title: Nonchimeric HLA-Identical Renal Transplant Tolerance: Regulatory Immunophenotypic/Genomic Biomarkers.
abstract: We previously described early results of a nonchimeric operational tolerance protocol in human leukocyte antigen (HLA)-identical living donor renal transplants and now update these results. Recipients given alemtuzumab, tacrolimus/MPA with early sirolimus conversion were multiply infused with donor hematopoietic CD34(+) stem cells. Immunosuppression was withdrawn by 24 months. Twelve months later, operational tolerance was confirmed by rejection-free transplant biopsies. Five of the first eight enrollees were initially tolerant 1 year off immunosuppression. Biopsies of three others after total withdrawal showed Banff 1A acute cellular rejection without renal dysfunction. With longer follow-up including 5-year posttransplant biopsies, four of the five tolerant recipients remain without rejection while one developed Banff 1A without renal dysfunction. We now add seven new subjects (two operationally tolerant), and demonstrate time-dependent increases of circulating CD4(+) CD25(+++) CD127(-) FOXP3(+) Tregs versus losses of Tregs in nontolerant subjects (p < 0.001). Gene expression signatures, developed using global RNA expression profiling of sequential whole blood and protocol biopsy samples, were highly associative with operational tolerance as early as 1 year posttransplant. The blood signature was validated by an external Immune Tolerance Network data set. Our approach to nonchimeric operational HLA-identical tolerance reveals association with Treg immunophenotypes and serial gene expression profiles.
authors.affiliation: Comprehensive Transplant Center, Northwestern University, Chicago, IL.|Department of Surgery-Transplantation, Northwestern University, Chicago, IL.
authors.forename: J R
authors.initials: JR
authors.lastname: Leventhal
authors.affiliation: Comprehensive Transplant Center, Northwestern University, Chicago, IL.|Department of Surgery-Transplantation, Northwestern University, Chicago, IL.|Department of Microbiology-Immunology, Northwestern University, Chicago, IL.
authors.forename: J M
authors.initials: JM
authors.lastname: Mathew
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
authors.forename: D R
authors.initials: DR
authors.lastname: Salomon
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
authors.forename: S M
authors.initials: SM
authors.lastname: Kurian
authors.affiliation: Comprehensive Transplant Center, Northwestern University, Chicago, IL.|Department of Medicine-Nephrology, Northwestern University, Chicago, IL.
authors.forename: J J
authors.initials: JJ
authors.lastname: Friedewald
authors.affiliation: Comprehensive Transplant Center, Northwestern University, Chicago, IL.|Department of Medicine-Nephrology, Northwestern University, Chicago, IL.
authors.forename: L
authors.initials: L
authors.lastname: Gallon
authors.affiliation: Comprehensive Transplant Center, Northwestern University, Chicago, IL.
authors.forename: I
authors.initials: I
authors.lastname: Konieczna
authors.affiliation: Comprehensive Transplant Center, Northwestern University, Chicago, IL.|Department of Surgery-Transplantation, Northwestern University, Chicago, IL.
authors.forename: A R
authors.initials: AR
authors.lastname: Tambur
authors.affiliation: Comprehensive Transplant Center, Northwestern University, Chicago, IL.|Department of Surgery-Transplantation, Northwestern University, Chicago, IL.
authors.forename: J
authors.initials: J
authors.lastname: Charette
authors.affiliation: Comprehensive Transplant Center, Northwestern University, Chicago, IL.|Department of Medicine-Hepatology, Northwestern University, Chicago, IL.
authors.forename: J
authors.initials: J
authors.lastname: Levitsky
authors.affiliation: Comprehensive Transplant Center, Northwestern University, Chicago, IL.
authors.forename: C
authors.initials: C
authors.lastname: Jie
authors.affiliation: Department of Pathology, Northwestern University, Chicago, IL.
authors.forename: Y S
authors.initials: YS
authors.lastname: Kanwar
authors.affiliation: Comprehensive Transplant Center, Northwestern University, Chicago, IL.|Department of Surgery-Transplantation, Northwestern University, Chicago, IL.|Department of Microbiology-Immunology, Northwestern University, Chicago, IL.
authors.forename: M M
authors.initials: MM
authors.lastname: Abecassis
authors.affiliation: Comprehensive Transplant Center, Northwestern University, Chicago, IL.|Department of Surgery-Transplantation, Northwestern University, Chicago, IL.
authors.forename: J
authors.initials: J
authors.lastname: Miller
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000032:analysis*; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D023281:Genomics / Q000379:methods; D005919:Glomerular Filtration Rate; D006085:Graft Survival; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology*; D006648:Histocompatibility; D006801:Humans; D016130:Immunophenotyping; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000276:immunology* / Q000601:surgery; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D018183:Transplantation Chimera / Q000235:genetics / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: D015415:Biomarkers; D006680:HLA Antigens
keywords: Biomarker; bone marrow/hematopoietic stem cell transplantation; clinical research/practice; clinical trial; genomics; immunobiology; kidney transplantation/nephrology; monitoring: immune; tolerance: clinical; translational research/science