023.04.022","article-title":"Targeting the interleukin-5 pathway improves cough hypersensitivity in patients with severe uncontrolled asthma","volume":"13","author":"Ito","year":"2023","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1172\/JCI17974","article-title":"Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics","volume":"112","author":"Phipps","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1900930","DOI":"10.1183\/13993003.00930-2019","article-title":"Computational modelling prediction and clinical validation of impact of benralizumab on airway smooth muscle mass in asthma","volume":"5","author":"Chachi","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1111\/all.15901","article-title":"Effect of dupilumab on sputum eosinophils in patients with moderate-to-severe asthma","volume":"7","author":"Svenningsen","year":"2024","journal-title":"Allergy"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1056\/NEJMoa2034975","article-title":"Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma","volume":"384","author":"Corren","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1016\/S2213-2600(21)00226-5","article-title":"Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): A double-blind, randomised, placebo-controlled, phase 2 trial","volume":"9","author":"Diver","year":"2021","journal-title":"Lancet Respir. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"S184","DOI":"10.1513\/AnnalsATS.201807-485AW","article-title":"Autopsy and imaging studies of mucus in asthma. Lessons learned about disease mechanisms and the role of mucus in airflow obstruction","volume":"15","author":"Dunican","year":"2018","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6262","DOI":"10.4049\/jimmunol.180.9.6262","article-title":"Identification of pendrin as a common mediator for mucus production in bronchial asthma and chronic obstructive pulmonary disease","volume":"180","author":"Nakao","year":"2008","journal-title":"J. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1164\/rccm.201306-1181OC","article-title":"Foxa3 induces goblet cell metaplasia and inhibits innate antiviral immunity","volume":"189","author":"Chen","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1172\/JCI29176","article-title":"SPDEF regulates goblet cell hyperplasia in the airway epithelium","volume":"117","author":"Park","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.1126\/science.282.5397.2258","article-title":"Interleukin-13: Central mediator of allergic asthma","volume":"282","author":"Luyimbazi","year":"1998","journal-title":"Science"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"L958","DOI":"10.1152\/ajplung.00247.2010","article-title":"Interleukin-13 inhibits proliferation and enhances contractility of human airway smooth muscle cells without change in contractile phenotype","volume":"300","author":"Risse","year":"2011","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.jaci.2019.10.037","article-title":"IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways","volume":"145","author":"Manson","year":"2020","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1159\/000113517","article-title":"Interleukin-4 and interleukin-13 enhance human bronchial smooth muscle cell proliferation","volume":"146","author":"Thompson","year":"2008","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1067\/mai.2001.113760","article-title":"IL-4, IL-13, and dexamethasone augment fibroblast proliferation in asthma","volume":"107","author":"Kraft","year":"2001","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S0014-4835(02)00248-8","article-title":"IL-4-induced cell proliferation and production of extracellular matrix proteins in human conjunctival fibroblasts","volume":"76","author":"Fujitsu","year":"2003","journal-title":"Exp. Eye Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4507","DOI":"10.4049\/jimmunol.166.7.4507","article-title":"STAT6 mediates eotaxin-1 expression in IL-4 or TNF-alpha-induced fibroblasts","volume":"166","author":"Hoeck","year":"2001","journal-title":"J. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.jaci.2006.02.046","article-title":"Periostin: A novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals","volume":"118","author":"Takayama","year":"2006","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1111\/all.12240","article-title":"Cell type-dependent effects of corticosteroid on periostin production by primary human tissue cells","volume":"68","author":"Shoda","year":"2013","journal-title":"Allergy"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1084\/jem.20042311","article-title":"In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma","volume":"201","author":"Jung","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1038\/labinvest.3780352","article-title":"Early interleukin 4-dependent response can induce airway hyperreactivity before development of airway inflammation in a mouse model of asthma","volume":"81","author":"To","year":"2001","journal-title":"Lab. Investig."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/1465-9921-6-46","article-title":"Antigen-sensitized CD4+CD62Llow memory\/effector T helper 2 cells can induce airway hyperresponsiveness in an antigen free setting","volume":"6","author":"Nakagome","year":"2005","journal-title":"Respir. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"eaaz4415","DOI":"10.1126\/sciimmunol.aaz4415","article-title":"M2-like, dermal macrophages are maintained via IL-4\/CCL24-mediated cooperative interaction with eosinophils in cutaneous leishmaniasis","volume":"5","author":"Lee","year":"2020","journal-title":"Sci. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.immuni.2014.04.013","article-title":"Basophil-derived interleukin-4 controls the function of natural helper cells, a member of ILC2s, in lung inflammation","volume":"40","author":"Motomura","year":"2014","journal-title":"Immunity"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2486","DOI":"10.1056\/NEJMoa1804092","article-title":"Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma","volume":"378","author":"Castro","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2102577","DOI":"10.1183\/13993003.02577-2021","article-title":"Dupilumab efficacy and safety in patients with asthma and blood eosinophils \u2265500 cells\u2022\u00b5L\u22121","volume":"59","author":"Rabe","year":"2022","journal-title":"Eur. Respir. J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1136\/thoraxjnl-2019-213415","article-title":"Normalisation of MRI ventilation heterogeneity in severe asthma by dupilumab","volume":"74","author":"Svenningsen","year":"2019","journal-title":"Thorax"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e01074","DOI":"10.1002\/rcr2.1074","article-title":"Successful treatment with dupilumab for mucus plugs in severe asthma","volume":"11","author":"Anai","year":"2022","journal-title":"Respirol. Case Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1164\/rccm.202110-2265OC","article-title":"Mucus Plugs Persist in Asthma, and Changes in Mucus Plugs Associate with Changes in Airflow over Time","volume":"205","author":"Tang","year":"2022","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1164\/rccm.202306-1102LE","article-title":"Effects of Dupilumab on Mucus Plugging and Ventilation Defects in Patients with Moderate-to-Severe Asthma: A Randomized, Double-Blind, Placebo-controlled Trial","volume":"208","author":"Svenningsen","year":"2023","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Tajiri, T., Suzuki, M., Nishiyama, H., Ozawa, Y., Kurokawa, R., Takeda, N., Ito, K., Fukumitsu, K., Kanemitsu, Y., and Mori, Y. (Allergol. Int., 2024). Efficacy of dupilumab for airway hypersecretion and airway wall thickening in patients with moderate-to-severe asthma: A prospective, observational study, Allergol. Int., in press.","DOI":"10.1016\/j.alit.2024.02.002"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S2213-2600(21)00322-2","article-title":"Long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma (TRAVERSE): An open-label extension study","volume":"10","author":"Wechsler","year":"2022","journal-title":"Lancet Respir. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1111\/resp.12838","article-title":"Comorbidities in difficult asthma are independent risk factors for frequent exacerbations, poor control and diminished quality of life","volume":"21","author":"Tay","year":"2016","journal-title":"Respirology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1111\/j.1365-2222.2011.03880.x","article-title":"Obesity and aspirin intolerance are risk factors for difficult-to-treat asthma in Japanese non-atopic women","volume":"42","author":"Fukutomi","year":"2012","journal-title":"Clin. Exp. Allergy"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.jaci.2003.10.068","article-title":"Clinical features of asthmatic patients with increased urinary leukotriene E4 excretion (hyperleukotrienuria): Involvement of chronic hyperplastic rhinosinusitis with nasal polyposis","volume":"113","author":"Higashi","year":"2004","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1513\/AnnalsATS.201609-720OC","article-title":"Serum Periostin as a Biomarker for Comorbid Chronic Rhinosinusitis in Patients with Asthma","volume":"14","author":"Asano","year":"2017","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1016\/S0140-6736(19)31881-1","article-title":"Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): Results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials","volume":"394","author":"Bachert","year":"2019","journal-title":"Lancet"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.jaip.2019.07.016","article-title":"Dupilumab Efficacy in Uncontrolled, Moderate-to-Severe Asthma with Self-Reported Chronic Rhinosinusitis","volume":"8","author":"Maspero","year":"2020","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.jaci.2022.04.007","article-title":"Rapid and sustained effect of dupilumab on clinical and mechanistic outcomes in aspirin-exacerbated respiratory disease","volume":"150","author":"Buchheit","year":"2022","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2201335","DOI":"10.1183\/13993003.01335-2022","article-title":"Dupilumab increases aspirin tolerance in NSAID-exacerbated respiratory disease","volume":"61","author":"Schneider","year":"2023","journal-title":"Eur. Respir. J."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.1016\/j.jaip.2023.04.033","article-title":"Nonsteroidal Anti-inflammatory Drug (NSAID) Tolerance After Biological Therapy in Patients With NSAID-Exacerbated Respiratory Disease: A Randomized Comparative Trial","volume":"11","author":"Lopez","year":"2023","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Lytvyn, Y., and Gooderham, M. (2023). Targeting Interleukin 13 for the Treatment of Atopic Dermatitis. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15020568"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1056\/NEJMoa1106469","article-title":"Lebrikizumab treatment in adults with asthma","volume":"365","author":"Corren","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1136\/thoraxjnl-2014-206719","article-title":"Lebrikizumab in moderate-to-severe asthma: Pooled data from two randomised placebo-controlled studies","volume":"70","author":"Hanania","year":"2015","journal-title":"Thorax"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/S2213-2600(16)30265-X","article-title":"Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): Replicate, phase 3, randomised, double-blind, placebo-controlled trials","volume":"4","author":"Hanania","year":"2016","journal-title":"Lancet Respir. Med."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Corren, J., Szefler, S.J., Sher, E., Korenblat, P., Soong, W., Hanania, N.A., Berman, G., Brusselle, G., Zitnik, R., and Natalie, C.R. (J. Allergy Clin. Immunol. Pract., 2024). Lebrikizumab in Uncontrolled Asthma: Reanalysis in a Well-Defined Type 2 Population, J. Allergy Clin. Immunol. Pract., in press.","DOI":"10.1016\/j.jaip.2024.02.007"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/S2213-2600(15)00197-6","article-title":"Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: A randomised, double-blind, placebo-controlled, phase 2b trial","volume":"3","author":"Brightling","year":"2015","journal-title":"Lancet Respir. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/S2213-2600(18)30184-X","article-title":"Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): Two randomised, double-blind, placebo-controlled, phase 3 clinical trials","volume":"6","author":"Panettieri","year":"2018","journal-title":"Lancet Respir. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1111\/bcp.12589","article-title":"A pharmacokinetic comparison of anrukinzumab, an anti- IL-13 monoclonal antibody, among healthy volunteers, asthma and ulcerative colitis patients","volume":"80","author":"Hua","year":"2015","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2910","DOI":"10.1016\/j.jaip.2021.02.020","article-title":"Efficacy of dupilumab in patients with aspirin-exacerbated respiratory disease and previous inadequate response to anti-IL-5 or anti-IL-5R\u03b1 in a real-world setting","volume":"9","author":"Bavaro","year":"2021","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1016\/j.jaip.2020.09.014","article-title":"Dupilumab Improves Asthma Control and Lung Function in Patients with Insufficient Outcome during Previous Antibody Therapy","volume":"9","author":"Munker","year":"2021","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.jaip.2021.12.006","article-title":"Respiratory Infections and Anti-Infective Medication Use from Phase 3 Dupilumab Respiratory Studies","volume":"10","author":"Geng","year":"2022","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s40257-019-00445-7","article-title":"Infections in Dupilumab Clinical Trials in Atopic Dermatitis: A Comprehensive Pooled Analysis","volume":"20","author":"Eichenfield","year":"2019","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1111\/all.12627","article-title":"Th2 cytokines impair innate immune responses to rhinovirus in respiratory epithelial cells","volume":"70","author":"Contoli","year":"2015","journal-title":"Allergy"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1164\/rccm.201406-1039OC","article-title":"IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo","volume":"190","author":"Jackson","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"5999","DOI":"10.4049\/jimmunol.0901194","article-title":"Counterregulation between the FcepsilonRI pathway and antiviral responses in human plasmacytoid dendritic cells","volume":"184","author":"Gill","year":"2010","journal-title":"J. Immunol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.jaci.2012.05.023","article-title":"Innate immune responses to rhinovirus are reduced by the high-affinity IgE receptor in allergic asthmatic children","volume":"130","author":"Durrani","year":"2012","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1016\/j.jaci.2017.07.035","article-title":"Enhanced plasmacytoid dendritic cell antiviral responses after omalizumab","volume":"141","author":"Gill","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1164\/rccm.201701-0120OC","article-title":"Effects of Omalizumab on Rhinovirus Infections, Illnesses, and Exacerbations of Asthma","volume":"196","author":"Esquivel","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1164\/rccm.201606-1145LE","article-title":"Omalizumab Is Associated with Reduced Acute Severity of Rhinovirus-triggered Asthma Exacerbation","volume":"194","author":"Kantor","year":"2016","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1056\/NEJMoa1610020","article-title":"Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis","volume":"375","author":"Simpson","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1111\/1346-8138.13408","article-title":"Potential preventive effects of proactive therapy on sensitization in moderate to severe childhood atopic dermatitis: A randomized, investigator-blinded, controlled study","volume":"43","author":"Fukuie","year":"2016","journal-title":"J. Dermatol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/cea.13514","article-title":"Blockade of IL-4R\u03b1 inhibits group 2 innate lymphoid cell responses in asthma patients","volume":"50","author":"Patel","year":"2020","journal-title":"Clin. Exp. Allergy"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"100003","DOI":"10.1016\/j.xjidi.2021.100003","article-title":"Dupilumab Effects on Innate Lymphoid Cell and Helper T Cell Populations in Patients with Atopic Dermatitis","volume":"1","author":"Imai","year":"2021","journal-title":"JID. Innov."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.jaci.2022.08.026","article-title":"Attenuating the atopic march: Meta-analysis of the dupilumab atopic dermatitis database for incident allergic events","volume":"151","author":"Geba","year":"2023","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2913","DOI":"10.1016\/j.jaip.2021.02.042","article-title":"Complications of switching from anti-IL-5 or anti-IL-5R to dupilumab in corticosteroid-dependent severe asthma","volume":"9","author":"Eger","year":"2021","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Kurihara, M., Masaki, K., Matsuyama, E., Fujioka, M., Hayashi, R., Tomiyasu, S., Sasahara, K., Sunata, K., Asaoka, M., and Akiyama, Y. (2022). How Can Dupilumab Cause Eosinophilic Pneumonia?. Biomolecules, 12.","DOI":"10.3390\/biom12121743"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.alit.2022.03.005","article-title":"Two cases of dupilumab-associated eosinophilic pneumonia in asthma with eosinophilic chronic rhinosinusitis: IL-5-driven pathology?","volume":"71","author":"Nishiyama","year":"2022","journal-title":"Allergol. 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