TY - JOUR
T1 - Immunological balance is associated with clinical outcome after autologous hematopoietic stem cell transplantation in type 1 diabetes
AU - Malmegrim, Kelen C.R.
AU - de Azevedo, Júlia T.C.
AU - Arruda, Lucas C.M.
AU - Abreu, Joana R.F.
AU - Couri, Carlos E.B.
AU - de Oliveira, Gislane L.V.
AU - Palma, Patricia V.B.
AU - Scortegagna, Gabriela T.
AU - Stracieri, Ana B.P.L.
AU - Moraes, Daniela A.
AU - Dias, Juliana B.E.
AU - Pieroni, Fabiano
AU - Cunha, Renato
AU - Guilherme, Luiza
AU - Santos, Nathália M.
AU - Foss, Milton C.
AU - Covas, Dimas T.
AU - Burt, Richard K.
AU - Simões, Belinda P.
AU - Voltarelli, Júlio C.
AU - Roep, Bart O.
AU - Oliveira, Maria C.
N1 - Publisher Copyright:
© 2017 Malmegrim, de Azevedo, Arruda, Abreu, Couri, de Oliveira, Palma, Scortegagna, Stracieri, Moraes, Dias, Pieroni, Cunha, Guilherme, Santos, Foss, Covas, Burt, Simões, Voltarelli, Roep and Oliveira.
PY - 2017/2/22
Y1 - 2017/2/22
N2 - 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.
AB - 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.
KW - Autologous hematopoietic stem cell transplantation
KW - Autoreactivity
KW - Immune reconstitution
KW - Immunoregulation
KW - Type 1 diabetes
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UR - http://www.scopus.com/inward/citedby.url?scp=85014313309&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2017.00167
DO - 10.3389/fimmu.2017.00167
M3 - Article
C2 - 28275376
AN - SCOPUS:85014313309
SN - 1664-3224
VL - 8
JO - Frontiers in immunology
JF - Frontiers in immunology
IS - FEB
M1 - 167
ER -
