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The IL-33 and IL-4Rα blocking antibodies, itepekimab and dupilumab, modulate distinct and common inflammatory mediators in asthma - mouse data

ABSTRACT: Biologics that target IL-4Ra or IL-33 pathways have demonstrated clinical efficacy in asthma and chronic obstructive pulmonary disease (COPD), highlighting the importance of IL-4, IL-13 and IL-33 in respiratory diseases. Despite this, there are limited studies that link preclinical models to human disease and evaluate disease biology in the setting of clinical trials. To address these gaps, we evaluated transcriptional, cellular and pathophysiological processes driven by IL-4/ IL-13 and IL-33 using human innate cells in vitro, a mouse model of airway inflammation and a Bronchial Allergen Challenge (BAC) in house dust mite (HDM)-sensitized individuals with mild asthma. Using the HDM mouse model of airway inflammation, we show that blockade of either IL-4Ra or IL-33 at the peak of type 2 (T2) inflammation leads to inhibition of airway inflammation and remodeling. While the combination of dupilumab and itepekimab was not additive, blockade of both IL-33 and IL-4Ra in a severe, late-phase mixed T1/T2 inflammation reduced all measured parameters. Consistent with some of these observations in mice, blocking either IL-33 or IL-4Ra in the context of T2 airway inflammation suppressed sputum gene expression in individuals with mild persistent asthma post-BAC. Overall, these results highlight that IL-33 and IL-4/IL-13 are key drivers of airway inflammation and remodeling and provide insight into the differences in targeting IL-4Ra or IL-33 pathways in asthma independently or in combination.

ORGANISM(S): Mus musculus

PROVIDER: GSE282861 | GEO | 2025/12/03

REPOSITORIES: GEO

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The IL-33 and IL-4Rα blocking antibodies, itepekimab and dupilumab, modulate distinct and common inflammatory mediators in asthma - human mast cell and eosinophil data

Project description:Biologics that target IL-4Ra or IL-33 pathways have demonstrated clinical efficacy in asthma and chronic obstructive pulmonary disease (COPD), highlighting the importance of IL-4, IL-13 and IL-33 in respiratory diseases. Despite this, there are limited studies that link preclinical models to human disease and evaluate disease biology in the setting of clinical trials. To address these gaps, we evaluated transcriptional, cellular and pathophysiological processes driven by IL-4/ IL-13 and IL-33 using human innate cells in vitro, a mouse model of airway inflammation and a Bronchial Allergen Challenge (BAC) in house dust mite (HDM)-sensitized individuals with mild asthma. Using the HDM mouse model of airway inflammation, we show that blockade of either IL-4Ra or IL-33 at the peak of type 2 (T2) inflammation leads to inhibition of airway inflammation and remodeling. While the combination of dupilumab and itepekimab was not additive, blockade of both IL-33 and IL-4Ra in a severe, late-phase mixed T1/T2 inflammation reduced all measured parameters. Consistent with some of these observations in mice, blocking either IL-33 or IL-4Ra in the context of T2 airway inflammation suppressed sputum gene expression in individuals with mild persistent asthma post-BAC. Overall, these results highlight that IL-33 and IL-4/IL-13 are key drivers of airway inflammation and remodeling and provide insight into the differences in targeting IL-4Ra or IL-33 pathways in asthma independently or in combination.

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2022-09-20 | PXD029237 | Pride

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Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Ra antibody, is required to broadly inhibit type 2 inflammation

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IL-22 inhibits allergic airway inflammation in house dust mite-induced asthma models

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2020-07-13 | GSE145013 | GEO

Transcriptome analysis of acute IL-33 or chronic HDM activated murine lung ILC2s

Project description:We have identified CD25high and CD25low ILC2 subsets in various mouse models of airway inflammation. Transcriptome analysis of acute IL-33 (CD25High) or chronic HDM (CD25Low) activated murine lung ILC2s suggests functional differences between these two ILC2 populations.

2020-05-13 | GSE99780 | GEO

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