2. Academic Validation
  3. Induced regulatory T cells modified by knocking down T-bet in combination with ectopic expression of inhibitory cytokines effectively protect Graft-versus-Host Disease

Induced regulatory T cells modified by knocking down T-bet in combination with ectopic expression of inhibitory cytokines effectively protect Graft-versus-Host Disease

  • Am J Transplant. 2023 Apr 19;S1600-6135(23)00415-X. doi: 10.1016/j.ajt.2023.04.017.
Rongrong Gao 1,  Ang Li 2,  Sen Li 1,  Xiangrong Li 1,  Shuye Zhang 1,  Xiaoyan Zhang 3,  Jianqing Xu 4
Affiliations

Affiliations

  • 1 Clinical Center for Biotherapy at Zhongshan Hospital & Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, P. R. China.
  • 2 Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, 201508, P. R. China.
  • 3 Clinical Center for Biotherapy at Zhongshan Hospital & Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, P. R. China; Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, 201508, P. R. China. Electronic address: zhangxiaoyan@fudan.edu.cn.
  • 4 Clinical Center for Biotherapy at Zhongshan Hospital & Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, P. R. China; Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, 201508, P. R. China. Electronic address: xujianqing@fudan.edu.cn.
PMID: 37084847 DOI: 10.1016/j.ajt.2023.04.017
Abstract

Induced regulatory T (iTreg) cells play a vital role in immune tolerance and in controlling chronic inflammation. Generated in the periphery, iTreg cells are suitable for responding to alloantigens and preventing transplant rejection. Nevertheless, their clinical application has been impeded by the plasticity and instability attributed to the loss of Foxp3 expression, raising concerns that iTreg may be converted to Teff cells and even exert a pathogenic effect. Herein, second-generation short hairpin RNAs (shRNAs) loaded with three pairs of small interfering RNAs (siRNAs) were utilized to target the transcription factor T-bet. In addition, two immunosuppressive cytokines, namely transforming growth factor beta (TGF-β) and interleukin-10 (IL-10), were constitutively expressed. This novel engineering strategy allowed the generation of stably-induced iTreg cells (SI Treg), which maintained the expression of Foxp3 even in an unfavorable environment and exerted potent immunosuppressive functions in vitro. Furthermore, SI Treg cells demonstrated an effector transcriptional profile. Finally, SI Treg showed a significant protective effect against GVHD-related deaths in a xenotransplantation model. Collectively, these results signify that SI Treg cells hold great promise for future clinical application and offer a rational therapeutic approach for transplant rejection.

Keywords

GvHD; T-bet shRNA; TGF-β; Transplantation; iT(reg).

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