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虽然不少动物实验证明了输入间充质干细胞（MSC）的安全性，但临床研究观察和评价更具有意义。今天了解一下间充质干细胞治疗的安全性问题。
撰文：东海先生
虽然不少动物实验证明了输入间充质干细胞（MSC）的安全性，但临床研究观察和评价更具有意义。
1.发热：免疫反应和炎症反应？
MSC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MSC引起的急性炎症反应有关[5]。但是，MSC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MSC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MSC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MSC治疗后并不出现免疫毒性[9]。因此，MSC治疗引起的发烧与免疫反应、炎症反应无关。
2.不良反应：胎牛血清
有研究发现利用胎牛血清（FBS）培养MSC，可能会增加MSC的免疫原性[10, 11]。但是大量的临床数据发现MSC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MSC细胞悬液中的胎牛血清残留量（国家规定不能超过50ng/ml）。
3.不良反应：DMSO
更值得注意的是，MSC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MSC细胞悬液中含有二甲基亚砜的量能减少MSC治疗引起的不良反应。
4.不良反应：内毒素
我们在临床应用中发现，如果MSC悬液中的内毒素含量超标（国家规定不能超过2EU/ml），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。
5.不良反应：神经系统不良事件
健康志愿者输入MSC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MSC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MSC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MSC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]。
6.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，MSC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MSC治疗组和对照组的感染率没有差异，明确提出MSC治疗不会增加感染的风险[15, 16, 18]，而且MSC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MSC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MSC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MSC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]。
其实人体中就广泛存在MSC，从来没发现人体内的MSC会癌变，或者肿瘤来源于MSC。MSC细胞本身是安全的，MSC治疗的不良反应与MSC悬液中的一些杂质有密切的联系，比如内毒素含量、胎牛血清的残留量等。
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。
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本文由东海先生授权发布，首发于《间充质干细胞》。
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