MRC Centre for Transplantation, King's College London, London, UK, SE1 9RT.
Centre for Craniofacial & Regenerative Biology, King's College London, London, UK, SE1 9RT.
Immunotherapy. 2018 Mar;10(3):201-211. doi: 10.2217/imt-2017-0117.
Mesenchymal stem cells (MSCs) show considerable promise as a cellular immunotherapy for the treatment of a number of autoimmune and inflammatory disorders. However, the precise physiologically and therapeutically relevant mechanism(s) by which MSCs mediate immune modulation remains elusive. Dental pulp stem cells are a readily available source of MSCs that have been reported to show similar immune modulation in vitro as bone marrow MSCs. To test their potential in vivo, we used a clinically relevant humanized mouse model of GvHD in which only human T cells engraft. In this model, we found no effects on either T-cell proliferation, T-cell phenotype or disease progression. To determine if this lack of efficacy was related to a failure of engraftment or persistence of the cells, we used viability dependent radioactive cell tracking and showed that no cells were detectable after 24-h postinjection. Given the apparent failure of MSC to survive following intravenous injection, we hypothesized that their apoptosis may account for the widely reported therapeutic effect in numerous experimental models in vivo. To address this, we employed a well-established model of allergic airway inflammation to compare the efficacy of live and apoptotic MSCs in a fully immunocompetent model. In this model, both live and apoptotic dental pulp MSCs induced a robust immune suppressive reaction that was substantially greater with apoptotic cells. We propose that the mechanism of immune modulation following systemic application of MSCs is a result of cell entrapment and apoptosis occurring in the lungs.
间充质干细胞（MSCs）作为一种细胞免疫疗法，在治疗多种自身免疫和炎症性疾病方面显示出巨大的应用潜力。然而，MSCs 介导免疫调节的确切生理和治疗相关机制仍不清楚。牙髓干细胞是一种易于获得的 MSC 来源，据报道，其在体外具有与骨髓 MSC 相似的免疫调节作用。为了测试它们在体内的潜在应用，我们使用了一种临床相关的人源化 GvHD 小鼠模型，该模型中只有人 T 细胞植入。在该模型中，我们没有观察到 T 细胞增殖、T 细胞表型或疾病进展的任何影响。为了确定这种疗效缺乏是否与细胞植入失败或细胞持续存在有关，我们使用了依赖细胞活力的放射性细胞追踪技术，结果显示在注射后 24 小时内无法检测到任何细胞。鉴于 MSC 经静脉注射后明显无法存活，我们假设它们的凋亡可能解释了在许多体内实验模型中广泛报道的治疗效果。为了解决这个问题，我们采用了一种成熟的过敏性气道炎症模型，比较了活 MSC 和凋亡 MSC 在完全免疫功能正常的模型中的疗效。在该模型中，活 MSC 和凋亡牙髓 MSC 均诱导了强烈的免疫抑制反应，而凋亡细胞的反应更强烈。我们提出，MSC 系统应用后免疫调节的机制是由于细胞在肺部被捕获和凋亡所致。
