Sun Yeting, Huang Sicheng, Zhang Bo, Peng Yu, Lu Hui, Jia Yimeng, Sun Ruijie, Zhang Fenghua, Zhou Jiaxin, Peng Linyi, Li Mengtao, Zhang Wen, Fei Yunyun
Department of Rheumatology and Clinical Immunology, Department of Health Management, Peking Union Medical College and Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, China; The Ministry of Education Key Laboratory, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Beijing, China.
State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
Int Immunopharmacol. 2025 Jan 3;145:113779. doi: 10.1016/j.intimp.2024.113779. Epub 2024 Dec 12.
Dysregulated B-cell activation plays pivotal roles in IgG4-related disease (IgG4-RD), which makes B-cell depletion a potential strategy for IgG4-RD treatment. In this study, we aimed to investigate the feasibility of applying anti-CD19 chimeric antigen receptor T(CAR-T) cell therapy to IgG4-RD treatment in a mouse disease model based on LatY136F knock-in (Lat) mice. 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 Lat mice. Next, we assessed the safety of CAR-T infusion by evaluating the risk of cytokine release syndrome (CRS) and the antiviral capabilities in a mouse influenza infection model. Finally, we performed human anti-CD19 CAR-T manufacturing from IgG4-RD patients and evaluated its activation level and functional effects in vitro. Compared with 1D3 antibody treatment, the adoptive transfer of anti-CD19 CAR-T cells with CD28 costimulatory motif showed comparable B-cell-depletion effect in Lat mice. Furthermore, the transfer of syngeneic anti-CD19 CAR-T cells also decreased the percentage of plasma cells as well as IL-4 secreting Th cells, therefore attenuating the inflammation and fibrosis condition. CAR-T cells with CD28 costimulatory motif showed better therapeutic efficiency without the incidence of serious CRS events or increasing the risk of infection. In addition, we validated the feasibility of human CAR-T preparation in vitro from IgG4-RD patients. Taken together, these results show that anti-CD19 CAR-T therapy was effective in the treatment of a murine model of IgG4-RD, indicating its potential for clinical use in patients.
B细胞激活失调在IgG4相关疾病（IgG4-RD）中起关键作用，这使得B细胞清除成为IgG4-RD治疗的一种潜在策略。在本研究中，我们旨在基于LatY136F基因敲入（Lat）小鼠的疾病模型，研究应用抗CD19嵌合抗原受体T（CAR-T）细胞疗法治疗IgG4-RD的可行性。我们构建了以CD28或4-1BB作为细胞内共刺激基序的鼠抗CD19 CAR，并通过将相应的CAR-T细胞注入Lat小鼠来评估其治疗功能。接下来，我们通过评估细胞因子释放综合征（CRS）风险和小鼠流感感染模型中的抗病毒能力，来评估CAR-T注入的安全性。最后，我们从IgG4-RD患者中制备人抗CD19 CAR-T，并在体外评估其激活水平和功能效应。与1D3抗体治疗相比，具有CD28共刺激基序的抗CD19 CAR-T细胞的过继转移在Lat小鼠中显示出相当的B细胞清除效果。此外，同基因抗CD19 CAR-T细胞的转移还降低了浆细胞以及分泌IL-4的Th细胞的百分比，从而减轻了炎症和纤维化状况。具有CD28共刺激基序的CAR-T细胞显示出更好的治疗效果，且未发生严重CRS事件或增加感染风险。此外，我们验证了从IgG4-RD患者体外制备人CAR-T的可行性。综上所述，这些结果表明抗CD19 CAR-T疗法在治疗IgG4-RD小鼠模型中是有效的，表明其在患者临床应用中的潜力。
