TY - JOUR
T1 - Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy
AU - Christakoudi, Sofia
AU - Runglall, Manohursingh
AU - Mobillo, Paula
AU - Rebollo-Mesa, Irene
AU - Tsui, Tjir Li
AU - Nova-Lamperti, Estefania
AU - Taube, Catharine
AU - Norris, Sonia
AU - Kamra, Yogesh
AU - Hilton, Rachel
AU - Augustine, Titus
AU - Bhandari, Sunil
AU - Baker, Richard
AU - Berglund, David
AU - Carr, Sue
AU - Game, David
AU - Griffin, Sian
AU - Kalra, Philip A.
AU - Lewis, Robert
AU - Mark, Patrick B.
AU - Marks, Stephen D.
AU - MacPhee, Iain
AU - McKane, William
AU - Mohaupt, Markus G.
AU - Paz-Artal, Estela
AU - Kon, Sui Phin
AU - Serón, Daniel
AU - Sinha, Manish D.
AU - Tucker, Beatriz
AU - Viklický, Ondrej
AU - Stahl, Daniel
AU - Lechler, Robert I.
AU - Lord, Graham M.
AU - Hernandez-Fuentes, Maria P.
N1 - Funding Information:
The authors acknowledge financial support from FP7-HEALTH-2012-INNOVATION-1 (project number 305147 : BIO-DrIM); Medical Research Council MRC grants to Maria P. Hernandez-Fuentes [ G0801537/ID: 88245 ] and to MRC Centre for Transplantation [MRC grant no. MR/J006742/1 ]); Guy's and St Thomas’ Charity [grants R080530 and R090782 ]; NIHR-BRC School for Translational and Experimental Medicine/Cluster 4 Early Career Award in Translational Science to Sofia Christakoudi. Sofia Christakoudi, Irene Rebollo-Mesa, Paula Mobillo, and Daniel Stahl were also funded by the EU project BIO-DrIM. Estefania Nova-Lamperti was funded by a scholarship from CONICYT Bicentennial Becas-Chile, Chile. Maria P. Hernandez-Fuentes has also received funding from the European Union , Seventh Framework Programme [FP7/2007–2013], under grant agreement [No HEALTH-F5–2010–260687 : The ONE Study]. Ondrej Viklický received funding from the Czech Ministry of Health [grant number NV19–06–00031 ]. The research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. All UK based centres received service support through Clinical Research Networks [study portfolio number 7521], this allowed the support of a large number of research nurses in the different centres, whose dedication has allowed the samples and clinical information to be collected. The study sponsors had no involvement in the study design; in the collection, analysis, and interpretation of the data; in the writing of the report; or in the decision to submit the paper for publication.
Funding Information:
Dr. Christakoudi reports grants from FP7-HEALTH-2012-INNOVATION-1 (project number 305147: BIO-DrIM), grants from National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London, during the conduct of the study. Mr. Runglall has nothing to disclose. Dr. Mobillo reports grants from FP7-HEALTH-2012-INNOVATION-1 (project number 305147: BIO-DrIM), during the conduct of the study. Dr. Rebollo-Mesa reports grants from [MR/J006742/1] to MRC Centre for Transplantation, grants from FP7-HEALTH-2012-INNOVATION-1 (project number 305147: BIO-DrIM), during the conduct of the study; other from UCB Pharma SRL, outside the submitted work. Mr. Tsui has nothing to disclose. Dr. Nova-Lamperti reports grants from CONICYT Bicentennial-Becas-Chile scholarship, during the conduct of the study. Dr. Taube has nothing to disclose. Dr. Norris has nothing to disclose. Mr. Kamra has nothing to disclose. Dr. Hilton reports personal fees from Chiesi Ltd, outside the submitted work. Dr. Augustine has nothing to disclose. Dr. Bhandari has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Berglund has nothing to disclose. Dr. Carr has nothing to disclose. Dr. Game reports personal fees from Advisory board Chiesi pharmaceuticals, personal fees from Advisory board Recordati Rare Diseases, personal fees from Advisory board Syneos Health, outside the submitted work. Dr. Griffin has nothing to disclose. Dr. Kalra has nothing to disclose. Dr. Lewis has nothing to disclose. Dr. Mark reports personal fees and non-financial support from Vifor, personal fees from Astrazeneca, grants from Boehringer Ingelheim, personal fees and non-financial support from Pharmacosmos, personal fees from Janssen, personal fees from Novartis, personal fees from Pfizer, personal fees from Bristol Myers Squibb, personal fees and non-financial support from Napp, outside the submitted work. Dr. Marks has nothing to disclose. Dr. MacPhee reports other from AstraZeneca, other from AstraZeneca, grants and personal fees from Chiesi, personal fees from Astellas, personal fees from Sandoz, outside the submitted work. Dr. McKane has nothing to disclose. Dr. Mohaupt has nothing to disclose. Dr. Paz-Artal has nothing to disclose. Dr. Kon has nothing to disclose. Dr. Seron has nothing to disclose. Dr. Sinha has nothing to disclose. Dr. Tucker has nothing to disclose. Prof. Viklicky reports grants from CZECH MINISTRY OF HEALTH, during the conduct of the study. Dr. Stahl reports grants from FP7-HEALTH-2012-INNOVATION-1 (project number 305147: BIO-DrIM), during the conduct of the study. Dr. Lechler has nothing to disclose. Dr. Lord has nothing to disclose. Dr. Hernandez-Fuentes reports grants from FP7-HEALTH-2012-INNOVATION-1 (project number 305147: BIO-DrIM), grants from Medical Research Council MRC grants to Maria P. Hernandez-Fuentes [G0801537/ID: 88245], grants from Guy's and St Thomas’ Charity [grants R080530 and R090782], grants from EU; FP7/2007–2013], under grant agreement [No HEALTH-F5–2010–260687: The ONE Study], grants and non-financial support from National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London, non-financial support from Clinical Research Networks [study portfolio number 7521], during the conduct of the study; other from UCB Celltech., outside the submitted work; .
Publisher Copyright:
© 2020 The Authors
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/8
Y1 - 2020/8
N2 - 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. Funding: FP7-HEALTH-2012-INNOVATION-1 [305147:BIO-DrIM] (SC,IR-M,PM,DSt); MRC [G0801537/ID:88245] (MPH-F); MRC [MR/J006742/1] (IR-M); Guy's&StThomas’ Charity [R080530]&[R090782]; CONICYT-Bicentennial-Becas-Chile (EN-L); EU:FP7/2007–2013 [HEALTH-F5–2010–260687: The ONE Study] (MPH-F); Czech Ministry of Health [NV19–06–00031] (OV); NIHR-BRC Guy's&StThomas' NHS Foundation Trust and KCL (SC); UK Clinical Research Networks [portfolio:7521].
AB - 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. Funding: FP7-HEALTH-2012-INNOVATION-1 [305147:BIO-DrIM] (SC,IR-M,PM,DSt); MRC [G0801537/ID:88245] (MPH-F); MRC [MR/J006742/1] (IR-M); Guy's&StThomas’ Charity [R080530]&[R090782]; CONICYT-Bicentennial-Becas-Chile (EN-L); EU:FP7/2007–2013 [HEALTH-F5–2010–260687: The ONE Study] (MPH-F); Czech Ministry of Health [NV19–06–00031] (OV); NIHR-BRC Guy's&StThomas' NHS Foundation Trust and KCL (SC); UK Clinical Research Networks [portfolio:7521].
KW - Biomarkers
KW - Immunosuppressive Drugs
KW - Kidney
KW - Operational Tolerance
KW - RT-qPCR
KW - Transplantation
U2 - 10.1016/j.ebiom.2020.102899
DO - 10.1016/j.ebiom.2020.102899
M3 - Article
C2 - 32707447
AN - SCOPUS:85088114344
SN - 2352-3964
VL - 58
JO - EBioMedicine
JF - EBioMedicine
M1 - 102899
ER -