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Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy
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. METHOD...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374249/ https://www.ncbi.nlm.nih.gov/pubmed/32707447 http://dx.doi.org/10.1016/j.ebiom.2020.102899 |
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author | Christakoudi, Sofia Runglall, Manohursingh Mobillo, Paula Rebollo-Mesa, Irene Tsui, Tjir-Li Nova-Lamperti, Estefania Taube, Catharine Norris, Sonia Kamra, Yogesh Hilton, Rachel Augustine, Titus Bhandari, Sunil Baker, Richard Berglund, David Carr, Sue Game, David Griffin, Sian Kalra, Philip A. Lewis, Robert Mark, Patrick B. Marks, Stephen D. MacPhee, Iain McKane, William Mohaupt, Markus G. Paz-Artal, Estela Kon, Sui Phin Serón, Daniel Sinha, Manish D. Tucker, Beatriz Viklický, Ondrej Stahl, Daniel Lechler, Robert I. Lord, Graham M. Hernandez-Fuentes, Maria P. |
author_facet | Christakoudi, Sofia Runglall, Manohursingh Mobillo, Paula Rebollo-Mesa, Irene Tsui, Tjir-Li Nova-Lamperti, Estefania Taube, Catharine Norris, Sonia Kamra, Yogesh Hilton, Rachel Augustine, Titus Bhandari, Sunil Baker, Richard Berglund, David Carr, Sue Game, David Griffin, Sian Kalra, Philip A. Lewis, Robert Mark, Patrick B. Marks, Stephen D. MacPhee, Iain McKane, William Mohaupt, Markus G. Paz-Artal, Estela Kon, Sui Phin Serón, Daniel Sinha, Manish D. Tucker, Beatriz Viklický, Ondrej Stahl, Daniel Lechler, Robert I. Lord, Graham M. Hernandez-Fuentes, Maria P. |
author_sort | Christakoudi, Sofia |
collection | PubMed |
description | 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]. |
format | Online Article Text |
id | pubmed-7374249 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-73742492020-07-23 Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy Christakoudi, Sofia Runglall, Manohursingh Mobillo, Paula Rebollo-Mesa, Irene Tsui, Tjir-Li Nova-Lamperti, Estefania Taube, Catharine Norris, Sonia Kamra, Yogesh Hilton, Rachel Augustine, Titus Bhandari, Sunil Baker, Richard Berglund, David Carr, Sue Game, David Griffin, Sian Kalra, Philip A. Lewis, Robert Mark, Patrick B. Marks, Stephen D. MacPhee, Iain McKane, William Mohaupt, Markus G. Paz-Artal, Estela Kon, Sui Phin Serón, Daniel Sinha, Manish D. Tucker, Beatriz Viklický, Ondrej Stahl, Daniel Lechler, Robert I. Lord, Graham M. Hernandez-Fuentes, Maria P. EBioMedicine Research paper 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]. Elsevier 2020-07-21 /pmc/articles/PMC7374249/ /pubmed/32707447 http://dx.doi.org/10.1016/j.ebiom.2020.102899 Text en © 2020 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research paper Christakoudi, Sofia Runglall, Manohursingh Mobillo, Paula Rebollo-Mesa, Irene Tsui, Tjir-Li Nova-Lamperti, Estefania Taube, Catharine Norris, Sonia Kamra, Yogesh Hilton, Rachel Augustine, Titus Bhandari, Sunil Baker, Richard Berglund, David Carr, Sue Game, David Griffin, Sian Kalra, Philip A. Lewis, Robert Mark, Patrick B. Marks, Stephen D. MacPhee, Iain McKane, William Mohaupt, Markus G. Paz-Artal, Estela Kon, Sui Phin Serón, Daniel Sinha, Manish D. Tucker, Beatriz Viklický, Ondrej Stahl, Daniel Lechler, Robert I. Lord, Graham M. Hernandez-Fuentes, Maria P. Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy |
title | Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy |
title_full | Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy |
title_fullStr | Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy |
title_full_unstemmed | Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy |
title_short | Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy |
title_sort | development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy |
topic | Research paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374249/ https://www.ncbi.nlm.nih.gov/pubmed/32707447 http://dx.doi.org/10.1016/j.ebiom.2020.102899 |
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