Allan Sarah E, Alstad Alicia N, Merindol Natacha, Crellin Natasha K, Amendola Mario, Bacchetta Rosa, Naldini Luigi, Roncarolo Maria Grazia, Soudeyns Hugo, Levings Megan K
Department of Surgery, University of British Columbia, Vancouver, Canada.
Mol Ther. 2008 Jan;16(1):194-202. doi: 10.1038/sj.mt.6300341. Epub 2007 Nov 6.
Therapies based on enhancing the numbers and/or function of T regulatory cells (Tregs) represent one of the most promising approaches to restoring tolerance in many immune-mediated diseases. Several groups have investigated whether human Tregs suitable for cellular therapy can be obtained by in vitro expansion, in vitro conversion of conventional T cells into Tregs, or gene transfer of the FOXP3 transcription factor. To date, however, none of these approaches has resulted in a homogeneous and stable population of cells that is as potently suppressive as ex vivo Tregs. We developed a lentivirus-based strategy to ectopically express high levels of FOXP3 that do not fluctuate with the state of T-cell activation. This method consistently results in the development of suppressive cells that are as potent as Tregs and can be propagated as a homogeneous population. Moreover, using this system, both naïve and memory CD4(+) T cells can be efficiently converted into Tregs. To date, this is the most efficient and reliable protocol for generating large numbers of suppressive CD4(+) Tregs, which can be used for further biological study and developed for antigen-specific cellular therapy applications.
基于增强调节性T细胞（Tregs）数量和/或功能的疗法，是恢复许多免疫介导疾病中免疫耐受最具前景的方法之一。多个研究团队探讨了是否可通过体外扩增、将常规T细胞体外转化为Tregs或FOXP3转录因子基因转移来获得适用于细胞治疗的人Tregs。然而，迄今为止，这些方法均未产生与体外Tregs一样具有高效抑制能力的均一且稳定的细胞群体。我们开发了一种基于慢病毒的策略，用于异位表达高水平且不随T细胞激活状态波动的FOXP3。该方法始终能产生与Tregs一样具有高效抑制能力的细胞，并且可以作为均一群体进行扩增。此外，使用该系统，初始和记忆性CD4(+) T细胞均可有效转化为Tregs。迄今为止，这是生成大量抑制性CD4(+) Tregs最有效且可靠的方案，可用于进一步的生物学研究，并开发用于抗原特异性细胞治疗应用。
