Objective

The use of mesenchymal stem cells (MSCs) for the treatment of equine joint disease is widely investigated because of their regenerative and immunomodulatory potential. Allogeneic MSCs provide a promising alternative to autologous MSCs, since the former are immediately available and enable a thorough donor screening. However, questions have been raised concerning the immunogenic potential of allogeneic MSCs, especially after repeated administration.

Methods

Current retrospective study assessed the cellular and humoral immunogenicity of ten jumping and dressage horses with naturally occurring degenerative joint disease which were treated 3 times intra-articularly with a 1 mL stem cell suspension containing 1.4–2.5 million chondrogenic induced equine allogeneic peripheral blood-derived MSCs (ciMSCs) combined with 1 mL equine allogeneic plasma. Stem cells from 2 donor horses were used. Horses were clinically evaluated for joint effusion, presence of pain to palpation and skin surface temperature at the local injection site, joint range of motion, occurrence of adverse events and the presence of ectopic tissue. The cellular immune response was analyzed using a modified mixed lymphocyte reaction and the humoral immune response was investigated using a flow cytometric crossmatch assay by which the presence of alloantibodies against the ciMSCs was evaluated. Presence of anti-bovine serum albumin antibodies was detected via ELISA.

Results

Clinical evaluation of the horses revealed no serious adverse effects or suspected adverse drug reactions and no ectopic tissue formation at the local injection site or in other areas of the body. Generally, repeated administration led to a decrease of horses with joint effusion of the affected joint. Pain to palpation, skin surface temperature and joint range of motion did not increase or even decreased after treatment administration.

Allogeneic ciMSCs did not induce a cellular immune response and no alloantibodies were detected in the recipients’ serum, regardless the presence of BSA antibodies in 70 % of the horses.

Conclusion

Repeated intra-articular injections with allogeneic equine ciMSCs did not elicit clinically relevant adverse events. Furthermore, current study indicates the absence of a cellular or a humoral immune response following repeated intra-articular injections.

中文翻译：

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马同种异体外周血来源间充质干细胞的重复关节内给药不会在马体内诱导细胞和体液免疫反应

客观的

使用间充质干细胞 (MSCs) 治疗马关节疾病因其再生和免疫调节潜力而受到广泛研究。同种异体 MSCs 为自体 MSCs 提供了一种有前途的替代方案，因为前者可以立即获得并能够进行彻底的供体筛选。然而，关于同种异体 MSCs 的免疫原性潜力的问题已经提出，特别是在重复给药后。

方法

目前的回顾性研究评估了 10 匹自然发生的退行性关节疾病的跳跃和盛装舞步马的细胞和体液免疫原性，这些马用含有 1.4-250 万个软骨诱导的马同种异体外周血来源的 MSCs 的 1 mL 干细胞悬液进行 3 次关节内治疗(ciMSCs) 与 1 mL 马同种异体血浆结合。使用了来自 2 匹供体马的干细胞。临床评估马的关节积液、局部注射部位的触诊疼痛和皮肤表面温度、关节活动范围、不良事件的发生和异位组织的存在。使用改良的混合淋巴细胞反应分析细胞免疫反应，并使用流式细胞术交叉配型试验研究体液免疫反应，通过该试验评估针对 ciMSCs 的同种抗体的存在。检测到存在抗牛血清白蛋白抗体通过ELISA。

结果

马的临床评估显示没有严重的不良反应或可疑的药物不良反应，并且在局部注射部位或身体其他部位没有异位组织形成。一般来说，重复给药导致受累关节关节积液的马减少。治疗给药后触诊疼痛、皮肤表面温度和关节活动度没有增加甚至减少。

同种异体 ciMSCs 不诱导细胞免疫反应，并且在接受者的血清中未检测到同种抗体，无论 70% 的马中是否存在 BSA 抗体。

结论

用同种异体马 ciMSCs 重复关节内注射不会引起临床相关的不良事件。此外，目前的研究表明重复关节内注射后没有细胞或体液免疫反应。