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Effects of interleukin-6 receptor blockade on allergen-induced airway responses in mild asthmatics.

ABSTRACT: Background:Interleukin (IL)-6 signalling has been implicated in allergic asthma by animal, genetic association and clinical studies. In this study, we tested the hypothesis that tocilizumab (TCZ), a human monoclonal antibody that blocks IL-6 signalling, can prevent the development of allergen-induced bronchoconstriction in humans. Methods:We performed a randomised, double-blind, placebo-controlled study, with eligible participants completing two allergen inhalation challenge tests, conducted before and after treatment with a single dose of TCZ or placebo. The primary efficacy endpoint was the magnitude of the late asthmatic response recorded between 3 and 7 after allergen challenge. The secondary efficacy endpoint was the early asthmatic response, measured 20 min to 2 h after allergen challenge. Results:A total of 66 patients enrolled between September 2014 and August 2017, when the trial was stopped for futility based on results from an interim analysis. Eleven patients fulfilled all eligibility criteria assessed at baseline and were subsequently randomised to the TCZ (n = 6) or placebo (n = 5) groups. Both the primary and secondary efficacy endpoints were not significantly different between the two groups. Five patients reported adverse events (AEs), three in the TCZ group (11 AEs) and two in the placebo group (four AEs). Only one AE was TCZ-related (mild neutropenia), and there were no serious AEs. Significant treatment effects were observed for serum levels of C-reactive protein, IL-6 and soluble IL-6R levels. Conclusion:In a small proof-of-concept clinical trial, we found no evidence that a single dose of tocilizumab was able to prevent allergen-induced bronchoconstriction. (Trial registered in the Australian New Zealand Clinical Trials Registry, number ACTRN12614000123640).

SUBMITTER: Revez JA

PROVIDER: S-EPMC6566140 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Effects of interleukin-6 receptor blockade on allergen-induced airway responses in mild asthmatics.

Revez Joana A JA Bain Lisa M LM Watson Rick M RM Towers Michelle M Collins Tina T Killian Kieran J KJ O'Byrne Paul M PM Gauvreau Gail M GM Upham John W JW Ferreira Manuel Ar MA

Clinical & translational immunology 20190614 6

<h4>Background</h4>Interleukin (IL)-6 signalling has been implicated in allergic asthma by animal, genetic association and clinical studies. In this study, we tested the hypothesis that tocilizumab (TCZ), a human monoclonal antibody that blocks IL-6 signalling, can prevent the development of allergen-induced bronchoconstriction in humans.<h4>Methods</h4>We performed a randomised, double-blind, placebo-controlled study, with eligible participants completing two allergen inhalation challenge tests ...[more]

PMID: 31223480

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Project description:Glutathione S-transferase P1 is a Phase II cytoprotective and detoxifying enzyme that is widely expressed in human airways. The glutathione S-transferase P1 Ile105Val polymorphism has been linked with atopic disorders and asthma. Yet, little remains known about the regulation of allergic inflammation by glutathione S-transferase P1 in human asthmatics.To establish the effect of the glutathione S-transferase P1 Ile105Val polymorphism on allergen-induced airway inflammation and oxidant stress, and non-specific bronchial hyperresponsiveness to methacholine and reactivity to specific allergen in mild human atopic asthmatics in vivo.Five Val(105)/Val(105) , twelve Val(105)/Ile(105) and twenty Ile(105)/Ile(105) mild atopic asthmatics underwent methacholine challenge, inhaled allergen challenge and endobronchial allergen provocation through a bronchoscope. A panel of inflammatory cytokines and chemokines, F2 -isoprostanes and isofuranes, markers of oxidative stress, thromboxane B2 and immunoglobulin E were measured in bronchoalveolar lavage fluid at baseline and 24 h after allergen instillation.Asthmatics with glutathione S-transferase P1 Val(105)/Val(105) compared with asthmatics with the glutathione S-transferase P1 Val(105)/Ile(105) and Ile(105)/Ile(105) had greater generation of acute phase cytokines (TNF-?, IL-6, CXCL8), IL-12, CCL11, thromboxane B2 and immunoglobulin E at 24 h after local allergen challenge. The GSTP1 genotype had no effect on airway hyperresponsiveness to methacholine and the reactivity to specific allergen.The glutathione S-transferase P1 Ile105Val polymorphism markedly modifies allergen-provoked airway inflammation in atopic asthmatics in vivo. Modulation of the biochemical milieu in response to allergen provides a mechanistic explanation for regulatory effects of glutathione S-transferase P1 polymorphism on airway pathophysiology, and may guide improvement of future therapeutic methods in human atopic asthmatics. These findings must me confirmed in a larger study population of asthmatics with various ethnicities.

Project description:BackgroundAirway obstruction is a physiologic feature of asthma, and IL-15 might have an important role in asthma pathogenesis.ObjectiveWe tested the hypothesis that regulation of IL-15 is critical for preservation of allergen-induced airway hyperresponsiveness (AHR), airway resistance, and compliance in response to methacholine.MethodsAirway inflammation, AHR, resistance, and compliance were assessed in Il15 gene-deficient mice and IL-15-overexpressing mice in an allergen-induced murine model of asthma. We assessed eosinophil numbers by using anti-major basic protein immunostaining, goblet cell hyperplasia by using periodic acid-Schiff staining, and cytokine and chemokine levels by performing quantitative PCR and ELISA.ResultsWe made a novel observation that IL-15 deficiency promotes baseline airway resistance in naive mice. Moreover, rIL-15 delivery to the lung downregulates expression of proinflammatory cytokines and improves allergen-induced AHR, airway resistance, and compliance. These observations were further validated in doxycycline-inducible CC10-IL-15 bitransgenic mice. Doxycycline-exposed, Aspergillus species extract-challenged CC10-IL-15 bitransgenic mice exhibited significantly reduced levels of proinflammatory cytokines (IL-4, IL-5, and IL-13) and decreased goblet cell hyperplasia. Airway obstruction, including AHR and airway resistance, was diminished in allergen-challenged doxycycline-exposed compared with non-doxycycline-exposed CC10-IL-15 bitransgenic mice. Mechanistically, we observed that IL-15-mediated protection of airway obstruction is associated with induced IFN-γ- and IL-10-producing regulatory CD4+CD25+ forkhead box p3 (Foxp3)+ T cells. Additionally, we found that a human IL-15 agonist (ALT-803) improved airway resistance and compliance in an experimental asthma model.ConclusionWe report our novel finding that IL-15 has a potent inhibitory effect on the airway obstruction that occurs in response to environmental allergens.

Dataset Information

Effects of interleukin-6 receptor blockade on allergen-induced airway responses in mild asthmatics.

Publications

Effects of interleukin-6 receptor blockade on allergen-induced airway responses in mild asthmatics.

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