Development and validation of a novel bioassay to determine glucocorticoid sensitivity

Biomarker Research - Tập 4 Số 1 - Trang 1-7 - 2016
Williams, Emily L.1,2, Stimpson, Madeleine L.1,2, Collins, Peter L.1,3, Enki, Doyo G.4, Sinha, Ashish3, Lee, Richard W.1,2, Dhanda, Ashwin D.1,5,6
1School of Clinical Sciences, Medical Sciences Building, University of Bristol, Bristol, UK
2National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK
3Department of Liver Medicine, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
4Biostatistics, Bioinformatics and Biomarkers research group, Plymouth University, Plymouth, UK
5Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK
6South West Liver Unit, Plymouth Hospitals NHS Trust, Plymouth, UK

Tóm tắt

Glucocorticoids (GCs) remain the first line treatment for almost all non-infectious inflammatory diseases, ranging from acute asthma to rheumatoid arthritis. However, across all conditions, patients have a variable response to GCs with approximately 30% being non-responders. This group of GC resistant patients is typically exposed to high-dose GCs and their side-effects before more appropriate immunotherapy is instituted. Hence, there is a pressing clinical need for a predictive biomarker of GC responsiveness. The availability of such a tool would also enable patient stratification for the conduct of smart clinical trials in GC resistance. Lymphocyte GC sensitivity has been shown to be closely associated with clinical GC sensitivity in a number of inflammatory diseases. However, the method for determining in vitro GC response is not standardized and requires the use of specialist equipment, including a radioisotope to quantify cellular proliferation, making it challenging to translate into clinical practice. Here we describe the optimization and validation of a novel non-radioactive in vitro bioassay based on measuring cellular proliferation by incorporation of bromodeoxyuridine (BrdU), termed the BrdU incorporation in lymphocyte steroid sensitivity assay (BLISS). In comparison to the current gold standard lymphocyte GC sensitivity assay in 101 healthy control samples, BLISS has an area under receiver operating characteristic of 0.82 and a sensitivity of 83% for correctly identifying GC resistant subjects. The performance of the novel BLISS bioassay makes it a strong candidate biomarker for clinical application. It now requires validation in a prospective patient cohort.

Tài liệu tham khảo

citation_journal_title=Br med j (clin res ed); citation_title=Corticosteroid resistance in chronic asthma; citation_author=J Carmichael, IC Paterson, P Diaz, GK Crompton, AB Kay, IW Grant; citation_volume=282; citation_issue=6274; citation_publication_date=1981; citation_pages=1419-1422; citation_doi=10.1136/bmj.282.6274.1419; citation_id=CR1 citation_journal_title=Br j rheumatol; citation_title=Intramuscular depot methylprednisolone induction of chrysotherapy in rheumatoid arthritis: a 24-week randomized controlled trial; citation_author=MM Corkill, BW Kirkham, IC Chikanza, T Gibson, GS Panayi; citation_volume=29; citation_issue=4; citation_publication_date=1990; citation_pages=274-279; citation_doi=10.1093/rheumatology/29.4.274; citation_id=CR2 citation_journal_title=Hepatology; citation_title=In vitro steroid resistance correlates with outcome in severe alcoholic hepatitis; citation_author=AJ Mambro, R Parker, A McCune, F Gordon, CM Dayan, P Collins; citation_volume=53; citation_issue=4; citation_publication_date=2011; citation_pages=1316-1322; citation_doi=10.1002/hep.24159; citation_id=CR3 citation_journal_title=Gastroenterology; citation_title=The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study; citation_author=WA Faubion, EV Loftus, WS Harmsen, AR Zinsmeister, WJ Sandborn; citation_volume=121; citation_issue=2; citation_publication_date=2001; citation_pages=255-260; citation_doi=10.1053/gast.2001.26279; citation_id=CR4 citation_journal_title=Mol cell endocrinol; citation_title=How glucocorticoid receptors modulate the activity of other transcription factors: a scope beyond tethering; citation_author=D Ratman, W Vanden Berghe, L Dejager, C Libert, J Tavernier, IM Beck, K Bosscher; citation_volume=380; citation_issue=1–2; citation_publication_date=2013; citation_pages=41-54; citation_doi=10.1016/j.mce.2012.12.014; citation_id=CR5 citation_journal_title=Rheumatology; citation_title=Immediate and past cumulative effects of oral glucocorticoids on the risk of acute myocardial infarction in rheumatoid arthritis: a population-based study; citation_author=JA Avina-Zubieta, M Abrahamowicz, MA Vera, HK Choi, EC Sayre, MM Rahman, MP Sylvestre, W Wynant, JM Esdaile, D Lacaille; citation_volume=52; citation_issue=1; citation_publication_date=2013; citation_pages=68-75; citation_doi=10.1093/rheumatology/kes353; citation_id=CR6 citation_journal_title=Pharmacol ther; citation_title=Mechanisms involved in the side effects of glucocorticoids; citation_author=H Schacke, WD Docke, K Asadullah; citation_volume=96; citation_issue=1; citation_publication_date=2002; citation_pages=23-43; citation_doi=10.1016/S0163-7258(02)00297-8; citation_id=CR7 citation_journal_title=Am rev respir dis; citation_title=Glucocorticoid resistance in chronic asthma. Glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics, and inhibition of peripheral blood T cell proliferation by glucocorticoids in vitro; citation_author=CJ Corrigan, PH Brown, NC Barnes, SJ Szefler, JJ Tsai, AJ Frew, AB Kay; citation_volume=144; citation_issue=5; citation_publication_date=1991; citation_pages=1016-1025; citation_doi=10.1164/ajrccm/144.5.1016; citation_id=CR8 citation_journal_title=J allergy clin immunol; citation_title=The effect of dexamethasone, cyclosporine, and rapamycin on T-lymphocyte proliferation in vitro: comparison of cells from patients with glucocorticoid-sensitive and glucocorticoid-resistant chronic asthma; citation_author=A Haczku, A Alexander, P Brown, B Assoufi, B Li, AB Kay, C Corrigan; citation_volume=93; citation_issue=2; citation_publication_date=1994; citation_pages=510-519; citation_doi=10.1016/0091-6749(94)90361-1; citation_id=CR9 citation_journal_title=J clin endocrinol metab; citation_title=Wide variation in lymphocyte steroid sensitivity among healthy human volunteers; citation_author=SD Hearing, M Norman, C Smyth, C Foy, CM Dayan; citation_volume=84; citation_issue=11; citation_publication_date=1999; citation_pages=4149-4154; citation_id=CR10 citation_journal_title=J immunol; citation_title=The effects of cytokines on suppression of lymphocyte proliferation by dexamethasone; citation_author=TJ Creed, RW Lee, PV Newcomb, AJ Mambro, M Raju, CM Dayan; citation_volume=183; citation_issue=1; citation_publication_date=2009; citation_pages=164-171; citation_doi=10.4049/jimmunol.0801998; citation_id=CR11 citation_journal_title=Gut; citation_title=Predicting therapeutic outcome in severe ulcerative colitis by measuring in vitro steroid sensitivity of proliferating peripheral blood lymphocytes; citation_author=SD Hearing, M Norman, CS Probert, N Haslam, CM Dayan; citation_volume=45; citation_issue=3; citation_publication_date=1999; citation_pages=382-388; citation_doi=10.1136/gut.45.3.382; citation_id=CR12 citation_journal_title=J crohns colitis; citation_title=In vitro sensitivity assays and clinical response to glucocorticoids in patients with inflammatory bowel disease; citation_author=JC Maranville, D Micic, SB Hanauer, A Rienzo, SS Kupfer; citation_volume=8; citation_issue=11; citation_publication_date=2014; citation_pages=1539-1547; citation_doi=10.1016/j.crohns.2014.06.013; citation_id=CR13 citation_journal_title=Hepatology; citation_title=Long-term outcome in patients with severe alcoholic hepatitis can be reliably determined using an in vitro measure of steroid sensitivity; citation_author=AD Dhanda, AJ Mambro, VL Hunt, CA McCune, CM Dayan, AD Dick, RW Lee, PL Collins; citation_volume=61; citation_issue=3; citation_publication_date=2015; citation_pages=1099; citation_doi=10.1002/hep.27211; citation_id=CR14 citation_journal_title=J rheumatol; citation_title=Response to glucocorticoid treatment in rheumatoid arthritis: in vitro cell mediated immune assay predicts in vivo responses; citation_author=BW Kirkham, MM Corkill, SC Davison, GS Panayi; citation_volume=18; citation_issue=6; citation_publication_date=1991; citation_pages=821-825; citation_id=CR15 citation_journal_title=J immunol methods; citation_title=Quantitation of 5-bromo-2-deoxyuridine incorporation into DNA: an enzyme immunoassay for the assessment of the lymphoid cell proliferative response; citation_author=T Porstmann, T Ternynck, S Avrameas; citation_volume=82; citation_issue=1; citation_publication_date=1985; citation_pages=169-179; citation_doi=10.1016/0022-1759(85)90236-4; citation_id=CR16 citation_journal_title=Curr protoc cytom; citation_title=Assessment of cell proliferation by 5-bromodeoxyuridine (BrdU) labeling for multicolor flow cytometry; citation_author=K Rothaeusler, N Baumgarth; citation_volume=7; citation_issue=7; citation_publication_date=2007; citation_pages=31; citation_id=CR17 citation_journal_title=Cancer res; citation_title=Differential effects of interleukin-2 and interleukin-15 versus interleukin-21 on CD4+ cutaneous T-cell lymphoma cells; citation_author=M Marzec, K Halasa, M Kasprzycka, M Wysocka, X Liu, JW Tobias, D Baldwin, Q Zhang, N Odum, AH Rook; citation_volume=68; citation_issue=4; citation_publication_date=2008; citation_pages=1083-1091; citation_doi=10.1158/0008-5472.CAN-07-2403; citation_id=CR18 citation_journal_title=Lancet; citation_title=Statistical methods for assessing agreement between two methods of clinical measurement; citation_author=JM Bland, DG Altman; citation_volume=1; citation_issue=8476; citation_publication_date=1986; citation_pages=307-310; citation_doi=10.1016/S0140-6736(86)90837-8; citation_id=CR19 Bland JM. How do I compare methods of measurement which give results in different units? https://www-users.york.ac.uk/~mb55/meas/diffunit.htm . Accessed 16 July 2016. citation_journal_title=Hepatology; citation_title=The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids; citation_author=A Louvet, S Naveau, M Abdelnour, MJ Ramond, E Diaz, L Fartoux, S Dharancy, F Texier, A Hollebecque, L Serfaty; citation_volume=45; citation_issue=6; citation_publication_date=2007; citation_pages=1348-1354; citation_doi=10.1002/hep.21607; citation_id=CR21 citation_journal_title=J immunol; citation_title=Characterization of pulmonary T cell response to helper-dependent adenoviral vectors following intranasal delivery; citation_author=R Kushwah, H Cao, J Hu; citation_volume=180; citation_issue=6; citation_publication_date=2008; citation_pages=4098-4108; citation_doi=10.4049/jimmunol.180.6.4098; citation_id=CR22
Thông tin
Thông tin xuất bản

Biomarker Research

Tập 4 Số 1

1-7

Thông tin tác giả