Airway proteomics reveals broad residual anti-inflammatory effects of prednisolone in mepolizumab-treated asthma

Imran Howell, Freda Yang, Vanessa Brown, Jennifer Cane, Emanuele Marchi, Adnan Azim, John Busby, Pamela J. McDowell, Sarah E. Diver, Catherine Borg, Liam G. Heaney, Ian D. Pavord, Christopher E. Brightling, Rekha Chaudhuri, Timothy S.C. Hinks

Research output: Contribution to journalArticlepeer-review

Abstract

Background: 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 remain the main treatment for these residual exacerbations.

Objective: Our study aimed to explore the corticosteroid-responsiveness of airway inflammation after mepolizumab treatment to find potentially treatable inflammatory mechanisms beyond the IL-5 pathway.

Method: 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 27 patients treated with mepolizumab for SEA. We analysed paired sputum (n=16) and plasma (n=25) samples from the MAPLE trial using high-throughput Olink® proteomics. We also analysed additional sputum proteins using ELISA.

Results: 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. 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.

Conclusion: At stable state, prednisolone has broad anti-inflammatory effects on top of mepolizumab. These effects are heterogeneous and may be clinically relevant in residual exacerbations.
Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
Early online date01 Aug 2024
DOIs
Publication statusEarly online date - 01 Aug 2024

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