title: Immunological Balance Is Associated with Clinical Outcome after Autologous Hematopoietic Stem Cell Transplantation in Type 1 Diabetes.
abstract: Autologous hematopoietic stem cell transplantation (AHSCT) increases C-peptide levels and induces insulin independence in patients with type 1 diabetes. This study aimed to investigate how clinical outcomes may associate with the immunological status, especially concerning the balance between immunoregulation and autoreactivity. Twenty-one type 1 diabetes patients were monitored after AHSCT and assessed every 6 months for duration of insulin independence, C-peptide levels, frequencies of islet-specific autoreactive CD8+T cells (CTL), regulatory lymphocyte subsets, thymic function, and T-cell repertoire diversity. In median follow-up of 78 (range 15-106) months, all patients became insulin-independent, resuming insulin after median of 43 (range 6-100) months. Patients were retrospectively divided into short- or prolonged-remission groups, according to duration of insulin independence. For the entire follow-up, CD3+CD4+T-cell numbers remained lower than baseline in both groups, whereas CD3+CD8+T-cell levels did not change, resulting in a CD4/CD8 ratio inversion. Memory CTL comprehended most of T cells detected on long-term follow-up of patients after AHSCT. B cells reconstituted to baseline levels at 2-3 months post-AHSCT in both patient groups. In the prolonged-remission-group, baseline islet-specific T-cell autoreactivity persisted after transplantation, but regulatory T cell counts increased. Patients with lower frequencies of autoreactive islet-specific T cells remained insulin-free longer and presented greater C-peptide levels than those with lower frequencies of these cells. Therefore, immune monitoring identified a subgroup of patients with superior clinical outcome of AHSCT. Our study shows that improved immunoregulation may balance autoreactivity endorsing better metabolic outcomes in patients with lower frequencies of islet-specific T cells. Development of new strategies of AHSCT is necessary to increase frequency and function of T and B regulatory cells and decrease efficiently autoreactive islet-specific T and B memory cells in type 1 diabetes patients undergoing transplantation.
authors.affiliation: Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Department of Clinical, Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Kelen C R
authors.initials: KC
authors.lastname: Malmegrim
authors.affiliation: Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Júlia T C
authors.initials: JT
authors.lastname: de Azevedo
authors.affiliation: Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Lucas C M
authors.initials: LC
authors.lastname: Arruda
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center , Leiden , Netherlands.
authors.forename: Joana R F
authors.initials: JR
authors.lastname: Abreu
authors.affiliation: Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Carlos E B
authors.initials: CE
authors.lastname: Couri
authors.affiliation: Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Gislane L V
authors.initials: GL
authors.lastname: de Oliveira
authors.affiliation: Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo , Ribeirão Preto , Brazil.
authors.forename: Patricia V B
authors.initials: PV
authors.lastname: Palma
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo , Ribeirão Preto , Brazil.
authors.forename: Gabriela T
authors.initials: GT
authors.lastname: Scortegagna
authors.affiliation: Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo , Ribeirão Preto , Brazil.
authors.forename: Ana B P L
authors.initials: AB
authors.lastname: Stracieri
authors.affiliation: Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo , Ribeirão Preto , Brazil.
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Moraes
authors.affiliation: Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo , Ribeirão Preto , Brazil.
authors.forename: Juliana B E
authors.initials: JB
authors.lastname: Dias
authors.affiliation: Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo , Ribeirão Preto , Brazil.
authors.forename: Fabiano
authors.initials: F
authors.lastname: Pieroni
authors.affiliation: Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo , Ribeirão Preto , Brazil.
authors.forename: Renato
authors.initials: R
authors.lastname: Cunha
authors.affiliation: Heart Institute (InCor), School of Medicine, University of São Paulo , São Paulo , Brazil.
authors.forename: Luiza
authors.initials: L
authors.lastname: Guilherme
authors.affiliation: Heart Institute (InCor), School of Medicine, University of São Paulo , São Paulo , Brazil.
authors.forename: Nathália M
authors.initials: NM
authors.lastname: Santos
authors.affiliation: Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo , Ribeirão Preto , Brazil.
authors.forename: Milton C
authors.initials: MC
authors.lastname: Foss
authors.affiliation: Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Dimas T
authors.initials: DT
authors.lastname: Covas
authors.affiliation: Division of Immunotherapy, Northwestern University Feinberg School of Medicine , Chicago, IL , USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Burt
authors.affiliation: Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Belinda P
authors.initials: BP
authors.lastname: Simões
authors.affiliation: Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo , Ribeirão Preto , Brazil.
authors.forename: Júlio C
authors.initials: JC
authors.lastname: Voltarelli
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands; Department of Diabetes Immunology, Diabetes & Metabolism Research Institute at City of Hope, Duarte, CA, USA.
authors.forename: Bart O
authors.initials: BO
authors.lastname: Roep
authors.affiliation: Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Oliveira
keywords: autologous hematopoietic stem cell transplantation; autoreactivity; immune reconstitution; immunoregulation; type 1 diabetes