Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium.
Department of Clinical Hematology, University Hospital Center of Liège, Liège, Belgium.
Front Immunol. 2019 Apr 2;10:619. doi: 10.3389/fimmu.2019.00619. eCollection 2019.
Mesenchymal stromal cells (MSCs) have potent immunomodulatory properties that make them an attractive tool against graft- vs.-host disease (GVHD). However, despite promising results in phase I/II studies, bone marrow (BM-) derived MSCs failed to demonstrate their superiority over placebo in the sole phase III trial reported thus far. MSCs from different tissue origins display different characteristics, but their therapeutic benefits have never been directly compared in GVHD. Here, we compared the impact of BM-, umbilical cord (UC-), and adipose-tissue (AT-) derived MSCs on T-cell function and assessed their efficacy for the treatment of GVHD induced by injection of human peripheral blood mononuclear cells in NOD-scid IL-2Rγ HLA-A2/HHD mice. , resting BM- and AT-MSCs were more potent than UC-MSCs to inhibit lymphocyte proliferation, whereas UC- and AT-MSCs induced a higher regulatory T-cell (CD4CD25FoxP3)/T helper 17 ratio. Interestingly, AT-MSCs and UC-MSCs activated the coagulation pathway at a higher level than BM-MSCs. , AT-MSC infusions were complicated by sudden death in 4 of 16 animals, precluding an analysis of their efficacy. Intravenous MSC infusions (UC- or BM- combined) failed to significantly increase overall survival (OS) in an analysis combining data from 80 mice (hazard ratio [HR] = 0.59, 95% confidence interval [CI] 0.32-1.08, = 0.087). In a sensitivity analysis we also compared OS in control vs. each MSC group separately. The results for the BM-MSC vs. control comparison was HR = 0.63 (95% CI 0.30-1.34, = 0.24) while the figures for the UC-MSC vs. control comparison was HR = 0.56 (95% CI 0.28-1.10, = 0.09). Altogether, these results suggest that MSCs from various origins have different effects on immune cells and . However, none significantly prevented death from GVHD. Finally, our data suggest that the safety profile of AT-MSC and UC-MSC need to be closely monitored given their pro-coagulant activities .
间充质基质细胞（MSCs）具有强大的免疫调节特性，使其成为对抗移植物抗宿主病（GVHD）的有吸引力的工具。然而，尽管在 I/II 期研究中取得了有希望的结果，但迄今为止唯一报告的 III 期试验表明，骨髓（BM）来源的 MSCs 并未显示优于安慰剂的优势。来自不同组织来源的 MSCs 表现出不同的特征，但它们的治疗益处从未在 GVHD 中直接比较过。在这里，我们比较了 BM、脐带（UC）和脂肪组织（AT）来源的 MSCs 对 T 细胞功能的影响，并评估了它们在注射人外周血单核细胞诱导的 NOD-scid IL-2Rγ HLA-A2/HHD 小鼠 GVHD 中的治疗效果。在静止状态下，BM 和 AT-MSCs 比 UC-MSCs 更能抑制淋巴细胞增殖，而 UC 和 AT-MSCs 诱导更高的调节性 T 细胞（CD4CD25FoxP3/T 辅助 17 比）。有趣的是，AT-MSCs 和 UC-MSCs 激活凝血途径的水平高于 BM-MSCs。值得注意的是，在 16 只动物中有 4 只在 AT-MSC 输注后突然死亡，这使得无法分析其疗效。静脉内 MSC 输注（UC 或 BM 联合）未能显著增加 80 只小鼠分析中的总生存率（OS）（风险比[HR] = 0.59，95%置信区间[CI] 0.32-1.08， = 0.087）。在敏感性分析中，我们还分别比较了对照组与每个 MSC 组的 OS。BM-MSC 与对照组比较的结果为 HR = 0.63（95%CI 0.30-1.34， = 0.24），而 UC-MSC 与对照组比较的结果为 HR = 0.56（95%CI 0.28-1.10， = 0.09）。总的来说，这些结果表明，来自不同来源的 MSCs 对免疫细胞有不同的影响，。然而，没有一种能显著预防 GVHD 引起的死亡。最后，我们的数据表明，由于其促凝活性，需要密切监测 AT-MSC 和 UC-MSC 的安全性。
