title: Longitudinal studies of a B cell-derived signature of tolerance in renal transplant recipients.
abstract: Biomarkers of transplant tolerance would enhance the safety and feasibility of clinical tolerance trials and potentially facilitate management of patients receiving immunosuppression. To this end, we examined blood from spontaneously tolerant renal transplant recipients and patients enrolled in two interventional tolerance trials using flow cytometry and gene expression profiling. Using a previously reported tolerant cohort as well as newly identified tolerant patients, we confirmed our previous finding that tolerance was associated with increased expression of B cell-associated genes relative to immunosuppressed patients. This was not accounted for merely by an increase in total B cell numbers, but was associated with the increased frequencies of transitional and naïve B cells. Moreover, serial measurements of gene expression demonstrated that this pattern persisted over several years, although patients receiving immunosuppression also displayed an increase in the two most dominant tolerance-related B cell genes, IGKV1D-13 and IGLL-1, over time. Importantly, patients rendered tolerant via induction of transient mixed chimerism, and those weaned to minimal immunosuppression, showed similar increases in IGKV1D-13 as did spontaneously tolerant individuals. Collectively, these findings support the notion that alterations in B cells may be a common theme for tolerant kidney transplant recipients, and that it is a useful monitoring tool in prospective trials.
authors.affiliation: Department of Surgery, Emory University, Atlanta, GA.
authors.forename: K A
authors.initials: KA
authors.lastname: Newell
authors.affiliation: Immune Tolerance Network, Bethesda, MD.|Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: A
authors.initials: A
authors.lastname: Asare
authors.affiliation: Department of Surgery, Emory University, Atlanta, GA.
authors.forename: I
authors.initials: I
authors.lastname: Sanz
authors.affiliation: Department of Surgery, Emory University, Atlanta, GA.
authors.forename: C
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY.
authors.forename: A
authors.initials: A
authors.lastname: Rosenberg
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Z
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Immune Tolerance Network, Bethesda, MD.|Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: S
authors.initials: S
authors.lastname: Kanaparthi
authors.affiliation: Immune Tolerance Network, Bethesda, MD.|Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: S
authors.initials: S
authors.lastname: Asare
authors.affiliation: Immune Tolerance Network, Bethesda, MD.|Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: N
authors.initials: N
authors.lastname: Lim
authors.affiliation: Immune Tolerance Network, Bethesda, MD.|Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: M
authors.initials: M
authors.lastname: Stahly
authors.affiliation: Immune Tolerance Network, Bethesda, MD.
authors.forename: M
authors.initials: M
authors.lastname: Howell
authors.affiliation: Department of Surgery, Emory University, Atlanta, GA.
authors.forename: S
authors.initials: S
authors.lastname: Knechtle
authors.affiliation: Department of Surgery, Emory University, Atlanta, GA.
authors.forename: A
authors.initials: A
authors.lastname: Kirk
authors.affiliation: Swedish Medical Center, Seattle, WA.
authors.forename: W H
authors.initials: WH
authors.lastname: Marks
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: T
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: T
authors.initials: T
authors.lastname: Spitzer
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: N
authors.initials: N
authors.lastname: Tolkoff-Rubin
authors.affiliation: Departments of Medicine, and Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY.
authors.forename: M
authors.initials: M
authors.lastname: Sykes
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: D H
authors.initials: DH
authors.lastname: Sachs
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: A B
authors.initials: AB
authors.lastname: Cosimi
authors.affiliation: Department of Surgery, University of Wisconsin, Madison, WI.
authors.forename: W J
authors.initials: WJ
authors.lastname: Burlingham
authors.affiliation: Immune Tolerance Network, Bethesda, MD.
authors.forename: D
authors.initials: D
authors.lastname: Phippard
authors.affiliation: Immune Tolerance Network, Bethesda, MD.|Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA.|Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: L A
authors.initials: LA
authors.lastname: Turka
mesh_terms: D000328:Adult; D064591:Allografts; D053264:B-Cell Activating Factor / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000235:genetics; D006085:Graft Survival / Q000235:genetics; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics*; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000379:methods; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012042:Registries; D018570:Risk Assessment; D066027:Transplant Recipients; D014181:Transplantation Immunology / Q000235:genetics; D023001:Transplantation Tolerance / Q000235:genetics* / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D053264:B-Cell Activating Factor; C505719:TNFSF13B protein, human