Combined administration of anti‐IL‐13 and anti‐IL‐17A at individually sub‐therapeutic doses limits asthma‐like symptoms in a mouse model of Th2/Th17 high asthma

Abstract

Background: Recent studies have demonstrated that Th2 responses have the ability to antagonize Th17 responses. In mouse models of allergic asthma, blockade of Th2-effector cytokines results in elaboration of Th17 responses and associated increases in pulmonary neutrophilia. While these can be controlled by simultaneous blockade of Th17associated effector cytokines, clinical trials of anti-IL-17/IL-17RA blocking therapies have demonstrated increased of risk of bacterial and fungal infections. Identification of minimally effective doses of cytokine-blocking therapies with the goal of reducing the potential emergence of infection-related complications is a translationally relevant goal.Objective: In the current report, we examine whether combined blockade of IL-13 and IL-17A, at individually sub-therapeutic levels, can limit the development of allergic asthma while sparing expression of IL-17A-associated anti-microbial effectors.Methods: House dust mite was given intratracheally to A/J mice. Anti-IL-13 and anti-IL-17A antibodies were administered individually, or concomitantly at sub-therapeutic doses. Airway hyper-reactivity, lung inflammation, magnitude of Th2-and Th17-associated cytokine production and expression of IL-13-and IL-17A-induced genes in the lungs was assessed.Results: Initial dosing studies identified sub-therapeutic levels of IL-13 and IL-17A blocking mAbs that have a limited effect on asthma parameters and do not impair responses to microbial products or infection. Subsequent studies demonstrated that combined sub-therapeutic dosing with IL-13 and IL-17A blocking mAbs resulted in significant improvement in airway hyperresponsiveness (AHR) and expression of IL-13-induced gene expression. Importantly, these doses neither exacerbated nor inhibited production of Th17-associated cytokines, or IL-17A-associated gene expression. Conclusion: This study suggests that combining blockade of individual Th2 andTh17 effector cytokines, even at individually sub-therapeutic levels, may be sufficient to limit disease development while preserving important anti-microbial pathways. Such a strategy may therefore have reduced potential for adverse events associated with blockade of these pathways.

Exacerbation of Mycobacterium avium pulmonary infection by comorbid allergic asthma is associated with diminished mycobacterium-specific Th17 responses

“…Second, increases in regulatory T cell numbers to control hyperinflammation in the context of comorbidity can decrease Th17 cell numbers to preserve host homeostasis [ 54 ]. Third, several studies have clarified that allergen-induced Th2-type cytokines can suppress Th17 responses [ 44 , 55 ], which supports our finding that only relatively late induction of allergic asthma inhibited preexisting Mav-specific Th17 responses and increased the number of CFUs at 5 w.p.i.…”

IL‐17 regulates DC migration to the peribronchial LNs and allergen presentation in experimental allergic asthma

“…We found that absence of IL‐17A/F or neutralization of IL‐17A alone led to attenuation of severity of experimental allergic asthma, either before sensitization or challenge. These findings are in line with the results of other studies using related mouse models [37, 38]. Moreover, we report that the observed reduction in pulmonary eosinophilic inflammation, AHR and goblet cell hyperplasia correlated with reduced conventional DC frequencies both in the lung and lung draining mediastinal LNs of IL‐17A/F KO allergic animals.…”

“…To our knowledge, this is the first evidence that links availability of IL‐17 in an experimental asthma model to reduced migration of DCs with a possible effect in attenuation of severity of inflammation and AHR. Given that IL‐17 and Th17 cells are involved in asthma development and shown to be associated with severity and course of disease [7‐9, 37, 38], we believe this is an important mechanism by which this cytokine enhances inflammation and associated pathologies such as those in asthma and allergy.…”

Diagnostic Tools and Biomarkers for Severe Drug Eruptions

“…IL-17-producing cells are involved in various inflammatory diseases, such as psoriasis [ 70 , 71 , 72 , 73 , 74 ], asthma [ 75 , 76 , 77 , 78 , 79 ], and atopic dermatitis [ 80 , 81 , 82 ], and contribute to the development of host defense against microorganisms [ 83 , 84 , 85 , 86 ]. As the importance of IL-17-producing cells in the human body, IL-17-targeted biologics treatment is proven by the current advancement of this field.…”