Immunological Balance Is Associated with Clinical Outcome after Autologous Hematopoietic Stem Cell Transplantation in Type 1 Diabetes

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Malmegrim, Kelen C. R. ; de Azevedo, Julia T. C. ; Arruda, Lucas C. M. ; Abreu, Joana R. F. ; Couri, Carlos E. B. ; de Oliveira, Gislane L. V. ; Palma, Patricia V. B. ; Scortegagna, Gabriela T. ; Stracieri, Ana B. P. L. ; Moraes, Daniela A. ; Dias, Juliana B. E. ; Pieroni, Fabiano ; Cunha, Renato ; Guilherme, Luiza ; Santos, Nathalia M. ; Foss, Milton C. ; Covas, Dimas T. ; Burt, Richard K. ; Simoes, Belinda P. ; Voltarelli, Julio C. ; Roep, Bart O. ; Oliveira, Maria C.

• Document type: Journal article
• Source: FRONTIERS IN IMMUNOLOGY; v. 8, FEB 22 2017.
• Web of Science Citations: 28

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. (AU)

• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC