Ex vivo-expanded but not in vitro-induced human regulatory T cells are candidates for cell therapy in autoimmune diseases thanks to stable demethylation of the FOXP3 regulatory T cell-specific demethylated region.
Ex vivo-expanded but not in vitro-induced human regulatory T cells are candidates for cell therapy in autoimmune diseases thanks to stable demethylation of the FOXP3 regulatory T cell-specific demethylated region.
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DOI：
10.4049/jimmunol.1401145
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发表时间：
2015-01-01
期刊：
影响因子：
--
通讯作者：
Albani S
中科院分区：
文献类型：
--
作者：
Rossetti M;Spreafico R;Saidin S;Chua C;Moshref M;Leong JY;Tan YK;Thumboo J;van Loosdregt J;Albani S
Treg1 cell therapy is a promising approach for transplant rejection and severe autoimmunity. Unfortunately, clinically meaningful Treg numbers can be obtained only upon in vitro culture. Functional stability of human expanded (e)Tregs2 and induced (i)Tregs3 has not been thoroughly addressed for all proposed protocols, hindering clinical translation. We undertook a systematic comparison of eTregs and iTregs to recommend the most suitable for clinical implementation, and then tested their effectiveness and feasibility in rheumatoid arthritis (RA)4. Regardless of the treatment, iTregs acquired suppressive function and FOXP3 expression, but lost them upon secondary restimulation in the absence of differentiation factors, which mimics in vivo reactivation. In contrast, eTregs expanded in the presence of Rapamycin (rapa)5 retained their regulatory properties and FOXP3 demethylation upon restimulation with no stabilizing agent. FOXP3 demethylation predicted Treg functional stability upon secondary TCR engagement. Rapa eTregs suppressed conventional T cell (Tconv)6 proliferation via both surface (CTLA-4) and secreted (IL-10, TGF-β and IL-35) mediators, similarly to ex vivo Tregs. Importantly, Treg expansion with rapa from RA patients produced functionally stable Tregs with yields comparable to healthy donors (HD)7. Moreover, rapa eTregs from RA patients were resistant to suppression reversal by the pro-inflammatory cytokine TNF-α, and were more efficient in suppressing synovial Tconv proliferation compared to their ex vivo counterparts, suggesting that rapa improves both Treg function and stability. In conclusion, our data indicate Treg expansion with rapa as the protocol of choice for clinical application in rheumatological settings, with assessment of FOXP3 demethylation as a necessary quality control step.
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影响因子：
32.4
作者：
Bailey-Bucktrout, Samantha L.;Martinez-Llordella, Marc;Zhou, Xuyu;Anthony, Bryan;Rosenthal, Wendy;Luche, Herve;Fehling, Hans J.;Bluestone, Jeffrey A.
通讯作者：
Bluestone, Jeffrey A.
影响因子：
5.4
作者：
Hoffmann, Petra;Boeld, Tina J.;Edinger, Matthias
通讯作者：
Edinger, Matthias
调节性T细胞在类风湿关节炎和抗TNFALPHA治疗中的逆转功能受损。
影响因子：
15.3
作者：
Ehrenstein, MR;Evans, JG;Singh, A;Moore, S;Warnes, G;Isenberg, DA;Mauri, C
通讯作者：
Mauri, C
影响因子：
3.1
作者：
Lange, Christian M.;Tran, Thuy Yen Vy;Hirche, Tim O.
通讯作者：
Hirche, Tim O.
影响因子：
29.7
作者：
Josefowicz SZ;Lu LF;Rudensky AY
通讯作者：
Rudensky AY