Therapeutic efficacy of anti-CD19 CAR-T cells in a mouse model of systemic lupus erythematosus
Therapeutic efficacy of anti-CD19 CAR-T cells in a mouse model of systemic lupus erythematosus
复制标题
抗CD19 CAR-T细胞对系统性红斑狼疮小鼠模型的治疗效果
DOI：
10.1038/s41423-020-0472-1
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发表时间：
2020-05-29
影响因子：
24.1
通讯作者：
Lu, Linrong
中科院分区：
文献类型：
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作者：
Jin, Xuexiao;Xu, Qin;Lu, Linrong
B细胞活化失调在系统性红斑狼疮（SLE）中起着关键作用，这使得B细胞耗竭成为SLE治疗的潜在策略。抗CD 19 CAR-T细胞治疗B细胞恶性肿瘤的临床成功引起了研究人员的关注。在这项研究中，我们的目的是研究在小鼠疾病模型中应用抗CD 19 CAR-T细胞疗法治疗SLE的可行性。我们构建了具有CD 28或4-1BB作为细胞内共刺激基序的鼠抗CD 19汽车，并通过将其输注到MRL-1 pr小鼠中来评估相应CAR-T细胞的治疗功能。此外，在疾病发作前将抗CD 19 CAR-T细胞转移到MRL-1 pr小鼠中，以确定其在SLE预防中的作用。根据我们的观察，与抗体治疗相比，我们的抗CD 19 CAR-T细胞的过继转移在MRL-lpr小鼠中显示出更持续的B细胞耗竭效应。同基因抗CD 19 CAR-T细胞的转移不仅在疾病症状发作前预防了疾病发病机制，而且在疾病进展后的后期阶段显示出治疗益处。我们还尝试优化治疗策略，发现与具有CD 28共刺激基序的CAR-T细胞相比，具有4-1BB共刺激基序的CAR-T细胞在没有细胞富集的情况下显示出更好的治疗效率。总之，这些结果表明抗CD 19 CAR-T细胞疗法在预防和治疗SLE小鼠模型中是有效的，表明其在患者中的临床应用潜力。
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.