Skuljec Jelena, Chmielewski Markus, Happle Christine, Habener Anika, Busse Mandy, Abken Hinrich, Hansen Gesine
Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.
Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany.
Front Immunol. 2017 Sep 12;8:1125. doi: 10.3389/fimmu.2017.01125. eCollection 2017.
Cellular therapy with chimeric antigen receptor (CAR)-redirected cytotoxic T cells has shown impressive efficacy in the treatment of hematologic malignancies. We explored a regulatory T cell (Treg)-based therapy in the treatment of allergic airway inflammation, a model for asthma, which is characterized by an airway hyper-reactivity (AHR) and a chronic, T helper-2 (Th2) cell-dominated immune response to allergen. To restore the immune balance in the lung, we redirected Tregs by a CAR toward lung epithelia in mice upon experimentally induced allergic asthma, closely mimicking the clinical situation. Adoptively transferred CAR Tregs accumulated in the lung and in tracheobronchial lymph nodes, reduced AHR and diminished eosinophilic airway inflammation, indicated by lower cell numbers in the bronchoalveolar lavage fluid and decreased cell infiltrates in the lung. CAR Treg cells furthermore prevented excessive pulmonary mucus production as well as increase in allergen-specific IgE and Th2 cytokine levels in exposed animals. CAR Tregs were more efficient in controlling asthma than non-modified Tregs, indicating the pivotal role of specific Treg cell activation in the affected organ. Data demonstrate that lung targeting CAR Treg cells ameliorate key features of experimental airway inflammation, paving the way for cell therapy of severe allergic asthma.
嵌合抗原受体（CAR）重定向细胞毒性T细胞的细胞疗法在血液系统恶性肿瘤的治疗中已显示出令人瞩目的疗效。我们探索了一种基于调节性T细胞（Treg）的疗法来治疗过敏性气道炎症，这是一种哮喘模型，其特征为气道高反应性（AHR）以及对过敏原的慢性、以辅助性T细胞2（Th2）为主导的免疫反应。为了恢复肺部的免疫平衡，我们在实验性诱导的过敏性哮喘小鼠中，通过CAR将Tregs重定向至肺上皮，这与临床情况极为相似。过继转移的CAR Tregs在肺和气管支气管淋巴结中积聚，降低了AHR，并减轻了嗜酸性气道炎症，支气管肺泡灌洗液中的细胞数量减少以及肺内细胞浸润减少表明了这一点。此外，CAR Treg细胞还可防止暴露动物肺部黏液过度产生以及过敏原特异性IgE和Th2细胞因子水平升高。CAR Tregs在控制哮喘方面比未修饰的Tregs更有效，表明特定Treg细胞激活在受影响器官中的关键作用。数据表明，靶向肺的CAR Treg细胞可改善实验性气道炎症的关键特征，为重度过敏性哮喘的细胞治疗铺平了道路。
