Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
Pulmonary Medicine Research Center, Taipei Medical University, Taipei, Taiwan.
Front Immunol. 2022 Apr 29;13:871828. doi: 10.3389/fimmu.2022.871828. eCollection 2022.
BACKGROUND AND OBJECTIVES: The novel coronavirus disease 2019 (COVID-19) has been a pandemic health issue in 30 January 2020. The mortality rate is as high as 50% in critically ill patients. Stem cell therapy is effective for those who are refractory to standard treatments. However, the immune responses that underlie stem cell therapy have not been well reported, particularly, in patients associated with moderate to severe acute respiratory distress syndrome (ARDS). METHODS: On Days 0 and 4, an intravenous infusion of 2 × 10 placenta-derived mesenchymal stem cells (pcMSCs) (MatriPlax) were administered to five severe COVID-19 patients refractory to current standard therapies. Peripheral blood inflammatory markers and immune profiles were determined by multi-parameter flow cytometry and studied at Days 0, 4, and 8. Clinical outcomes were also observed. RESULTS: None of the pc-MSC treated patients experienced 28-day mortality compared with the control group and showed a significant improvement in the PaO/FiO ratio, Murray's lung injury scores, reduction in serum ferritin, lactate dehydrogenase (LDH), and C-reactive protein (CRP) levels. The cytokine profiles also showed a reduction in IL-1β, IFN-γ, IL-2, and IL-6, and an increase in IL-13 and IL-5 type 2 cytokines within 7 days of therapy. Lymphopenia was also significantly improved after 7 days of treatment. Immune cell profiles showed an increase in the proportions of CD4 T cells (namely, CD4 naïve T cells and CD4 memory T cell subtypes), Treg cells, CD19 B cells (namely, CD19 naïve B cells, CD27 switched B cell subtypes) and dendritic cells, and a significant decrease in the proportion of CD14 monocytes (namely, CD16 classical and CD16 non-classical subtypes), and plasma/plasmablast cells. No adverse effects were seen at the serial follow-up visits for 2 months after initial therapy. CONCLUSION: pc-MSCs therapy suppressed hyper-inflammatory states of the innate immune response to COVID-19 infection by increasing Treg cells, decreasing monocytes and plasma/plasmablast cells, and promoting CD4 T cells and CD19 B cells toward adaptive immune responses in severely critically ill COVID-19 patients with moderate to severe ARDS, especially those who were refractory to current standard care and immunosuppressive therapies.
背景与目的：新型冠状病毒病 2019（COVID-19）自 2020 年 1 月 30 日以来一直是一个全球性的健康问题。危重症患者的死亡率高达 50%。对于那些对标准治疗无反应的患者，干细胞治疗是有效的。然而，干细胞治疗所涉及的免疫反应尚未得到很好的报道，特别是在与中度至重度急性呼吸窘迫综合征（ARDS）相关的患者中。
方法：在第 0 天和第 4 天，5 名对目前标准治疗无反应的重症 COVID-19 患者接受了 2×10 个胎盘来源间充质干细胞（pcMSCs）（MatriPlax）的静脉输注。通过多参数流式细胞术测定外周血炎症标志物和免疫谱，并在第 0、4 和 8 天进行研究。还观察了临床结果。
结果：与对照组相比，接受 pc-MSC 治疗的患者无一例在 28 天内死亡，并表现出 PaO/FiO 比值、Murray 肺损伤评分、血清铁蛋白、乳酸脱氢酶（LDH）和 C 反应蛋白（CRP）水平的显著改善。细胞因子谱也显示 IL-1β、IFN-γ、IL-2 和 IL-6 减少，治疗后 7 天内 2 型细胞因子 IL-13 和 IL-5 增加。淋巴细胞减少也在治疗后 7 天内显著改善。免疫细胞谱显示 CD4 T 细胞（即 CD4 幼稚 T 细胞和 CD4 记忆 T 细胞亚型）、Treg 细胞、CD19 B 细胞（即 CD19 幼稚 B 细胞、CD27 转换 B 细胞亚型）和树突状细胞的比例增加，而 CD14 单核细胞（即 CD16 经典和 CD16 非经典亚型）和血浆/浆母细胞的比例显著下降。在初始治疗后 2 个月的连续随访中，未观察到不良反应。
结论：pc-MSCs 治疗通过增加 Treg 细胞、减少单核细胞和血浆/浆母细胞、促进 CD4 T 细胞和 CD19 B 细胞向适应性免疫反应，抑制 COVID-19 感染固有免疫反应的过度炎症状态，在中重度 ARDS 的严重危重症 COVID-19 患者中，特别是在对当前标准治疗和免疫抑制治疗无反应的患者中，具有显著疗效。
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