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Biomarkers of tolerance in kidney transplantation – are we predicting tolerance or response to immunosuppressive treatment?

Research output: Contribution to journalArticle

Irene Rebollo-Mesa, Estefania Nova-Lamperti, Paula Mobillo, Manohursingh Runglall, Sofia Christakoudi, Sonia Norris, Nicola Smallcombe, Yogesh Kamra, Rachel Hilton, Indices of Tolerance EU Consortium, Sunil Bhandari, Richard Baker, David Berglund, Sue Carr, David Game, Sian Griffin, Philip A Kalra, Robert Lewis, Patrick B. Mark, Stephen Marks & 12 more Iain Macphee, William McKane, Markus G. Mohaupt, R. Pararajasingam, Sui Phin Kon, Daniel Serón, Manish Sinha, Beatriz Tucker, Ondrej Viklický, Robert I Lechler, Graham M. Lord, Maria P. Hernandez-Fuentes

Original languageEnglish
JournalAmerican Journal of Transplantation
Early online date21 Jun 2016
DOIs
Publication statusE-pub ahead of print - 21 Jun 2016

Bibliographical note

Prior publications from our group and others had shown a strong association between alterations of expression of B-lymphocyte related genes and Transplantation Tolerance. This article shows that this association needs to be revisited in view of the confounding effect exerted on the expression of these genes by immunosuppressive drugs as well as on peripheral transitional B cells; later demonstrating that correcting for the effect of immunosuppressive drugs on gene expression is possible and an equally accurate signature of tolerance arises.

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  • Biomarkers of tolerance in kidney_REBOLLO-MESA_Accepted8June2016_GOLD VoR

    Biomarkers_of_tolerance_in_kidney_REBOLLO_MESA_Accepted8June2016_GOLD_VoR.pdf, 1.09 MB, application/pdf

    15/08/2016

    Final published version

    CC BY

    This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

King's Authors

Abstract

We and others have previously described signatures of tolerance in kidney transplantation showing differential-expression of B-cell related genes and relative expansions of B-cell subsets. However, in all of these studies, the index group, namely the tolerant recipients, were not receiving immunosuppressive (IS) treatment unlike the rest of the comparator groups. We aimed to assess the confounding effect of these regimens and develop a novel IS-independent signature of tolerance. Analyzing gene-expression in three independent kidney transplant patient cohorts (232-recipients +14-tolerants), we have established that the expression of the previously reported signature was biased by IS regimens, which also influenced transitional B-cells. We have defined and validated a new gene-expression signature that was independent of drug effects and also differentiated tolerant patients from healthy controls (Cross-validated-AUC=0.81). In a prospective cohort we have demonstrated that the new signature remained stable before and after steroid withdrawal. Concisely, we report on a validated and highly accurate gene-expression signature that could be used reliably to identify patients suitable for IS reduction (~12% stable patients), irrespective of the IS drugs they are receiving. Only a similar approach will make the conduct of pilot clinical trials for IS-minimization safe, and hence allow critical improvements in kidney post-transplant management.

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