Gene expression and DNA methylation changes induced by Mepolizumab in the nasal epithelium in severe asthma

Rakkar, Kamini; Pang, Y L; Rajasekar, P; Portelli, M A; Hall, R; Clifford, R L; Shaw, D; Sayers, I

doi:10.1183/13993003.congress-2022.4497

Cited by 2 publications

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“…This would be consistent with previous nasal transcriptome data in mepolizumab-treated children where increased expression of epithelial signalling and extracellular matrix pathways were associated with more exacerbations, likely due to increased cycles of epithelial repair post-exacerbation 38 . In adults, nasal epithelial cytokine and alarmin activation (IL-4, TSLP, IL-33) after mepolizumab treatment was associated with non-responder status 39 , suggesting a clinically relevant subgroup of severe eosinophilic asthma where inflammation is driven more by alarmins and the IL-4/13 pathway than by IL-5-mediated eosinophilia. As this epithelial signalling pathway was steroid-responsive, we speculate this inflammation could also be targeted using anti-IL4Rα, anti-TSLP, anti-IL33, or JAK inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory effects of oral prednisolone at stable state in people treated with mepolizumab: a proteomic and bulk transcriptomics analysis

Howell,

Yang,

Brown

et al. 2024

Preprint

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Mepolizumab is an anti-interleukin-5 monoclonal antibody treatment for severe eosinophilic asthma (SEA) that reduces asthma exacerbations. Residual airway inflammation on mepolizumab may lead to persistent exacerbations. Oral corticosteroids have broad anti-inflammatory effects and remain the main treatment for these residual exacerbations. Our study aimed to explore the nature and corticosteroid-responsiveness of airway inflammation after mepolizumab treatment to find potentially treatable inflammatory mechanisms. The MAPLE trial was a multi-centre, randomized, double-blind, placebo-controlled, crossover study of 2 weeks of high-dose oral prednisolone treatment at stable state in patients treated with mepolizumab for SEA. We analysed sputum and plasma samples from the MAPLE trial using high-throughput Olink proteomics. We also analysed plasma microRNA, sputum proteins using ELISA, and nasal mucosal bulk RNA sequencing. In patients receiving mepolizumab, prednisolone significantly downregulated sputum proteins related to type-2 inflammation and chemotaxis including IL-4, IL-5, IL-13, CCL24, CCL26, EDN, CCL17, CCL22, OX40 receptor, FCER2, and the ST2 receptor. Prednisolone also downregulated cell adhesion molecules, prostaglandin synthases, mast cell tryptases, MMP1, MMP12, and neuroimmune mediators. Tissue repair and neutrophilic pathways were upregulated. Type-2 proteins were also downregulated in plasma, combined with IL-12, IFN-γ, and IP-10. IL-10 and amphiregulin were upregulated. In the nasal transcriptome, prednisolone suppressed genes involved in leucocyte chemotaxis, mast cell tryptase, 15-lipoxygenase and MMP12. By contrast, mepolizumab differentially regulated only Galectin-10 in plasma and no sputum proteins, and in nasal tissue affected genes related to cilia, keratinisation, extracellular matrix formation, and IL-4/13 signalling. At stable state, prednisolone has broad anti-inflammatory effects on top of mepolizumab.

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Section: Discussionmentioning

confidence: 99%

Anti-inflammatory effects of oral prednisolone at stable state in people treated with mepolizumab: a proteomic and bulk transcriptomics analysis

Howell,

Yang,

Brown

et al. 2024

Preprint

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“…While anti-IL-5 biologics are now well established in the management of severe asthma, some of their mechanistic effects are not fully understood, such as their effect on the airway epithelium. One study presented at the Congress showed that mepolizumab induces gene expression and DNA methylation changes in the nasal airway epithelium, leading to the inhibition of downstream cytokines (such as TNF-α) [ 40 ]. Moreover, the role of anti-IL-5 biologics in obesity-related T2 asthma was highlighted: body mass index positively correlated with T2 biomarkers in sputum, while anti-IL-5 reduced obesity-induced NLRP4 inflammasome activity and steroid-resistant airway hyperresponsiveness [ 41 ].…”

Section: Asthmamentioning

confidence: 99%

ERS International Congress 2022: highlights from the Airway Diseases Assembly

et al. 2023

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The European Respiratory Society (ERS) celebrated the return of an in-person meeting in Barcelona, Spain, after two years of virtual congresses. The congress programme was replete with symposia, skills workshops and abstract presentations from all 14 assemblies, encompassing over 3000 abstracts presented in the form of thematic poster discussion and oral presentations. In this article, highlights from this year's congress (including that from thematic poster sessions, oral presentations and symposia from keynote speakers), presented by Assembly 5: Airway diseases, Asthma, COPD and Chronic Cough, are reviewed by Early Career Members and experts in the field, with the aim of presenting key recent findings in the field.

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Gene expression and DNA methylation changes induced by Mepolizumab in the nasal epithelium in severe asthma

Cited by 2 publications

References 0 publications

Anti-inflammatory effects of oral prednisolone at stable state in people treated with mepolizumab: a proteomic and bulk transcriptomics analysis

Anti-inflammatory effects of oral prednisolone at stable state in people treated with mepolizumab: a proteomic and bulk transcriptomics analysis

ERS International Congress 2022: highlights from the Airway Diseases Assembly

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