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中华重症医学电子杂志

中华重症医学电子杂志 ›› 2021, Vol. 07 ›› Issue (01) : 55 -65. doi: 10.3877/cma.j.issn.2096-1537.2021.01.010

所属专题： 文献；

综述

间充质干细胞在调节新型冠状病毒肺炎患者免疫功能中的应用
卢昆1, 耿仕涛2, 夏婧1, 唐士凯1, 张玮1, 吴海鹰1, 钱传云1,†()   
  1. 1. 650032 昆明医科大学第一附属医院急诊科
    2. 650032 昆明医科大学国家卫健委毒品依赖与戒治重点实验室
  • 收稿日期:2020-06-22 出版日期:2021-02-28
  • 通信作者: 钱传云
  • 基金资助:
    云南省后备人才项目(H-201616); 昆明医科大学研究生创新基金项目(2020S165)

Application of mesenchymal stem cells in regulating immune function of patients with coronavirus disease-2019

Kun Lu1, Shitao Geng2, Jing Xia1, Shikai Tang1, Wei Zhang1, Haiying Wu1, Chuanyun Qian1,†()   

  1. 1. Emergency Department, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, China
    2. NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming 650032, China
  • Received:2020-06-22 Published:2021-02-28
  • Corresponding author: Chuanyun Qian
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卢昆, 耿仕涛, 夏婧, 唐士凯, 张玮, 吴海鹰, 钱传云. 间充质干细胞在调节新型冠状病毒肺炎患者免疫功能中的应用[J]. 中华重症医学电子杂志, 2021, 07(01): 55-65.

Kun Lu, Shitao Geng, Jing Xia, Shikai Tang, Wei Zhang, Haiying Wu, Chuanyun Qian. Application of mesenchymal stem cells in regulating immune function of patients with coronavirus disease-2019[J]. Chinese Journal of Critical Care & Intensive Care Medicine(Electronic Edition), 2021, 07(01): 55-65.

新型冠状病毒肺炎（COVID-19）是一种具有潜在致死性的传染性疾病，严重损害机体免疫系统，会导致免疫细胞过度激活，使炎性细胞因子大量释放，形成细胞因子风暴，从而加剧组织损伤和病情的发展。有效控制炎症因子风暴，已成为治疗COVID-19患者的关键点。间充质干细胞（MSCs）凭借其低免疫原性和对先天性和适应性免疫的调节能力，能够有效控制异常的免疫反应，抑制其对人体多器官造成的损伤。结合COVID-19患者免疫改变的特征和先前的研究，MSCs对COVID-19的治疗可能具有有良好的效果。本文通过分析COVID-19患者先天性和适应性免疫反应的改变，阐明MSCs对免疫的调节作用及机制，以期为COVID-19患者临床免疫治疗提供新的思路和理论基础。

关键词: 新型冠状病毒肺炎, 免疫功能, 间充质干细胞

Coronavirus disease-2019(COVID-19) is a potentially fatal infectious disease. COVID-19 can seriously damage the immune system, leading to the over-activation of immune cells, so that a large number of inflammatory cytokines are released, forming cytokine storm, thereby exacerbating tissue damage and disease development. To effectively control inflammatory storm has become a key point in the treatment of patients with COVID-19. Mesenchymal stem cells (MSCs) can effectively control abnormal immune response and inhibit damage to multiple human organs due to the virtue of low immunogenicity and regulating ability to both innate and adaptive immunity. According to the characteristics of immune dysfunction in COVID-19 patients and previous studies, MSCs may have a good effect on treatment of COVID-19. This article focuses on analyzing changes of innate and adaptive immune responses in COVID-19 patients and elucidates the regulation mechanism of MSCs on immunity, in order to provide new insights and theory for clinical immunotherapy in COVID-19 patients.

Key words: Coronavirus disease-2019, Immune function, Mesenchymal stem cells
表1 MSCs对免疫细胞的调节[69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101]
细胞类型 MSCs的调节作用及机制
先天性免疫细胞

NK

MSCs抑制NK的增殖和功能：

（1）通过抑制NK细胞激活的受体（NKp30/44、NKG2D、CD60）的表达抑制其细胞毒作用；

（2）通过可溶性因子（PGE2、HLA-G、IDO）抑制NK细胞的增殖和细胞毒作用；

（3）IFN-γ诱导MSCs高表达HLA-I类分子，与NK的抑制性受体共同作用，抑制NK细胞毒作用

DC

MSCs抑制DC的分化、成熟与活性：

（1）抑制多能造血干细胞向DC的分化和DC的成熟，降低CD1a、CD80、CD83、CD86、HLA-DR的表达，减少IL-2的分泌；

（2）主要通过细胞接触和可溶性因子实现对DC的抑制

巨噬细胞

MSCs通过多种机制调节巨噬细胞的功能：

（1）细胞接触：MSCs通过与巨噬细胞相互作用，上调巨噬细胞中与吞噬功能相关分子的表达，增强其对病原体的吞噬能力；

（2）可溶性因子：MSCs通过表达PGE2、IL-6、CX3CL1和IDO直接诱导单核细胞分化为M2型巨噬细胞或诱导M1型转化为M2型巨噬细胞；

（3）炎性微环境中时，促炎因子可刺激MSCs分泌TSG-6与巨噬细胞膜上CD44受体相互作用，下调NF-κB信号通路活性，减少促炎因子的表达，削弱促炎级联反应

中性粒细胞

（1）MSCs通过IL-6依赖的途径减轻其氧爆发，抑制中性粒细胞迁徙；抑制中性粒细胞凋亡，延长寿命；

（2）诱导Th2产生IL-17，增强中性粒细胞吞噬功能，使其主要发挥清除病原体的作用

MCs

 MSCs能显著降低IgE的产生、组胺的释放和MCs的活化；MSCs产生TGF-β1，通过降低FcεRI的表达，导致FcεRI介导的MCs脱颗粒作用减弱
适应性免疫细胞

T细胞

MSCs具有抑制T细胞增殖、抑制T细胞向Th1、Th17分化、促进Tregs的产生的作用：抑制Th1和Th17细胞产生的促炎细胞因子，如TNF-α、IFN-γ和IL-17，增强Th2细胞产生的抗炎细胞因子，如IL-4；抑制CTL的增殖和细胞毒性功能；诱导CD4+T细胞以细胞-细胞接触依赖的方式分化为Tregs

（1）细胞接触：ICAM-1是MSCs发挥抑制作用不可或缺的；PD-1/PD-L1相互作用参与了这一过程；

（2）可溶性因子：MSCs产生的IDO、PGE、IL-10、TGF-β、NO、HLA-G5、PD-L1、PD-L2和TSG-6等因子与MSCs的免疫抑制功能有关；MSCs以PGE2依赖的方式抑制Th1细胞因子的产生；对于Th17细胞，MSCs通过上调PD-1的表达、IL-10的分泌和PGE2的产生以及CCL2依赖的方式来抑制其分化；PGE2、IL-6、IL-10和TGF-β，参与了CD4+T细胞分化为Tregs的过程；

（3）MSCs可抑制T细胞增殖过程，使T细胞被阻滞在G0/G1期

B细胞

MSCs抑制B细胞的活化、增殖、分化、抗体产生和趋化等一系列活性：

（1）MSCs以旁分泌方式阻止B细胞在G0/G1期增殖；

（2）细胞-细胞接触依赖性方式，如PD-1与其配体PDL-1的相互作用，介导MSCs对B细胞的抑制；

（3）MSCs可以通过下调B淋巴细胞诱导成熟蛋白-1（Blimp-1）的mRNA表达来抑制B细胞向浆细胞的分化
表2 已注册的间充质干细胞治疗COVID-19的临床实验
注册号 题目 试验开始时间 患者数量 实验持续时间 研究类型
NCT4348461 Battle against COVID-19 using mesenchymal stromal cells 2020/4/6 100 5个月 干预性研究
NCT4315987 Mesenchymal stem cell to treat patients with severe COVID-19 pneumonia 2020/3/20 66 3个月 干预性研究
NCT4352803 Adipose mesenchymal cells for abatement of SARS-CoV-2 respiratory compromise in COVID-19 disease 2020/4/20 20 6年 干预性研究
NCT4252118 Mesenchymal stem cell treatment for pneumonia patients infected with COVID-19 2020/1/27 20 1年 干预性研究
NCT4345601 Mesenchymal stromal cells for the treatment of SARS-CoV-2 induced acute respiratory failure （COVID-19 disease） 2020/4/14 30 2年 干预性研究
NCT4313322 Treatment of COVID-19 patients using Whartons Jelly-mesenchymal stem cells 2020/3/16 5 6个月 干预性研究
NCT4288102 Treatment with mesenchymal stem cells for severe corona virus disease 2019 2020/4/5 90 4个月 干预性研究
NCT4346368 Bone marrow-derived mesenchymal stem cell treatment for sebere patients with corona virus disease 2019 （COVID-19） 2020/4/15 20 8个月 干预性研究
NCT4336254 Safety and efficacy study of allogenic human dental pulp mesenchymal stem cells to treat severe COVID-19 patients 2020/4/6 20 8个月 干预性研究
NCT4273646 Study of human umbilical cord mesenchymal stem cells in the treatment of severe COVID-19 2020/4/20 48 5个月 干预性研究
NCT4302519 Novel coronavirus induced severe pneumonia treated by dental pulp mesenchymal stem cells 2020/4/5 24 4个月 干预性研究
NCT4339660 Clinical Research of Human Mesenchymal Stem Cells in the Treatment of COVID-19 Pneumonia 2020/2/1 30 4个月 干预性研究
NCT4355728 Use of UC-MSCs for COVID-19 Patients 2020/4/17 24 1 年 干预性研究
NCT4362189 Efficacy and Safety Study of Allogeneic HB-adMSCs for the Treatment of COVID-19 2020/5/15 110 5个月 干预性研究
NCT4361942 Treatment of Severe COVID-19 Pneumonia With Allogeneic Mesenchymal Stromal Cells （COVID_MSV） （COVID_MSV） 2020/4/24 24 8个月 干预性研究
NCT3042143 Repair of Acute Respiratory Distress Syndrome by Stromal Cell Administration （REALIST） （COVID-19） （REALIST） 2019/1/7 75 3年 干预性研究
NCT4269525 Umbilical Cord （UC）-Derived Mesenchymal Stem Cells （MSCs） Treatment for the 2019-novel Coronavirus（nCOV） Pneumonia 2020/2/6 10 7个月 干预性研究
NCT4333368 Cell Therapy Using Umbilical Cord-derived Mesenchymal Stromal Cells in SARS-CoV-2-related ARDS （STROMA-CoV2） 2020/4/1 60 1年 干预性研究
NCT4341610 ASC Therapy for Patients With Severe Respiratory COVID-19 （ASC COVID-19） 2020/4/20 40 1年 干预性研究
NCT4366323 Clinical Trial to Assess the Safety and Efficacy of Intravenous Administration of Allogeneic Adult Mesenchymal Stem Cells of Expanded Adipose Tissue in Patients With Severe Pneumonia Due to COVID-19 2020/4/28 26 18个月 干预性研究
NCT4371601 Safety and Effectiveness of Mesenchymal Stem Cells in the Treatment of Pneumonia of Coronavirus Disease 2019 2020/5/1 60 18个月 干预性研究
NCT4366063 Mesenchymal Stem Cell Therapy for SARS-CoV-2-related Acute Respiratory Distress Syndrome 2020/4/28 60 6个月 干预性研究
NCT4382547 Treatment of Covid-19 Associated Pneumonia With Allogenic Pooled Olfactory Mucosa-derived Mesenchymal Stem Cells 2020/4/21 24 1年 干预性研究
NCT4366271 Clinical Trial of Allogeneic Mesenchymal Cells From Umbilical Cord Tissue in Patients With COVID-19 2020/4/28 106 1年 干预性研究
NCT4390152 Safety and Efficacy of Intravenous Wharton's Jelly Derived Mesenchymal Stem Cells in Acute Respiratory Distress Syndrome Due to COVID 19 2020/5/15 40 1年 干预性研究
NCT4377334 Mesenchymal Stem Cells （MSCs） in Inflammation-Resolution Programs of Coronavirus Disease 2019 （COVID-19） Induced Acute Respiratory Distress Syndrome （ARDS） 2020/5/6 40 9个月 干预性研究
NCT4390139 Efficacy and Safety Evaluation of Mesenchymal Stem Cells for the Treatment of Patients With Respiratory Distress Due to COVID-19 2020/5/15 30 7个月 干预性研究
NCT4392778 Clinical Use of Stem Cells for the Treatment of Covid-19 2020/4/1 30 5个月 干预性研究
NCT4397796 Study of the Safety of Therapeutic Tx With Immunomodulatory MSC in Adults With COVID-19 Infection Requiring Mechanical Ventilation 2020/5/21 45 1年 干预性研究
NCT4371393 MSCs in COVID-19 ARDS 2020/5/1 300 2年 干预性研究
NCT4398303 ACT-20 in Patients With Severe COVID-19 Pneumonia 2020/5/21 70 5个月 干预性研究
NCT4400032 Cellular Immuno-Therapy for COVID-19 Acute Respiratory Distress Syndrome - Vanguard 2020/5/25 9 1年 干预性研究
NCT4276987 A Pilot Clinical Study on Inhalation of Mesenchymal Stem Cells Exosomes Treating Severe Novel Coronavirus Pneumonia 2020/2/15 30 5个月 干预性研究
ChiCTR2000031430 人间充质干细胞治疗新型冠状病毒肺炎（COVID-19）患者肺间质性损害的临床研究 2020/3/31 100 21个月 干预性研究
ChiCTR2000030944 人自然杀伤细胞联合间充质干细胞治疗重症新型冠状病毒肺炎（COVID-19）的临床研究 2020/3/18 10 5个月 干预性研究
ChiCTR2000030866 脐带间充质干细胞治疗重型和危重型新型冠状病毒肺炎（COVID-19）的开放性临床观察研究 2020/03/16 30 10个月 观察性研究
ChiCTR2000030835 间充质干细胞（MSC）治疗重型新型冠状病毒肺炎（COVID-19）的有效性临床研究 2020/03/15 10 1年 干预性研究
ChiCTR2000030484 脐带间充质干细胞联合细胞外泌体静脉输注对新型冠状病毒肺炎（COVID-19）肺损伤修复的临床应用研究 2020/03/03 30 1年 干预性研究
ChiCTR2000030138 人间充质干细胞治疗重症新型冠状病毒（COVID-19）感染肺炎临床研究（该研究目前尚未获得伦理委员会批准） 2020/02/24 30 3个月 干预性研究
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