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Therapeutic efficacy of anti-CD19 CAR-T cells in a mouse model of systemic lupus erythematosus

Cellular & Molecular Immunology volume 18, pages 1896–1903 (2021)Cite this article

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Abstract

Dysregulated B-cell activation plays pivotal roles in systemic lupus erythematosus (SLE), which makes B-cell depletion a potential strategy for SLE treatment. The clinical success of anti-CD19 CAR-T cells in treating B-cell malignancies has attracted the attention of researchers. In this study, we aimed to investigate the feasibility of applying anti-CD19 CAR-T cell therapy to SLE treatment in a mouse disease model. We constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic function of the corresponding CAR-T cells by infusing them into MRL-lpr mice. Furthermore, anti-CD19 CAR-T cells were transferred to MRL-lpr mice before the onset of disease to determine their role in SLE prevention. According to our observations, compared with antibody treatment, the adoptive transfer of our anti-CD19 CAR-T cells showed a more sustained B-cell-depletion effect in MRL-lpr mice. The transfer of syngeneic anti-CD19 CAR-T cells not only prevented disease pathogenesis before the onset of disease symptoms but also displayed therapeutic benefits at a later stage after disease progression. We also tried to optimize the treatment strategy and found that compared with CAR-T cells with the CD28 costimulatory motif, CAR-T cells with the 4-1BB costimulatory motif showed better therapeutic efficiency without cell enrichment. Taken together, these results show that anti-CD19 CAR-T cell therapy was effective in the prevention and treatment of a murine model of SLE, indicating its potential for clinical use in patients.

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Acknowledgements

The authors thank Dr. Richard Sloan (University of Edinburgh) for manuscript editing, Yingying Huang from the core facilities (ZJU School of Medicine) for technical assistance in FACS analysis, and Huihui Su from the ZJU Affiliated Animal Hospital for technical assistance in the analysis of mouse samples. This work was supported by grants from the National Natural Science Foundation of China (31770954, 31530019 to L.L. and 31900628 to Q.X.) and the Fundamental Research Funds for the Central Universities (2018XZZX001-12 to L.L.).

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Authors and Affiliations

  1. Zhejiang University–University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, 314400, PR China

    Xuexiao Jin, Kaixiang Zhu & Linrong Lu

  2. Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, PR China

    Xuexiao Jin, Kaixiang Zhu, Yu Jiang & Linrong Lu

  3. Department of Rheumatology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, PR China

    Xuexiao Jin, Qin Xu, Yongmei Han & Linrong Lu

  4. Innovative Cellular Therapeutics Co., Ltd., Shanghai, 201203, PR China

    Chengfei Pu, Cheng Lu & Lei Xiao

  5. Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, PR China

    Linrong Lu

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  1. Xuexiao Jin
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Contributions

X.J., C.P., C.L., L.X., and L.L. designed the research; X.J., Q.X., K.Z., and Y.J. performed the research; X.J. and L.L. analyzed the data; and X.J., Y.H., L.X., and L.L. wrote the paper.

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Correspondence to Yongmei Han or Linrong Lu.

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Jin, X., Xu, Q., Pu, C. et al. Therapeutic efficacy of anti-CD19 CAR-T cells in a mouse model of systemic lupus erythematosus. Cell Mol Immunol 18, 1896–1903 (2021). https://doi.org/10.1038/s41423-020-0472-1

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  • DOI: https://doi.org/10.1038/s41423-020-0472-1

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