posted on 2015-08-21, 10:42authored byD. F. Choy, K. M. Hart, L. A. Borthwick, Aarti Shikotra, D. R. Nagarkar, Salman Siddiqui, G. Jia, Chandra M. Ohri, E. Doran, K. M. Vannella, C. A. Butler, Beverley Hargadon, J. C. Sciurba, R. L. Gieseck, R. W. Thompson, S. White, A. R. Abbas, J. Jackman, L. C. Wu, J. G. Egen, L. G. Heaney, T. R. Ramalingam, J. R. Arron, T. A. Wynn, Peter Bradding
Increasing evidence suggests that asthma is a heterogeneous disorder regulated
by distinct molecular mechanisms. Here, 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/Th17-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 IL-13 and IL-17A. To understand this dichotomous pattern of 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-1
and IL-17 protected subjects from eosinophilia, mucus hyperplasia, 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.
Funding
Supported in part by the Intramural Research Program of the NIH, NIAID.
Work in Leicester was supported by grants from Asthma UK project grant AUK-PG-
2013-208 and a grant-in-aid from Genentech,Inc., and was supported by the National
Institute for Health Research Leicester Respiratory Biomedical Research Unit.
History
Citation
Science Translational Medicine 19 Aug 2015: Vol. 7, Issue 301, pp. 301ra129
Author affiliation
/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Infection, Immunity and Inflammation
Version
AM (Accepted Manuscript)
Published in
Science Translational Medicine 19 Aug 2015: Vol. 7
Publisher
American Association for the Advancement of Science