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Sci Transl Med. 2015 Aug 19;7(301):301ra129. doi: 10.1126/scitranslmed.aab3142.

TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma.

Author information

1
Genentech Inc., South San Francisco, CA 94080, USA.
2
Program in Tissue Immunity and Repair, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
3
Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
4
Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester LE3 9QP, UK.
5
Genentech Inc., South San Francisco, CA 94080, USA. Centre for Infection and Immunity, Health Sciences Building, Queens University Belfast, Lisburn Road, Belfast BT9 7AB, Northern Ireland, UK.
6
Centre for Infection and Immunity, Health Sciences Building, Queens University Belfast, Lisburn Road, Belfast BT9 7AB, Northern Ireland, UK.
7
Genentech Inc., South San Francisco, CA 94080, USA. arron.joseph@gene.com.

Abstract

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: TH2-high, TH17-high, and TH2/17-low. TH2-high and TH17-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 (TH2) and TH17 signatures, we investigated the potential of type 2 cytokine suppression in promoting TH17 responses in a preclinical model of allergen-induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased TH17 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 TH2 and TH17 endotypes.

PMID:
26290411
DOI:
10.1126/scitranslmed.aab3142
[Indexed for MEDLINE]

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