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Lookup NU author(s): Dr Lee Borthwick
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. In a cross-sectional study of asthmatics of varying severity (n = 51), endobronchial tissue gene expression analysis revealed three major patient clusters: T(H)2-high, T(H)17-high, and T(H)2/17-low. T(H)2-high and T(H)17-high patterns were mutually exclusive in individual patient samples, and their gene signatures were inversely correlated and differentially regulated by interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (T(H)2) and T(H)17 signatures, we investigated the potential of type 2 cytokine suppression in promoting T(H)17 responses in a preclinical model of allergen-induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased T(H)17 cells and neutrophilic inflammation in the lung. However, neutralization of IL-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population comprising both T(H)2 and T(H)17 endotypes.
Author(s): Choy DF, Hart KM, Borthwick LA, Shikotra A, Nagarkar DR, Siddiqui S, Jia GQ, Ohri CM, Doran E, Vannella KM, Butler CA, Hargadon B, Sciurba JC, Gieseck RL, Thompson RW, White S, Abbas AR, Jackman J, Wu LC, Egen JG, Heaney LG, Ramalingam TR, Arron JR, Wynn TA, Bradding P
Publication type: Article
Publication status: Published
Journal: Science Translational Medicine
Year: 2015
Volume: 7
Issue: 301
Pages: 1-10
Online publication date: 19/08/2015
Acceptance date: 02/07/2015
Date deposited: 26/05/2016
ISSN (print): 1946-6234
ISSN (electronic): 1946-6242
Publisher: American Association for the Advancement of Science
URL: http://dx.doi.org/10.1126/scitranslmed.aab3142
DOI: 10.1126/scitranslmed.aab3142
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