Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy

被引：16

作者：

Christakoudi, Sofia ^{[1
,2
,28
]}

Runglall, Manohursingh ^{[3
]}

Mobillo, Paula ^{[1
]}

Rebollo-Mesa, Irene ^{[1
,2
,29
]}

Tsui, Tjir-Li ^{[1
,4
]}

Nova-Lamperti, Estefania ^{[1
,30
]}

Taube, Catharine ^{[1
]}

Norris, Sonia ^{[1
,31
]}

Kamra, Yogesh ^{[1
,32
]}

Hilton, Rachel ^{[4
]}

Augustine, Titus ^{[5
,33
]}

Bhandari, Sunil ^{[6
,33
]}

Baker, Richard ^{[7
,33
]}

Berglund, David ^{[8
,33
]}

Carr, Sue ^{[9
,33
]}

Game, David ^{[4
,33
]}

Griffi, Sian ^{[10
,33
]}

Kalra, Philip A. ^{[11
,33
]}

Lewis, Robert ^{[12
,33
]}

Mark, Patrick B. ^{[13
,33
]}

Marks, Stephen D. ^{[14
,15
,33
]}

MacPhee, Iain ^{[16
,17
,33
,34
]}

McKane, William ^{[18
,33
]}

Mohaupt, Markus G. ^{[19
,20
,21
,33
]}

Paz-Artal, Estela ^{[22
,33
]}

Kon, Sui Phin ^{[23
,33
]}

Seron, Daniel ^{[24
,33
]}

Sinha, Manish D. ^{[25
,26
,33
]}

Tucker, Beatriz ^{[23
,33
]}

Viklicky, Ondrej ^{[27
,33
]}

Stahl, Daniel ^{[2
]}

Lechler, Robert I. ^{[1
,26
]}

Lord, Graham M. ^{[1
,3
,4
,35
]}

Hernandez-Fuentes, Maria P. ^{[1
,26
]}

机构：

[1] Kings Coll London, MRC Ctr Transplantat, London SE1 9RT, England

[2] Kings Coll London, Inst Psychiat Psychol & Neurosci, Biostat & Hlth Informat Dept, 16 De Crespigny Pk, London SE5 8AF, England

[3] Guys & St Thomas NHS Fdn Trust & Kings Coll Londo, NIHR Biomed Res Ctr, London SE1 9RT, England

[4] Guys & St Thomas NHS Fdn Trust, London SE1 9RT, England

[5] Manchester Royal Infirm, Oxford Rd, Manchester M13 9WL, Lancs, England

[6] Hull Univ Teaching Hosp NHS Trust, Anlaby Rd, Kingston Upon Hull HU3 2JZ, N Humberside, England

[7] St James Univ Hosp, Beckett St, Leeds LS9 7TF, W Yorkshire, England

[8] Uppsala Univ, Dept Immunol Genet & Pathol, Rudbecklaboratoriet, S-75185 Uppsala, Sweden

[9] Leicester Gen Hosp, Gwendolen Rd, Leicester LE5 4PW, Leics, England

[10] Cardiff & Vale Univ Hlth Board, Cardiff CF14 4XW, Wales

[11] Salford Royal NHS Fdn Trust, Stott Ln, Salford M6 8HD, Lancs, England

[12] Queen Alexandra Hosp, Southwick Hill Rd, Portsmouth PO6 3LY, Hants, England

[13] Univ Glasgow, Univ Ave, Glasgow G12 8QQ, Lanark, Scotland

[14] Great Ormond St Hosp Children NHS Fdn Trust, Dept Paediat Nephrol, Great Ormond St, London WC1N 3JH, England

[15] Univ Coll London Great Ormond St Inst Child Hlth, NIHR Great Ormond St Hosp Biomed Res Ctr, London WC1N, England

[16] St George Hosp, Blackshaw Rd, London SW17 0QT, England

[17] Univ London, Inst Med & Biomed Educ, Cranmer Terrace, London SW17 0RE, England

[18] Northern Gen Hosp, Herries Rd, Sheffield S5 7AU, S Yorkshire, England

[19] Lindenhofgrp Berne, Internal Med, Bern, Switzerland

[20] Univ Bern, Bern, Switzerland

[21] Univ Nottingham, Sch Med, Nottingham NG5, England

[22] Univ Hosp 12 Octubre, Dept Immunol & Imas12 Res Inst, Madrid, Spain

[23] Kings Coll Hosp NHS Fdn Trust, Denmark Hill, London SE5 9RS, England

[24] Hosp Univ Vall dHebron, Passeig Vall dHebron 119-129, Barcelona 08035, Spain

[25] Evelina London Childrens Hosp, Bridge Rd, London SE1 7EH, England

[26] Guys Hosp, Kings Hlth Partners, London SE1 9RT, England

[27] IKEM, Videnska 1958-9, Prague 14021 4, Czech Republic

[28] Imperial Coll London, Epidemiol & Biostat Dept, Norfolk Pl,St Marys Campus, London W2 1PG, England

[29] UCB Pharma SA, UCB Celltech, Brussels, Belgium

[30] Univ Concepcion, Pharm Fac, Dept Clin Biochem & Immunol, Lab Mol & Translat Immunol, Concepcion, Chile

[31] Modis, Ave Edison 19C, B-1300 Wavre, Belgium

[32] Kings Coll London, Peter Gorer Dept Immunobiol, London, England

[33] Kings Coll London, London, England

[34] AstraZeneca, Cambridge, England

[35] Univ Manchester, Fac Biol Med & Hlth, Manchester, Lancs, England

来源：

EBIOMEDICINE | 2020年 / 58卷

基金：

英国医学研究理事会;

关键词：

Kidney; Transplantation; Operational Tolerance; Biomarkers; Immunosuppressive Drugs; RT-qPCR; B-CELLS; WITHDRAWAL; BIOMARKERS; TRIAL; LEADS; MZB1; PCR;

D O I：

10.1016/j.ebiom.2020.102899

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background: Kidney transplant recipients (KTRs) with "operational tolerance" (OT) maintain a functioning graft without immunosuppressive (IS) drugs, thus avoiding treatment complications. Nevertheless, IS drugs can influence gene-expression signatures aiming to identify OT among treated KTRs. Methods: We compared five published signatures of OT in peripheral blood samples from 18 tolerant, 183 stable, and 34 chronic rejector KTRs, using gene-expression levels with and without adjustment for IS drugs and regularised logistic regression. Findings: IS drugs explained up to 50% of the variability in gene-expression and 20-30% of the variability in the probability of OT predicted by signatures without drug adjustment. We present a parsimonious consensus gene-set to identify OT, derived from joint analysis of IS-drug-adjusted expression of five published signature gene-sets. This signature, including CD40, CTLA4, HSD11B1, IGKV4-1, MZB1, NR3C2, and RAB40C genes, showed an area under the curve 0.92 (95% confidence interval 0.88-0.94) in cross-validation and 0.97 (0.93-1.00) in six months follow-up samples. Interpretation: We advocate including adjustment for IS drug therapy in the development stage of gene-expression signatures of OT to reduce the risk of capturing features of treatment, which could be lost following IS drug minimisation or withdrawal. Our signature, however, would require further validation in an independent dataset and a biomarker-led trial. (c) 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license. (http://creativecommons.org/licenses/by/4.0/)

引用

页数：13

共 1 条

[1] Clinical Validation of an Immune Quiescence Gene Expression Signature in Kidney Transplantation
Akalin, Enver
Weir, Matthew R.
Bunnapradist, Suphamai
Brennan, Daniel C.
Delos Santos, Rowena
Langone, Anthony
Djamali, Arjang
Xu, Hua
Jin, Xia
Dholakia, Sham
Woodward, Robert N.
Bromberg, Jonathan S.
KIDNEY360, 2021, 2 (12): : 1998 - 2009

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