间充质干细胞能改善睡眠障碍吗-间充质干细胞排异有改善吗

间充质干细胞能改善睡眠障碍吗-间充质干细胞排异有改善吗

执笔:东海老师

首先:间充质干细胞

尽管间充质干细胞(MSC)药物已经在一些国家被批准上市,但许多人仍然对MSC的安全性充满疑虑。当然,这里指的是合格的、质量有保证的干细胞。虽然很多动物实验已经证明了间充质干细胞的安全性,但临床观察和评估更有意义。

1 间充质干细胞治疗出现不良反应的因素

发热:免疫反应和炎症反应?

MSCs治疗后,发热是最常见的不良反应,文献中最高发生率约为39%[1-4]。一般患者会自然恢复,无需特殊治疗。研究推测发热原因可能与同种异体MSCs引起的急性炎症反应有关[5]。而MSCs具有低免疫原性和“免疫性”的特点,很难引起免疫排斥[6]。更直接的证据是,MSCs可以有效治疗各种免疫性疾病,尤其是GVHD[7]。

动物实验证明,MSCs能有效治疗和消除炎症[8]。研究评估了137名类风湿性关节炎患者,这些患者在MSCs治疗后没有出现免疫毒性[9]。因此,MSCs治疗引起的发热与免疫反应和炎症反应无关。

不良反应:胎牛血清。

已经发现,通过用胎牛血清(FBS)培养MSCs可以增加MSCs的免疫原性[10,11]。但大量临床资料发现,MSCs细胞悬液中胎牛血清残留与不良反应之间没有相关性。即便如此,考虑到胎牛血清中有大量的外源蛋白,还是要尽可能的减少MSCs细胞悬液中胎牛血清的残留量(国家规定不得超过50ng/ml)。

不良反应:二甲基亚砜

更有甚者,含有DMSO (DMSO,细胞冻存的必要试剂)的MSCs细胞悬液会明显增加毒副作用,引起超敏反应[1,12,13]。因此,减少MSCs细胞悬液中二甲基亚砜的用量可以减少MSCs治疗引起的不良反应。

副作用:内毒素。

在临床应用中,我们发现如果MSCs悬液内毒素含量超标,无论是否同种异体,都容易引起发热。胎儿血清残留量、二甲基亚砜、内毒素都与生产工艺密切相关,与间充质干细胞本身无关。

不良反应:神经不良事件系统。

健康志愿者输入MSCs后,无输入毒性反应(心率、呼吸、血氧饱和度、血压),各器官功能无异常[14]。大多数研究发现,MSCs输入后没有或只有轻微的输入毒性[2,4,7,9,15-30]。只有三项临床试验报告了MSCs引起的心**性,表现为短暂性心律失常,发生率为7%(30例患者中的2例)[23,31,32]。只有一项随机对照试验发现,MSCs治疗了16名患者,其中3名患者有系统症状。而在对照组中,有5名患者出现了相同的症状[16]。

不良反应:感染和肿瘤发生的风险。

虽然有一项非随机对照试验,但MSCs治疗组的3名患者和对照组的3名患者在治疗后因感染死亡[33]。但更多的随机对照临床试验,通过统计分析,发现MSCs治疗组与对照组感染率无差异,并明确提出MSCs治疗不会增加感染风险[15,16,18],MSCs治疗组与对照组恶病质和肿瘤发生率无差异[15-18]。长期观察未发现患者增加微生物感染和间充质干细胞引起肿瘤[7,34]。有学者对41例软骨损伤患者给予MSCs治疗,观察11年,未发现肿瘤[35]。

大样本临床研究证明了MSCs疗法的安全性[7,9,36-38]。有学者对大量临床试验文献进行了荟萃分析,发现MSCs输入疗法仅与发热有关,而与其他文献报道的不良反应无必然联系,认为MSC疗法是安全的[39]。

2 小结与问题

总的来说,间充质干细胞治疗的安全性记录良好,对患者没有明显的毒副作用。少数患者注射后出现局部不适,一过性低热等。所以对症治疗就够了。

描述:

原文首发于《间充质干细胞》,“干细胞理论”科普平台获授权转载,引起业内广泛讨论。当时国内还没有细胞药物申报。这些年来,干细胞药物的申请数量已经达到30个,默示许可的临床试验已经达到2个。

2项,感慨万千,见证了中国干细胞行业从无序到有序。干细胞制剂安全性依然还是首要问题,但只要工艺靠谱,已不是大问题。

——步步先生

下面是当时评论留言(为保护隐私,码去昵称和头像),只留下精彩评论

干细胞质量相关法规

  • 2020年,《人源性干细胞及其衍生细胞治疗产品临床试验技术指导原则(征求意见稿)》

  • 2019年,《GMP附录-细胞治疗产品》(征求意见稿)

  • 2018年,《细胞治疗产品申请临床试验药学研究和申报资料的考虑要点》

  • 2017年,《细胞治疗产品研究与评价技术指导原则(试行)》

  • 2015年,《干细胞制剂质量控制及临床前研究指导原则(试行)》

  • 2003年,《人体细胞治疗研究和制剂质量控制技术指导原则》

团体标准

  • 2021年,中国细胞生物学学会组织编写的 《人间充质干细胞》

当然,还有 中国医药生物技术协会组织编写的《干细胞制剂制备质量管理自律规范》、深圳市细胞治疗协会组织编写的《临床研究用人脐带来源间充质干细胞制剂规范》、中国整形美容协会组织编写的《干细胞制剂制备与质检行业标准(试行)》等一些约束各自会员的标准。

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谁持彩练当空舞 :干细胞基础与临床研究进展

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