We and others have previously described signatures of tolerance in kidney transplantation showing the differential expression of B cell-related genes and the relative expansions of B cell subsets. However, in all of these studies, the index group-namely, the tolerant recipients-were not receiving immunosuppression (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 and 14 tolerant patients), 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 is independent of drug effects and also differentiates tolerant patients from healthy controls (cross-validated area under the receiver operating characteristic curve [AUC] = 0.81). In a prospective cohort, we have demonstrated that the new signature remained stable before and after steroid withdrawal. In addition, we report on a validated and highly accurate gene expression signature that can be reliably used to identify patients suitable for IS reduction (approximately 12% of 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 posttransplant management.

Cardiff and Vale University Health Board Cardiff United Kingdom

Evelina London Children's Hospital London United Kingdom

Great Ormond Street Hospital for Children NHS Foundation Trust London United Kingdom

Guy's and St Thomas' NHS Foundation Trust London United Kingdom

Hospital Universitari Vall d'Hebr_on Barcelona Spain

Hull and East Yorkshire Hospitals NHS Trust Hull United Kingdom

INSELSPITAL Universitätsspital Bern Klinik für Nephrologie Hypertonie Abteilung für Hypertonie Bern Switzerland

King's College Hospital NHS Foundation Trust London United Kingdom

Leicester General Hospital Leicester United Kingdom

Manchester Royal Infirmary Manchester United Kingdom

Medical Research Council Centre for Transplantation King's College London London United Kingdom

Medical Research Council Centre for Transplantation King's College London London United Kingdom Biostatistics Institute of Psychiatry Psychology and Neuroscience King's College London London United Kingdom

Medical Research Council Centre for Transplantation King's College London London United Kingdom Biostatistics Institute of Psychiatry Psychology and Neuroscience King's College London London United Kingdom UCB Celltech UCB Pharma S A Slough United Kingdom

Medical Research Council Centre for Transplantation King's College London London United Kingdom King's Health Partners London United Kingdom

Medical Research Council Centre for Transplantation King's College London London United Kingdom National Institute for Health Research Biomedical Research Centre Guy's and St Thomas' National Health Service Foundation Trust King's College London London United Kingdom

Medical Research Council Centre for Transplantation King's College London London United Kingdom National Institute for Health Research Biomedical Research Centre Guy's and St Thomas' National Health Service Foundation Trust King's College London London United Kingdom Guy's and St Thomas' NHS Foundation Trust London United Kingdom

Medical Research Council Centre for Transplantation King's College London London United Kingdom Peter Gorer Department of Immunobiology King's College London London United Kingdom

Medical Research Council Centre for Transplantation King's College London London United Kingdom University College London London United Kingdom

National Institute for Health Research Biomedical Research Centre Guy's and St Thomas' National Health Service Foundation Trust King's College London London United Kingdom

Northern General Hospital Sheffield United Kingdom

Queen Alexandra Hospital Portsmouth United Kingdom

Salford Royal Hospital Salford United Kingdom

St George's Hospital London United Kingdom

St James's University Hospital Leeds United Kingdom

Transplantační laboratoř IKEM Prague Czech Republic

University of Glasgow Glasgow United Kingdom

Uppsala University Hospital Uppsala Sweden

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$a Biomarkers of Tolerance in Kidney Transplantation: Are We Predicting Tolerance or Response to Immunosuppressive Treatment / $c I. Rebollo-Mesa, E. Nova-Lamperti, P. Mobillo, M. Runglall, S. Christakoudi, S. Norris, N. Smallcombe, Y. Kamra, R. Hilton, . , S. Bhandari, R. Baker, D. Berglund, S. Carr, D. Game, S. Griffin, PA. Kalra, R. Lewis, PB. Mark, S. Marks, I. Macphee, W. McKane, MG. Mohaupt, R. Pararajasingam, SP. Kon, D. Serón, MD. Sinha, B. Tucker, O. Viklický, RI. Lechler, GM. Lord, MP. Hernandez-Fuentes,

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