Therapeutic potential of anti-IL-6 therapies for granulocytic airway inflammation in asthma

Abstract

BackgroundDetermining the cellular and molecular phenotypes of inflammation in asthma can identify patient populations that may best benefit from targeted therapies. Although elevated IL-6 and polymorphisms in IL-6 signalling are associated with lung dysfunction in asthma, it remains unknown if elevated IL-6 levels are associated with a specific cellular inflammatory phenotype, and how IL-6 blockade might impact such inflammatory responses.MethodsPatients undergoing exacerbations of asthma were phenotyped according to their airway inflammatory characteristics (normal cell count, eosinophilic, neutrophilic, mixed granulocytic), sputum cytokine profiles, and lung function. Mice were exposed to the common allergen, house dust-mite (HDM), in the presence or absence of endogenous IL-6. The intensity and nature of lung inflammation, and levels of pro-granulocytic cytokines and chemokines under these conditions were analyzed.ResultsElevated IL-6 was associated with a lower FEV1 in patients with mixed eosinophilic-neutrophilic bronchitis. In mice, allergen exposure increased lung IL-6 and IL-6 was produced by dendritic cells and alveolar macrophages. Loss-of-function of IL-6 signalling (knockout or antibody-mediated neutralization) abrogated elevations of eosinophil and neutrophil recruiting cytokines/chemokines and allergen-induced airway inflammation in mice.ConclusionsWe demonstrate the association of pleiotropic cellular airway inflammation with IL-6 using human and animal data. These data suggest that exacerbations of asthma, particularly those with a combined eosinophilic and neutrophilic bronchitis, may respond to therapies targeting the IL-6 pathway and therefore, provide a rational basis for initiation of clinical trials to evaluate this.

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

“…Second, the provoked model of asthma that we used might not be the most effective approach to assess the efficacy of therapies that target non‐type 2 inflammatory pathways. Based on historical data, we expected that ~40% of patients tested using this model would develop airway inflammation during the LAR that was rich in both eosinophils and neutrophils, the inflammatory subtype that we and others have suggested is more likely to respond to TCZ treatment. However, at 7 h postchallenge, only one of the 11 patients was found to have mixed‐granulocytic sputum, with an additional two patients having this subtype at 24 h postchallenge.…”

“…[18][19][20] In clinical studies, IL-6 levels have been reported to be elevated in asthmatics, both systemically and in the airways. [21][22][23] In turn, high IL-6 levels have been associated with reduced lung function [24][25][26] and more severe disease symptoms. 24,27 Allergen (but not methacholine) challenge has also been shown to increase serum levels of both IL-6 21 and sIL-6R.…”

Secretion of an immunoreactive single-chain variable fragment antibody against mouse interleukin 6 by Lactococcus lactis

“…For example, in IBD including Crohn's disease and ulcerative colitis, IL-6 has been associated with mucosal inflammation in gastrointestinal tract mediated by various cellular mechanisms such as the regulation of T cell differentiation, activation, and proliferation (Hunter and Jones 2015;Waldner and Neurath 2014). A recent study in asthma patients demonstrated that IL-6 impaired lung function through exacerbation of mixed eosinophilic-neutrophilic bronchitis (Chu et al 2015). In addition, IL-6-dependent activation of signal transducer and activator of transcription 3 (STAT3)…”

“…Based on these findings, it has suggested that IL-6/IL-6R signaling is a potential therapeutic target in those diseases. Indeed, several pre-clinical studies with model animals have demonstrated that systemic application of an antibody against IL-6 or IL-6R could inhibit the development of inflammation and tumor in respiratory and gastrointestinal tracts (Chu et al 2015;Song et al 2014;Yamamoto et al 2000). Therefore, direct delivery of rIL6scFv to the mucosa using NZ-IL6scFv might be a good strategy for the treatment of IBD, asthma, and cancer of the mucosal tissue, among others.…”

Mechanisms and therapeutic strategies for non‐T2 asthma

“…The investigators found that lung IL‐6 levels were higher for mice exposed to house dust mite intranasally than those exposed to saline. House dust mite provoked inflammatory responses in the airway were blunted in IL‐6 knockout mice and wild‐type mice treated with anti‐IL‐6 antibody, with all airway and tissue cell types including neutrophils and eosinophils significantly reduced . Peters et al demonstrated that high plasma IL‐6 levels were associated with metabolic syndrome (hypertension, diabetes, and higher BMI), worse lung function, and higher risk of exacerbations.…”