单次输注工程化的长寿命和多功能T细胞可使小鼠哮喘得到持久缓解
2024/06/26
摘要
哮喘是最常见的呼吸道疾病，每年影响3亿多人，造成25万多人死亡。2型重度哮喘的特征是白细胞介素（IL）-5驱动的嗜酸性粒细胞增多，以及由IL-4和IL-13引起的气道炎症和重塑。在这里，我们利用IL-5作为靶向结构域，并耗尽BCOR和ZC3H12A来设计能够根除嗜酸性粒细胞的长寿命嵌合抗原受体（CAR）T细胞。我们称这些细胞为永生样和功能性IL-5 CAR T细胞（5TIF）细胞。5TIF细胞被进一步修饰以分泌阻断IL-4和IL-13信号传导的IL-4突变蛋白，称为5TIF4细胞。在哮喘模型中，在没有任何调理方案的情况下，在完全免疫活性的小鼠中单次输注5TIF4细胞，可以持续抑制肺部炎症并减轻哮喘症状。这些数据表明，哮喘是一种常见的慢性疾病，单剂量的长寿命CAR T细胞可以使其长期缓解。
A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice
Gang Jin, Yanyan Liu, Lixia Wang, Zihao He, Xiaocui Zhao, Yuying Ma, Yuting Jia, Zhuoyang Li, Na Yin, Min Peng
Abstract
Asthma, the most prevalent respiratory disease, affects more than 300 million people and causes more than 250,000 deaths annually. Type 2-high asthma is characterized by interleukin (IL)-5-driven eosinophilia, along with airway inflammation and remodeling caused by IL-4 and IL-13. Here we utilize IL-5 as the targeting domain and deplete BCOR and ZC3H12A to engineer long-lived chimeric antigen receptor (CAR) T cells that can eradicate eosinophils. We call these cells immortal-like and functional IL-5 CAR T cells (5TIF) cells. 5TIF cells were further modified to secrete an IL-4 mutein that blocks IL-4 and IL-13 signaling, designated as 5TIF4 cells. In asthma models, a single infusion of 5TIF4 cells in fully immunocompetent mice, without any conditioning regimen, led to sustained repression of lung inflammation and alleviation of asthmatic symptoms. These data show that asthma, a common chronic disease, can be pushed into long-term remission with a single dose of long-lived CAR T cells.
哮喘是最常见的呼吸道疾病，每年影响3亿多人，造成25万多人死亡。2型重度哮喘的特征是白细胞介素（IL）-5驱动的嗜酸性粒细胞增多，以及由IL-4和IL-13引起的气道炎症和重塑。在这里，我们利用IL-5作为靶向结构域，并耗尽BCOR和ZC3H12A来设计能够根除嗜酸性粒细胞的长寿命嵌合抗原受体（CAR）T细胞。我们称这些细胞为永生样和功能性IL-5 CAR T细胞（5TIF）细胞。5TIF细胞被进一步修饰以分泌阻断IL-4和IL-13信号传导的IL-4突变蛋白，称为5TIF4细胞。在哮喘模型中，在没有任何调理方案的情况下，在完全免疫活性的小鼠中单次输注5TIF4细胞，可以持续抑制肺部炎症并减轻哮喘症状。这些数据表明，哮喘是一种常见的慢性疾病，单剂量的长寿命CAR T细胞可以使其长期缓解。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Nat Immunol. 2024 May 27. doi: 10.1038/s41590-024-01834-9.)
(Nat Immunol. 2024 May 27. doi: 10.1038/s41590-024-01834-9.)
A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice
Gang Jin, Yanyan Liu, Lixia Wang, Zihao He, Xiaocui Zhao, Yuying Ma, Yuting Jia, Zhuoyang Li, Na Yin, Min Peng
Abstract
Asthma, the most prevalent respiratory disease, affects more than 300 million people and causes more than 250,000 deaths annually. Type 2-high asthma is characterized by interleukin (IL)-5-driven eosinophilia, along with airway inflammation and remodeling caused by IL-4 and IL-13. Here we utilize IL-5 as the targeting domain and deplete BCOR and ZC3H12A to engineer long-lived chimeric antigen receptor (CAR) T cells that can eradicate eosinophils. We call these cells immortal-like and functional IL-5 CAR T cells (5TIF) cells. 5TIF cells were further modified to secrete an IL-4 mutein that blocks IL-4 and IL-13 signaling, designated as 5TIF4 cells. In asthma models, a single infusion of 5TIF4 cells in fully immunocompetent mice, without any conditioning regimen, led to sustained repression of lung inflammation and alleviation of asthmatic symptoms. These data show that asthma, a common chronic disease, can be pushed into long-term remission with a single dose of long-lived CAR T cells.
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选择性产生 IL-33 中和自身抗体可改善哮喘反应和严重程度
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重度哮喘患者对omalizumab、benralizumab和mepolizumab完全缓解者与非完全缓解者的临床特征:
