Airway Interleukin-33 and type 2 cytokines in adult patients with acute asthma

Poulsen, Nadia Nicholine; Bjerregaard, Asger; Khoo, Siew-Kim; Laing, Ingrid A.; Souëf, Peter Le; Backer, Vibeke; Rapley, Laura; Cohen, Suzanne; Barrett, Lucy W.; Thompson, Philip J.; Baltic, Svetlana; Porsbjerg, Celeste

doi:10.1016/j.rmed.2018.05.016

Cited by 15 publications

(9 citation statements)

References 30 publications

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“…In epicutaneously ovalbumin-sensitized mice that were later orally challenged with ovalbumin, IL-33 was found to be essential for inducing IgE-dependent anaphylaxis in the gut (20). IL-33 is expressed more abundantly in subjects with asthma than in healthy individuals (21)(22)(23)(24). Many anti-IL-33 pathway inhibitors are being tested in clinical studies for allergy and/or asthma (NCT02999711, NCT03112577, NCT01928368).…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

Phase 2a randomized, placebo-controlled study of anti–IL-33 in peanut allergy

et al. 2019

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Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

Phase 2a randomized, placebo-controlled study of anti–IL-33 in peanut allergy

et al. 2019

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“… 2 Despite treatment, almost half of patients with asthma continue to experience exacerbations. 3 These are often associated with an acute rise in ‘type 2’ inflammation, as demonstrated by increases in the type 2 cytokines interleukin (IL)−4, IL-5 and IL-13 in airways samples, 4 5 which correlate with symptom severity. 5 Type 2 inflammation has been shown to impair antiviral immunity, 6–8 thus suppressing type 2 inflammation may confer beneficial effects on host immunity and exacerbation susceptibility.…”

Section: Introductionmentioning

confidence: 99%

Effect of CRTH2 antagonism on the response to experimental rhinovirus infection in asthma: a pilot randomised controlled trial

Farne

Glanville

Johnson

et al. 2021

Thorax

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Background and aimsThe chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) antagonist timapiprant improved lung function and asthma control in a phase 2 study, with evidence suggesting reduced exacerbations. We aimed to assess whether timapiprant attenuated or prevented asthma exacerbations induced by experimental rhinovirus (RV) infection. We furthermore hypothesised that timapiprant would dampen RV-induced type 2 inflammation and consequently improve antiviral immune responses.MethodsAtopic patients with partially controlled asthma on maintenance inhaled corticosteroids were randomised to timapiprant (n=22) or placebo (n=22) and challenged with RV-A16 3 weeks later. The primary endpoint was the cumulative lower respiratory symptom score over the 14 days post infection. Upper respiratory symptoms, spirometry, airway hyperresponsiveness, exhaled nitric oxide, RV-A16 virus load and soluble mediators in upper and lower airways samples, and CRTH2 staining in bronchial biopsies were additionally assessed before and during RV-A16 infection.ResultsSix subjects discontinued the study and eight were not infected; outcomes were assessed in 16 timapiprant-treated and 14 placebo-treated, successfully infected subjects. There were no differences between treatment groups in clinical exacerbation severity including cumulative lower respiratory symptom score day 0–14 (difference 3.0 (95% CI −29.0 to 17.0), p=0.78), virus load, antiviral immune responses, or RV-A16-induced airway inflammation other than in the bronchial biopsies, where CRTH2 staining was increased during RV-A16 infection in the placebo-treated but not the timapiprant-treated group. Timapiprant had a favourable safety profile, with no deaths, serious adverse events or drug-related withdrawals.ConclusionTimapiprant treatment had little impact on the clinicopathological changes induced by RV-A16 infection in partially controlled asthma.

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“…Airway IL33 levels have been associated with type 2 cytokines levels, and a positive correlation with eosinophil numbers in patients with asthma was recently reported. 13 High IL33 levels have been found in induced sputum and bronchial biopsies of patients with asthma compared with in those of nonasthmatic controls. [14][15][16] Moreover, IL33 may have a paracrine effect on the airway epithelium, as this epithelium has been shown to be responsive to IL33.…”

mentioning

confidence: 99%

Phenotypic and functional translation of IL33 genetics in asthma

Ketelaar

Portelli

Dijk

et al. 2021

Journal of Allergy and Clinical Immunology

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Background: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown. Objective: This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function. Methods: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs. Results: We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV 1 , FEV 1 / forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species-capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function. Conclusions: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma. (J Allergy Clin Immunol 2020;nnn:nnn-nnn.)

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Airway Interleukin-33 and type 2 cytokines in adult patients with acute asthma

Cited by 15 publications

References 30 publications

Phase 2a randomized, placebo-controlled study of anti–IL-33 in peanut allergy

Phase 2a randomized, placebo-controlled study of anti–IL-33 in peanut allergy

Effect of CRTH2 antagonism on the response to experimental rhinovirus infection in asthma: a pilot randomised controlled trial

Phenotypic and functional translation of IL33 genetics in asthma

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