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Dual inhibition of airway inflammation and fibrosis by common β cytokine receptor blockade

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dc.contributor.authorWang, H.
dc.contributor.authorYip, K.H.
dc.contributor.authorKeam, S.P.
dc.contributor.authorVlahos, R.
dc.contributor.authorNichol, K.
dc.contributor.authorWark, P.
dc.contributor.authorToubia, J.
dc.contributor.authorKral, A.
dc.contributor.authorCildir, G.
dc.contributor.authorPant, H.
dc.contributor.authorHercus, T.R.
dc.contributor.authorWilson, N.
dc.contributor.authorOwczarek, C.
dc.contributor.authorLopez, A.F.
dc.contributor.authorBozinovski, S.
dc.contributor.authorTumes, D.J.
dc.date.issued2024
dc.descriptionAvailable online November 4, 2023
dc.description.abstractBackground: Patients with severe asthma can present with eosinophilic type 2 (T2), neutrophilic, or mixed inflammation that drives airway remodeling and exacerbations and represents a major treatment challenge. The common β (βc) receptor signals for 3 cytokines, GM-CSF, IL-5, and IL-3, which collectively mediate T2 and neutrophilic inflammation. Objective: To determine the pathogenesis of βc receptor–mediated inflammation and remodeling in severe asthma and to investigate βc antagonism as a therapeutic strategy for mixed granulocytic airway disease. Methods: βc gene expression was analyzed in bronchial biopsy specimens from patients with mild-to-moderate and severe asthma. House dust mite extract and Aspergillus fumigatus extract (ASP) models were used to establish asthma-like pathology and airway remodeling in human βc transgenic mice. Lung tissue gene expression was analyzed by RNA sequencing. The mAb CSL311 targeting the shared cytokine binding site of βc was used to block βc signaling. Results: βc gene expression was increased in patients with severe asthma. CSL311 potently reduced lung neutrophils, eosinophils, and interstitial macrophages and improved airway pathology and lung function in the acute steroid-resistant house dust mite extract model. Chronic intranasal ASP exposure induced airway inflammation and fibrosis and impaired lung function that was inhibited by CSL311. CSL311 normalized the ASP-induced fibrosis-associated extracellular matrix gene expression network and strongly reduced signatures of cellular inflammation in the lung. Conclusions: βc cytokines drive steroid-resistant mixed myeloid cell airway inflammation and fibrosis. The anti-βc antibody CSL311 effectively inhibits mixed T2/neutrophilic inflammation and severe asthma-like pathology and reverses fibrosis gene signatures induced by exposure to commonly encountered environmental allergens.
dc.description.statementofresponsibilityHao Wang, Kwok Ho Yip, Simon P. Keam, Ross Vlahos, Kristy Nichol, Peter Wark, John Toubia, Anita C. Kral, Gökhan Cildir, Harshita Pant, Timothy R. Hercus, Nick Wilson, Catherine Owczarek, Angel F. Lopez, Steven Bozinovski, and Damon J. Tumes
dc.identifier.citationJournal of Allergy and Clinical Immunology, 2024; 153(3):672-683.e6
dc.identifier.doi10.1016/j.jaci.2023.10.021
dc.identifier.issn0091-6749
dc.identifier.issn1097-6825
dc.identifier.orcidLopez, A.F. [0000-0001-7430-0135]
dc.identifier.orcidTumes, D.J. [0000-0001-5709-857X]
dc.identifier.urihttps://hdl.handle.net/2440/141498
dc.language.isoen
dc.publisherElsevier
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT1127290
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT2004288
dc.rights© 2023 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY-NCND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
dc.source.urihttp://dx.doi.org/10.1016/j.jaci.2023.10.021
dc.subjectAsthma; common b cytokine; CSL311; antibody; biologic; trabikibart; fibrosis; collagen; remodeling; airway; inflammation; hyperactivity; eosinophils; neutrophils; macrophages; IL-3; IL-5; GM-CSF
dc.subject.meshLung
dc.subject.meshAnimals
dc.subject.meshMice, Transgenic
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.meshPyroglyphidae
dc.subject.meshAsthma
dc.subject.meshFibrosis
dc.subject.meshInflammation
dc.subject.meshSteroids
dc.subject.meshReceptors, Cytokine
dc.subject.meshAllergens
dc.subject.meshCytokines
dc.subject.meshAirway Remodeling
dc.titleDual inhibition of airway inflammation and fibrosis by common β cytokine receptor blockade
dc.title.alternativeDual inhibition of airway inflammation and fibrosis by common beta cytokine receptor blockade
dc.typeJournal article
pubs.publication-statusPublished

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