低免疫原性CD19嵌合抗原受体T细胞治疗具有自发性系统性红斑狼疮特征的同种异体小鼠。
Hypoimmune CD19 CAR T cells treat allogeneic mice with features of spontaneous systemic lupus erythematosus.
作者信息
Hu Xiaomeng, White Kathy, Olroyd Ari G, Friera Annabelle, Wang Chenyan, Caruso Carolin B, Connolly Andrew J, Deuse Tobias, Schrepfer Sonja
机构信息
Sana Biotechnology Inc., 1 Tower Place, South San Francisco, CA, USA.
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
出版信息
iScience. 2025 May 31;28(7):112806. doi: 10.1016/j.isci.2025.112806. eCollection 2025 Jul 18.
Hypoimmune (HIP) MHC class I- and II-deficient and CD47-overexpressing CD19 CAR T cells were generated and tested in an allogeneic NZB/W mouse model of spontaneous systemic lupus erythematosus with established disease. HIP CAR T cells showed persistent engraftment, achieved lasting deep tissue B cell depletion, diminished antibody levels and systemic pro-inflammatory cytokine levels, mitigated proteinuria and glucosuria, alleviated structural kidney injury, and improved survival after 21 weeks. HIP CAR T cells did not induce any immune activation in this fully allogeneic model and thus completely escaped allorejection. In contrast, MHC-replete, non-HIP-edited wild-type (WT) CD19 CAR T cells induced a strong adaptive immune response and vanished quickly without inducing meaningful B cell depletion and without improving disease markers or survival. Conditioning of NZB/W mice with irradiation did not enhance the HIP CAR T cell efficacy and might hint at their potency for autoimmune patients without prior lymphodepletion.
制备了低免疫（HIP）的MHC I类和II类缺陷且CD47过表达的CD19嵌合抗原受体（CAR）T细胞，并在患有自发性系统性红斑狼疮且疾病已确诊的同种异体NZB/W小鼠模型中进行了测试。HIP CAR T细胞表现出持续植入，实现了持久的深部组织B细胞耗竭，降低了抗体水平和全身促炎细胞因子水平，减轻了蛋白尿和糖尿，减轻了肾脏结构损伤，并在21周后提高了生存率。在这个完全同种异体模型中，HIP CAR T细胞没有诱导任何免疫激活，因此完全避免了同种异体排斥。相比之下，MHC完整、未进行HIP编辑的野生型（WT）CD19 CAR T细胞诱导了强烈的适应性免疫反应，并迅速消失，没有诱导有意义的B细胞耗竭，也没有改善疾病指标或生存率。用辐射对NZB/W小鼠进行预处理并没有增强HIP CAR T细胞的疗效，这可能暗示了它们对未经预先淋巴细胞清除的自身免疫患者的效力。
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