title: A composite score associated with spontaneous operational tolerance in kidney transplant recipients.
abstract: New challenges in renal transplantation include using biological information to devise a useful clinical test for discerning high- and low-risk patients for individual therapy and ascertaining the best combination and appropriate dosages of drugs. Based on a 20-gene signature from a microarray meta-analysis performed on 46 operationally tolerant patients and 266 renal transplant recipients with stable function, we applied the sparse Bolasso methodology to identify a minimal and robust combination of six genes and two demographic parameters associated with operational tolerance. This composite score of operational tolerance discriminated operationally tolerant patients with an area under the curve of 0.97 (95% confidence interval 0.94-1.00). The score was not influenced by immunosuppressive treatment, center of origin, donor type, or post-transplant lymphoproliferative disorder history of the patients. This composite score of operational tolerance was significantly associated with both de novo anti-HLA antibodies and tolerance loss. It was validated by quantitative polymerase chain reaction using independent samples and demonstrated specificity toward a model of tolerance induction. Thus, our score would allow clinicians to improve follow-up of patients, paving the way for individual therapy.
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Danger
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Chesneau
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Paul
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
authors.forename: Pierrick
authors.initials: P
authors.lastname: Guérif
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
authors.forename: Maxim
authors.initials: M
authors.lastname: Durand
authors.affiliation: Department of Surgery, Emory University, Atlanta, Georgia, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Newell
authors.affiliation: Immune Tolerance Network, Bethesda, Maryland, USA.
authors.forename: Sai
authors.initials: S
authors.lastname: Kanaparthi
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Turka
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soulillou
authors.affiliation: INSERM UMR 954, Nancy, France; CHU de Nancy, DRCI, Nancy, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Houlgatte
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; Université de Nantes, Faculté de Médecine, Nantes, France; CIC Biotherapy, CHU Nantes, Nantes, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Giral
authors.affiliation: LINA DUKe, UMR 6241, Université de Nantes, Ecole des Mines de Nantes and CNRS, Nantes, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Ramstein
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; CIC Biotherapy, CHU Nantes, Nantes, France. Electronic address: sophie.brouard@univ-nantes.fr.
authors.forename: Sophie
authors.initials: S
authors.lastname: Brouard
mesh_terms: D019540:Area Under Curve; D000066491:Clinical Decision-Making; D003661:Decision Support Techniques; D020869:Gene Expression Profiling / Q000379:methods*; D005819:Genetic Markers; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000235:genetics; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007518:Isoantibodies / Q000097:blood; D016030:Kidney Transplantation / Q000009:adverse effects; D020411:Oligonucleotide Array Sequence Analysis; D018579:Patient Selection; D016133:Polymerase Chain Reaction; D057285:Precision Medicine; D011237:Predictive Value of Tests; D012372:ROC Curve; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D059467:Transcriptome; D066027:Transplant Recipients; D023001:Transplantation Tolerance; D016896:Treatment Outcome
chemical_list: D005819:Genetic Markers; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D007518:Isoantibodies
keywords: biomarker; gene expression; graft survival; operational tolerance; renal transplantation