IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways

Manson, Martijn L.; Säfholm, Jesper; James, Anna; Johnsson, Anna‐Karin; Bergman, Per; Al‐Ameri, Mamdoh; Orre, Ann-Charlotte; Kärrman-Mårdh, Carina; Dahlén, Sven‐Erik; Adner, Mikael

doi:10.1016/j.jaci.2019.10.037

Cited by 103 publications

(80 citation statements)

References 45 publications

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“…Accumulating evidence indicates that classical type 2 cytokines (IL-4, IL-5, IL-13) play critical roles in the induction of airway hyperreactivity, allergic inflammation, tissue remodeling, and mucus production in the airways. 91,92 CRSwNP is characterized by infiltration with IL-4-and IL-13-expressing cells, including T H 2 CD4 1 cells, ILC2 cells, basophils, and mast cells. T H 2 cells and ILC2s are the major producers of IL-13, 93,94 whereas IL-4 is produced mostly by basophils and T H 2 cells in asthmatic lungs.…”

Section: Type 2 Crswnp: Orchestrated By Il-4 and Il-13mentioning

confidence: 99%

Biologics for chronic rhinosinusitis with nasal polyps

Bachert

Zhang

Cavaliere

et al. 2020

Journal of Allergy and Clinical Immunology

130

101

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With the increasing recognition of the role of type 2 immune responses in chronic rhinosinusitis, its severity, recurrence, and comorbidities, several biologics targeting IL-4, IL-5, and IL-13 as well as IgE have been administered in small proof-of-concept studies. Recently, the first phase 3 trials have been reported with dupilumab, an IL-4 receptor antagonist, demonstrating a significant and clinically relevant reduction of the disease burden from polyp size and sinus involvement to symptoms and smell; these changes consecutively led to an important increase in quality of life. Finally, the biologic versus placebo treatment reduced the need for systemic glucocorticosteroids and sinus surgery significantly and clinically meaningfully. Dupilumab today is registered for the treatment of chronic rhinosinusitis with nasal polyps in Europe and the United States. Within a year, 2 further phase 3 trials with omalizumab and mepolizumab will be reported. With this development, without any doubt, a new era for the treatment of severe uncontrolled chronic rhinosinusitis with nasal polyps has begun. Questions on the indication of the biologics, the selection of patients, and finally criteria for monitoring the efficacy in individual patients need to be urgently answered, and care pathways need to be established integrating the current standard of care including surgery.

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Section: Type 2 Crswnp: Orchestrated By Il-4 and Il-13mentioning

confidence: 99%

Biologics for chronic rhinosinusitis with nasal polyps

Bachert

Zhang

Cavaliere

et al. 2020

Journal of Allergy and Clinical Immunology

130

101

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“…AHR refers to the predisposition of the airways to narrow excessively in response to stimuli, such as allergens, environmental irritants, and exercise. IL-13 and IL-4 are considered to provoke AHR of airway smooth muscle [26], and the association between serum periostin and AHR has been demonstrated in asthmatic children [27]. Therefore, AHR via IL-4 and IL-13 pathway including periostin may also be involved in the development of DH.…”

Section: Discussionmentioning

confidence: 99%

Serum periostin reflects dynamic hyperinflation in patients with asthma

Asano¹,

Ohbayashi²,

Ariga³

et al. 2020

ERJ Open Res

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IntroductionDynamic hyperinflation (DH) is sometimes observed and is associated with impaired daily life activities of asthma. We assessed the relationship between DH and asthma biomarkers (blood eosinophil, fractional exhaled nitric oxide (FeNO) and serum periostin) in patients with asthma.MethodsFifty patients with stable asthma were prospectively recruited and underwent blood test, FeNO measurement, spirometry and metronome-paced tachypnoea (MPT) test to assess DH. In MPT tests, inspiratory capacity (IC) was measured at baseline and after 30 s of MPT with breathing frequencies of 20, 30 and 40 breaths·min−1. DH was assessed by the decline of IC from baseline, and maximal IC reduction ≥10% was considered as positive DH.ResultsThirty patients (60%) showed positive DH. Patients with positive DH showed higher serum periostin levels (107.0±30.7 ng·mL−1) than patients with negative DH (89.7±23.7) (p=0.04). Patients in Global Initiative for Asthma treatment steps 4–5 (n=19) showed higher serum periostin levels (p=0.01) and more severe IC reduction after MPT (p<0.0001) than patients in steps 1–3 (n=31). Maximal IC reduction after MPT was significantly correlated with asthma control test score (r=−0.28, p=0.05), forced expiratory volume in 1 s (r=−0.56, p<0.0001), and serum periostin levels (r=0.41, p=0.003).ConclusionSerum periostin may have the possibility to reflect DH in patients with stable asthma.

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“…Perhaps, the lack of IL‐5‐mediated airway hyperresponsiveness in small airways could be due to the preponderance of airway smooth muscle in the bronchioles wall and the significantly lower, and almost absent, number of eosinophils in bronchioles compared to medium bronchi we have used in our experiments (Faul et al, 1997; Hyde, Hamid, & Irvin, 2009). Furthermore, a possible bias leading to the absence of airway hyperresponsiveness in the bronchioles used by Manson et al (2019) is that their tissues were not passively sensitized, a procedure that induces airway hyperresponsiveness via IgE in the presence of further serum factors (Ichinose et al, 1996; Mitchell et al, 1997; Schmidt & Rabe, 2000; Schmidt et al, 1999). In fact, it is noteworthy that airway hyperresponsiveness is dependent upon still unknown serum factors that seem to be IgE related (Watson, Ruhlmann, Magnussen, & Rabe, 1998).…”

Section: Discussionmentioning

confidence: 99%

Targeting IL‐5 pathway against airway hyperresponsiveness: A comparison between benralizumab and mepolizumab

Calzetta

Ritondo

Matera

et al. 2020

British J Pharmacology

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Background and Purpose Airway hyperresponsiveness (AHR) is a central abnormality in asthma. IL‐5 may modulate AHR in animal models of asthma, but the available data is inconsistent on the impact of targeting IL‐5 pathway against AHR. The difference between targeting IL‐5 or the IL‐5 receptor, α subunit (IL‐5Rα) in modulating AHR remains to be investigated in human airways. The aim of this study was to compare the role of the anti‐IL‐5Rα benralizumab and the anti‐IL‐5 mepolizumab against AHR and to assess whether these agents influence the levels of cAMP. Experimental Approach Passively sensitized human airways were treated with benralizumab and mepolizumab. The primary endpoint was the inhibition of AHR to histamine. The secondary endpoints were the protective effect against AHR to parasympathetic activation and mechanical stress, and the tissue modulation of cAMP. Key Results Benralizumab and mepolizumab significantly inhibited the AHR to histamine (maximal effect −134.14 ± 14.93% and −108.29 ± 32.16%, respectively), with benralizumab being 0.73 ± 0.10 logarithm significantly more potent than mepolizumab. Benralizumab and mepolizumab significantly inhibited the AHR to transmural stimulation and mechanical stress. Benralizumab was 0.45 ± 0.16 logarithm significantly more potent than mepolizumab against AHR to parasympathetic activation. The effect of these agents was significantly correlated with increased levels of cAMP. Conclusion and Implications Targeting the IL‐5/IL‐5Rα axis is an effective strategy to prevent the AHR. Benralizumab was more potent than the mepolizumab and the concentration‐dependent beneficial effects of both these monoclonal antibodies were related to improved levels of cAMP in hyperresponsive airways.

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IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways

Abstract: were employed at Astra Zeneca during parts of this study. The rest of the authors declare that they have no relevant conflicts of interest.

Cited by 103 publications

References 45 publications

Biologics for chronic rhinosinusitis with nasal polyps

Biologics for chronic rhinosinusitis with nasal polyps

Serum periostin reflects dynamic hyperinflation in patients with asthma

Targeting IL‐5 pathway against airway hyperresponsiveness: A comparison between benralizumab and mepolizumab

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