Izrael Michal, Molakandov Kfir, Revel Ariel, Slutsky Shalom Guy, Sonnenfeld Tehila, Weiss Julia Miriam, Revel Michel
Research and Development Department at Kadimastem Ltd, Nes-Ziona, Israel.
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Front Med (Lausanne). 2021 Oct 29;8:740071. doi: 10.3389/fmed.2021.740071. eCollection 2021.
An acute respiratory distress syndrome (ARDS) is caused by the increased amounts of pro-inflammatory cytokines and neutrophil-mediated tissue injury. To date, there is no effective treatment for the ARDS available, while the need for one is growing due to the most severe complications of the current coronavirus disease-2019 (COVID-19) pandemic. The human astrocytes (AstroRx) have shown immunomodulatory properties in the central nervous system (CNS). This study aimed to evaluate the capacity of astrocytes to decrease lung inflammation and to be applied as a treatment therapy in ARDS. First, we assessed the ability of clinical-grade AstroRx to suppress T-cell proliferation in a mixed lymphocyte reaction test. Next, we tested the therapeutical potential of AstroRx cells in a lipopolysaccharide (LPS)-based ARDS mouse model by injecting AstroRx intravenously (i.v). We determined the degree of lung injury by using a severity scoring scale of 0-2, based on the American Thoracic Society. The scoring measured the presence of neutrophils, fibrin deposits, and the thickening of alveolar walls. The state of inflammation was further assessed by quantifying the immune-cell infiltration to the bronchoalveolar lavage fluid (BALF) and by the presence of proinflammatory cytokines and chemokines in the BALF and serum. We detected that AstroRx cells were capable to suppress T-cell proliferation after exposure to the mitogen concanavalin A (ConA). , AstroRx cells were able to lower the degree of lung injury in LPS-treated animals compared with the sham injected animals ( = 0.039). In this study, 30% of AstroRx treated mice showed no lung lesions (responder mice), these mice presented a steady number of eosinophils, T cells, and neutrophils comparable with the level of naïve control mice. The inflammatory cytokines and chemokines, such as TNFα, IL1b, IL-6, and CXCL1, were also kept in check in responder AstroRx-treated mice and were not upregulated as in the sham-injected mice ( < 0.05). As a result, the LPS-treated ARDS mice had a higher survival rate when they were treated with AstroRx. Our results demonstrate that the immunosuppressive activity of AstroRx cells support the application of AstroRx cells as a cell therapy treatment for ARDS. The immunoregulatory activity may also be a part of the mechanism of action of AstroRx reported in the amyotrophic lateral sclerosis (ALS) neurodegenerative disease.
急性呼吸窘迫综合征（ARDS）是由促炎细胞因子数量增加和中性粒细胞介导的组织损伤引起的。迄今为止，尚无针对ARDS的有效治疗方法，而由于当前2019冠状病毒病（COVID-19）大流行的最严重并发症，对有效治疗方法的需求正在增加。人星形胶质细胞（AstroRx）已在中枢神经系统（CNS）中显示出免疫调节特性。本研究旨在评估星形胶质细胞减轻肺部炎症的能力，并将其作为ARDS的一种治疗方法应用。首先，我们在混合淋巴细胞反应试验中评估了临床级AstroRx抑制T细胞增殖的能力。接下来，我们通过静脉注射（i.v.）AstroRx，在基于脂多糖（LPS）的ARDS小鼠模型中测试了AstroRx细胞的治疗潜力。我们根据美国胸科学会使用0至2的严重程度评分量表来确定肺损伤程度。该评分测量中性粒细胞的存在、纤维蛋白沉积以及肺泡壁增厚情况。通过量化支气管肺泡灌洗液（BALF）中的免疫细胞浸润以及BALF和血清中促炎细胞因子和趋化因子的存在，进一步评估炎症状态。我们检测到AstroRx细胞在暴露于促有丝分裂原刀豆球蛋白A（ConA）后能够抑制T细胞增殖。与假注射动物相比，AstroRx细胞能够降低LPS处理动物的肺损伤程度（P = 0.039）。在本研究中，30%接受AstroRx治疗的小鼠未出现肺部病变（反应小鼠），这些小鼠的嗜酸性粒细胞、T细胞和中性粒细胞数量稳定，与未处理的对照小鼠水平相当。在反应性AstroRx治疗的小鼠中，炎性细胞因子和趋化因子，如TNFα、IL1b、IL - 6和CXCL1，也受到控制，且未像假注射小鼠那样上调（P < 0.05）。结果，用AstroRx治疗的LPS诱导的ARDS小鼠存活率更高。我们的结果表明，AstroRx细胞的免疫抑制活性支持将AstroRx细胞作为ARDS的细胞治疗方法应用。这种免疫调节活性也可能是在肌萎缩侧索硬化症（ALS）神经退行性疾病中报道的AstroRx作用机制的一部分。
