Autologous stem cell transplantation aids autoimmune patients by functional renewal and TCR diversification of regulatory T cells.

Abstract

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.

• Authors: Eveline M Delemarre, Theo van den Broek, Gerdien Mijnheer, Jenny Meerding, Ellen J Wehrens, Sven Olek, Marianne Boes, Martijn J C van Herwijnen, Femke Broere, Annet van Royen, Nico M Wulffraat, Berent J Prakken, Eric Spierings, Femke van Wijk
• Journal: Blood (Blood) Vol. 127 Issue 1 Pg. 91-101 (Jan 07 2016) ISSN: 1528-0020 [Electronic] United States
• PMID: 26480932 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by The American Society of Hematology.

Chemical References

• Forkhead Transcription Factors
• Foxp3 protein, mouse
• RNA, Messenger
• Receptors, Antigen, T-Cell

Topics

• Animals
• Autoimmune Diseases (immunology, therapy)
• Blotting, Western
• Bone Marrow Transplantation
• Cells, Cultured
• Female
• Flow Cytometry
• Forkhead Transcription Factors (physiology)
• Humans
• Immune Tolerance
• Inflammation (immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Receptors, Antigen, T-Cell (immunology)
• Reverse Transcriptase Polymerase Chain Reaction
• T-Lymphocytes, Regulatory (immunology)
• Transplantation, Autologous