Department of Surgery, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Health Sciences University, Istanbul, Turkey.
Stem Cell and Gene Therapies Application and Research Center, Health Sciences University, Istanbul, Turkey.
Cell Transplant. 2021 Jan-Dec;30:9636897211024942. doi: 10.1177/09636897211024942.
The aim of this clinical trial was to control the cytokine storm by administering mesenchymal stem cells (MSCs) to critically-ill COVID-19 patients, to evaluate the healing effect, and to systematically investigate how the treatment works. Patients with moderate and critical COVID-19 clinical manifestations were separated as Group 1 (moderate cases, = 10, treated conventionally), Group 2 (critical cases, = 10, treated conventionally), and Group 3 (critical cases, = 10, treated conventionally plus MSCs transplantation therapy of three consecutive doses on treatment days 0, 3, and 6, (as 3 × 10 cells/kg, intravenously). The treatment mechanism of action was investigated with evaluation markers of the cytokine storm, via biochemical parameters, levels of proinflammatory and anti-inflammatory cytokines, analyses of tissue regeneration via the levels of growth factors, apoptosis markers, chemokines, matrix metalloproteinases, and granzyme-B, and by the assessment of the immunomodulatory effects via total oxidant/antioxidant status markers and the levels of lymphocyte subsets. In the assessment of the overall mortality rates of all the cases, six patients in Group-2 and three patients in Group-3 died, and there was no loss in Group-1. Proinflammatory cytokines IFNγ, IL-6, IL-17A, IL-2, IL-12, anti-inflammatory cytokines IL-10, IL-13, IL-1ra, and growth factors TGF-β, VEGF, KGF, and NGF levels were found to be significant in Group-3. When Group-2 and Group-3 were compared, serum ferritin, fibrinogen and CRP levels in Group-3 had significantly decreased. CD45 +, CD3 +, CD4 +, CD8 +, CD19 +, HLA-DR +, and CD16 + / CD56 + levels were evaluated. In the statistical comparison of the groups, significance was only determined in respect of neutrophils. The results demonstrated the positive systematic and cellular effects of MSCs application on critically ill COVID-19 patients in a versatile way. This effect plays an important role in curing and reducing mortality in critically ill patients.
本临床试验的目的是通过向危重症 COVID-19 患者输注间充质干细胞（MSCs）来控制细胞因子风暴，评估其治疗效果，并系统研究其作用机制。将具有中度和重度 COVID-19 临床表现的患者分为三组：第 1 组（中度病例，n=10，常规治疗）、第 2 组（重度病例，n=10，常规治疗）和第 3 组（重度病例，n=10，常规治疗+在治疗第 0、3 和 6 天分别给予 3 剂 MSC 移植治疗（每次 3×10 个细胞/kg，静脉内给药）。通过细胞因子风暴的评估标志物、生化参数、促炎和抗炎细胞因子水平、通过生长因子、凋亡标志物、趋化因子、基质金属蛋白酶和颗粒酶 B 的组织再生分析、通过总氧化剂/抗氧化剂状态标志物和淋巴细胞亚群水平评估免疫调节作用，来研究治疗的作用机制。在评估所有病例的总体死亡率时，第 2 组的 6 例患者和第 3 组的 3 例患者死亡，第 1 组无死亡。第 3 组 IFNγ、IL-6、IL-17A、IL-2、IL-12 等促炎细胞因子和 IL-10、IL-13、IL-1ra 等抗炎细胞因子以及 TGF-β、VEGF、KGF 和 NGF 等生长因子水平显著升高。与第 2 组相比，第 3 组的血清铁蛋白、纤维蛋白原和 CRP 水平显著降低。评估了 CD45+、CD3+、CD4+、CD8+、CD19+、HLA-DR+和 CD16+/CD56+水平。在对各组进行的统计学比较中，仅中性粒细胞具有统计学意义。结果表明，MSC 应用对危重症 COVID-19 患者具有全面的系统和细胞作用。这种作用在治疗和降低危重症患者死亡率方面发挥着重要作用。
