@article{9dcd8c165cb743e7ad935ad1407c76da,
title = "An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup",
abstract = "BACKGROUND. Chronic obstructive pulmonary disease (COPD) is a heterogeneous smoking-related disease characterized by airway obstruction and inflammation. This inflammation may persist even after smoking cessation and responds variably to corticosteroids. Personalizing treatment to biologically similar {"}molecular phenotypes{"} may improve therapeutic efficacy in COPD. IL-17A is involved in neutrophilic inflammation and corticosteroid resistance, and thus may be particularly important in a COPD molecular phenotype. METHODS. We generated a gene expression signature of IL-17A response in bronchial airway epithelial brushings from smokers with and without COPD (n = 238), and validated it using data from 2 randomized trials of IL-17 blockade in psoriasis. This IL-17 signature was related to clinical and pathologic characteristics in 2 additional human studies of COPD: (a) SPIROMICS (n = 47), which included former and current smokers with COPD, and (b) GLUCOLD (n = 79), in which COPD participants were randomized to placebo or corticosteroids. RESULTS. The IL-17 signature was associated with an inflammatory profile characteristic of an IL-17 response, including increased airway neutrophils and macrophages. In SPIROMICS the signature was associated with increased airway obstruction and functional small airways disease on quantitative chest CT. In GLUCOLD the signature was associated with decreased response to corticosteroids, irrespective of airway eosinophilic or type 2 inflammation. CONCLUSION. These data suggest that a gene signature of IL-17 airway epithelial response distinguishes a biologically, radiographically, and clinically distinct COPD subgroup that may benefit from personalized therapy.",
author = "Christenson, {Stephanie A.} and {Van Den Berge}, Maarten and Alen Faiz and Kai Inkamp and Nirav Bhakta and Bonser, {Luke R.} and Zlock, {Lorna T.} and Barjaktarevic, {Igor Z.} and Barr, {R. Graham} and Bleecker, {Eugene R.} and Boucher, {Richard C.} and Bowler, {Russell P.} and Comellas, {Alejandro P.} and Curtis, {Jeffrey L.} and Han, {Mei Lan K.} and Hansel, {Nadia N.} and Hiemstra, {Pieter S.} and Kaner, {Robert J.} and Krishnanm, {Jerry A.} and Martinez, {Fernando J.} and O'Neal, {Wanda K.} and Robert Paine and Wim Timens and Wells, {J. Michael} and Avrum Spira and Erle, {David J.} and Woodruff, {Prescott G.}",
note = "Funding Information: We thank the SPIROMICS and GLUCOLD participants and participating physicians, investigators, and staff for making this research possible. More information about the study and how to access SPIROMICS data is at www.spiromics.org. In the Supplemental Acknowledgments online, we acknowledge current and former investigators of the SPIROMICS sites and reading centers. Grants from the NIH (U19AI077439 to DJE, LRB, and LTZ; K23HL123778 to SAC; K12HL11999 to SAC and DJE; K24HL137013 and R01HL121774 to PGW) and a RESPIRE2 grant from the European Respiratory Society (to AF) supported this work. Human cell culture experiments were partially funded by the UCSF Cystic Fibrosis Cell Models Core (Walter Finkbeiner, director; NIH grant DK072517 and Cystic Fibrosis Foundation grant DR613-CR11). The GLUCOLD study (for which these are secondary unfunded analyses) was supported by the Netherlands Organization for Scientific Research (NWO), the Dutch Asthma Foundation, GlaxoSmithKline, the University Medical Center Groningen, and Leiden University Medical Center. SPIROMICS was supported by contracts from the NIH/National Heart, Lung, and Blood Institute (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268-200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation by AstraZeneca/MedImmune, Bayer, Bellerophon Therapeutics, Boehringer-Ingelheim Pharmaceuticals Inc., Chiesi Farmaceutici SpA, Forest Research Institute Inc., GlaxoSmithKline, Grifols Therapeutics Inc., Ikaria Inc., Nycomed GmbH, Takeda Pharmaceutical Co., Novartis Pharmaceuticals Corp., ProterixBio, Regeneron Pharmaceuticals Inc., Sanofi, and Sunovion. SPIROMICS II is supported by NIH grant U01 HL137880. Funding Information: FUNDING. Primary support from the NIH, grants K23HL123778, K12HL11999, U19AI077439, DK072517, U01HL137880, K24HL137013 and R01HL121774 and contracts HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C and HHSN268200900020C. Publisher Copyright: {\textcopyright} 2019 American Society for Clinical Investigation. All rights reserved.",
year = "2019",
month = jan,
day = "2",
doi = "10.1172/JCI121087",
language = "English (US)",
volume = "129",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "1",
}