TY - JOUR
T1 - Autologous stem cell transplantation aids autoimmune patients by functional renewal and TCR diversification of regulatory T cells
AU - Delemarre, Eveline M.
AU - Van Den Broek, Theo
AU - Mijnheer, Gerdien
AU - Meerding, Jenny
AU - Wehrens, Ellen J.
AU - Olek, Sven
AU - Boes, Marianne
AU - Van Herwijnen, Martijn J C
AU - Broere, Femke
AU - van Royen, Annet
AU - Wulffraat, Nico W.
AU - Prakken, Berent J.
AU - Spierings, Eric
AU - Van Wijk, Femke
PY - 2016/1/7
Y1 - 2016/1/7
N2 - 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)inaproteoglycan-inducedarthritis (PGIA) mousemodel. Inaddition, wedetermined 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 Foxp3GFP+ Tregs during BMT. Infusion of Foxp3GFP+ 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.
AB - 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)inaproteoglycan-inducedarthritis (PGIA) mousemodel. Inaddition, wedetermined 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 Foxp3GFP+ Tregs during BMT. Infusion of Foxp3GFP+ 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.
KW - Adding regulatory t cells to the graft does not lead to additional clinical improvement but results in delayed donor t-cell reconstitution
KW - Autologous HSCT induces functional renewal of regulatory t cells as well as a strong treg TCR diversification in autoimmune patients
UR - http://www.scopus.com/inward/record.url?scp=84955505585&partnerID=8YFLogxK
U2 - 10.1182/blood-2015-06-649145
DO - 10.1182/blood-2015-06-649145
M3 - Article
C2 - 26480932
AN - SCOPUS:84955505585
SN - 0006-4971
VL - 127
SP - 91
EP - 101
JO - Blood
JF - Blood
IS - 1
ER -