Autologous stem cell transplantation aids autoimmune patients by functional renewal and TCR diversification of regulatory T cells.
Autologous hematopoietic stem cell transplantation (HSCT) is increasingly considered for patients with severe autoimmune diseases whose prognosis is poor with standard treatments. Regulatory T cells (Tregs) are thought to be important for disease remission after HSCT. However, eliciting the role of donor and host Tregs in autologous HSCT is not possible in humans due to the autologous nature of the intervention. Therefore, we investigated their role during immune reconstitution and re-establishment of immune tolerance and their therapeutic potential following congenic bone marrow transplantation (BMT) in a proteoglycan-induced arthritis (PGIA) mouse model. In addition, we determined Treg T-cell receptor (TCR) CDR3 diversity before and after HSCT in patients with juvenile idiopathic arthritis and juvenile dermatomyositis. In the PGIA BMT model, after an initial predominance of host Tregs, graft-derived Tregs started dominating and displayed a more stable phenotype with better suppressive capacity. Patient samples revealed a striking lack of diversity of the Treg repertoire before HSCT. This ameliorated after HSCT, confirming reset of the Treg compartment following HSCT. In the mouse model, a therapeutic approach was initiated by infusing extra Foxp3(GFP+) Tregs during BMT. Infusion of Foxp3(GFP+) Tregs did not elicit additional clinical improvement but conversely delayed reconstitution of the graft-derived T-cell compartment. These data indicate that HSCT-mediated amelioration of autoimmune disease involves renewal of the Treg pool. In addition, infusion of extra Tregs during BMT results in a delayed reconstitution of T-cell compartments. Therefore, Treg therapy may hamper development of long-term tolerance and should be approached with caution in the clinical autologous setting.
Laboratory of Translational Immunology, Department of Paediatric Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands;
Eveline M
EM
Delemarre
Laboratory of Translational Immunology, Department of Paediatric Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands;
Theo
T
van den Broek
Laboratory of Translational Immunology, Department of Paediatric Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands;
Gerdien
G
Mijnheer
Laboratory of Translational Immunology, Department of Paediatric Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands;
Jenny
J
Meerding
Laboratory of Translational Immunology, Department of Paediatric Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands;
Ellen J
EJ
Wehrens
Epiontis GmbH, Berlin, Germany;
Sven
S
Olek
Laboratory of Translational Immunology, Department of Paediatric Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands;
Marianne
M
Boes
Faculty of Veterinary Medicine, Utrecht University, The Netherlands; and.
Martijn J C
MJ
van Herwijnen
Faculty of Veterinary Medicine, Utrecht University, The Netherlands; and.
Femke
F
Broere
Laboratory of Translational Immunology, Department of Paediatric Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands;
Annet
A
van Royen
Laboratory of Translational Immunology, Department of Paediatric Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands;
Nico M
NM
Wulffraat
Laboratory of Translational Immunology, Department of Paediatric Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands;
Berent J
BJ
Prakken
Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Eric
E
Spierings
Laboratory of Translational Immunology, Department of Paediatric Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands;
Femke
F
van Wijk
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000628:therapy*; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006801:Humans; D007108:Immune Tolerance; D007249:Inflammation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014182:Transplantation, Autologous
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell