输间充质干细胞的风险
虽然间充质干细胞(MSC)药物已经被一些国家批准上市，但是依然不少人对间充质干细胞的安全性充满疑虑。当然，这里指的是质量合格有保障的干细胞。虽然不少动物实验证明了输入间充质干细胞的安全性，但临床研究观察和评价更具有意义。
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输入治疗后，发热是最常见的不良反应，文献中的最高发生率大概为39%[1-4]。一般无需特别处理，病人会自然恢复。有研究推测发烧的原因可能与输入异体MSCs引起的急性炎症反应有关[5]。但是，MSCs具有低免疫原性，而且有“免疫豁免”的特性，因此难于引起免疫排斥反应[6]。更直接的证据就是MSCs能有效地治疗各种免疫性疾病，尤其是治疗GVHD[7]。
动物实验证明MSCs能有效地治疗消除炎症[8]。有研究评价了137例类风湿性关节炎患者，患者在MSCs治疗后并不出现免疫毒性[9]。因此，MSCs治疗引起的发烧与免疫反应、炎症反应无关。
不良反应:胎牛血清
有研究发现利用胎牛血清(FBS)培养MSCs，可能会增加MSCs的免疫原性[10, 11]。但是大量的临床数据发现MSCs细胞悬液中的胎牛血清残留和不良反应没有关联性。即使如此，考虑到胎牛血清中存在大量的异种蛋白，我们也应该尽可能地降低MSCs细胞悬液中的胎牛血清残留量(国家规定不能超过50ng/ml)。
不良反应:DMSO
更值得注意的是，MSCs细胞悬液中含有二甲基亚砜(DMSO，细胞冻存必须要用的试剂)能明显增加毒副作用，引起超敏反应[1, 12,13]。因此，降低MSCs细胞悬液中含有二甲基亚砜的量能减少MSCs治疗引起的不良反应。
不良反应:内毒素
我们在临床应用中发现，如果MSCs悬液中的内毒素含量超标，则很容易引起发热，而与是否异体无关。胎牛血清残留量、二甲基亚砜和内毒素均与生产工艺密切相关，与间充质干细胞的细胞本身没有关系。
不良反应:神经系统不良事件
健康志愿者输入MSCs后，不出现输入性毒性反应(心率、呼吸、血氧饱和度、血压)，各器官功能未见异常[14]。大部分研究发现患者输入MSCs后，没出现或者轻微的输入性毒性反应[2, 4, 7, 9,15-30]。仅有三个临床试验报道MSCs引起心脏毒性，表现为一过性心律不齐，发生率为7%(30例患者中有2例出现)[23, 31, 32]。只有一个随机对照试验发现MSCs治疗16名患者，有3名患者神经系统症状;而对照组36名患者中，有5名患者出现相同症状[16]。
不良反应:感染风险和成瘤风险
虽然有一个非随机对照试验中，MSCs治疗组100名患者中的3名患者，及对照组100名患者中的3名患者，由于治疗后出现感染而导致死亡[33]。但是，更多的随机对照临床试验，通过统计学分析，发现MSCs治疗组和对照组的感染率没有差异，明确提出MSCs治疗不会增加感染的风险[15, 16, 18]，而且MSCs治疗组和对照组在恶液质和成瘤方面没有差异[15-18]。长期观察也没有发现病人增加微生物感染和间充质干细胞致瘤的现象[7, 34]。更有学者给41例软骨损伤的病人输入MSCs治疗，观察了11年，均未发现肿瘤的发生[35]。
大样本临床研究证明MSCs治疗的安全性[7, 9, 36-38]。亦有学者对目前大量的临床试验的文献进行分析(Meta-Analysis)，发现MSCs输入治疗仅仅与发热存在一定的关联性，而与其他文献所报道的不良反应没有必要的联系，认为MSC治疗是安全的[39]。
2、小结与问题
总体来看，间充质干细胞治疗具有良好的安全性记录，对病人无明显毒副作用，少数病人出现注射局部不适、短暂低热等，对症处理即可。
数年过去了，干细胞药物申请申请已经达到30个，其中获得默示许可的临床试验也已经22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。
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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内容来源:瑞宝恩Reborn