IF 4.8 2区 医学 Q2 IMMUNOLOGY
International immunopharmacology Pub Date : 2025-01-03 Epub Date: 2024-12-12 DOI:10.1016/j.intimp.2024.113779
Yeting Sun, Sicheng Huang, Bo Zhang, Yu Peng, Hui Lu, Yimeng Jia, Ruijie Sun, Fenghua Zhang, Jiaxin Zhou, Linyi Peng, Mengtao Li, Wen Zhang, Yunyun Fei
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引用次数: 0

摘要

失调的B细胞活化在IgG4相关疾病(IgG4-RD)中起着关键作用,这使得B细胞耗竭成为治疗IgG4-RD的一种潜在策略。在这项研究中,我们的目的是在基于LatY136F基因敲入(Lat)小鼠的疾病模型中,研究将抗CD19嵌合抗原受体T(CAR-T)细胞疗法应用于IgG4-RD治疗的可行性。我们构建了以CD28或4-1BB为细胞内激动基团的小鼠抗CD19 CAR,并通过将其注入Lat小鼠体内评估了相应CAR-T细胞的治疗功能。接下来,我们通过评估细胞因子释放综合征(CRS)的风险和小鼠流感感染模型中的抗病毒能力,评估了CAR-T输注的安全性。最后,我们从 IgG4-RD 患者身上制造了人类抗 CD19 CAR-T,并在体外评估了其活化水平和功能效果。与 1D3 抗体治疗相比,带有 CD28 costimulatory motif 的抗 CD19 CAR-T 细胞对 Lat 小鼠的 B 细胞消耗效果相当。此外,共生抗CD19 CAR-T细胞还能降低浆细胞和分泌IL-4的Th细胞的比例,从而减轻炎症和纤维化状况。带有CD28共价键的CAR-T细胞显示出更高的治疗效率,同时不会发生严重的CRS事件或增加感染风险。此外,我们还验证了从 IgG4-RD 患者体外制备人类 CAR-T 的可行性。总之,这些结果表明,抗 CD19 CAR-T 疗法能有效治疗 IgG4-RD 小鼠模型,这表明它有可能用于患者的临床治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Efficacy and safety of anti-CD19 CAR-T in a mouse model of IgG4-related disease.

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.

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来源期刊
CiteScore
8.40
自引率
3.60%
发文量
935
审稿时长
53 days
期刊介绍: International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.
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