Enhancement of the immunoregulatory potency of mesenchymal stromal cells by treatment with immunosuppressive drugs
Enhancement of the immunoregulatory potency of mesenchymal stromal cells by treatment with immunosuppressive drugs
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DOI：
10.1016/j.jcyt.2015.05.009
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发表时间：
2015-09-01
期刊：
影响因子：
4.5
通讯作者：
Navarrete, Cristina V.
中科院分区：
文献类型：
--
作者：
Girdlestone, John;Pido-Lopez, Jeffrey;Navarrete, Cristina V.
背景目标。多能间充质基质细胞（MSC）的特点是它们能够分化成许多再生医学感兴趣的基质衍生物，但它们也具有免疫调节特性，正在许多临床环境中进行测试。方法.我们发现，与雷帕霉素，依维莫司，FK 506或环孢霉素A的短暂孵育增加了MSC和其他细胞类型的免疫抑制效力。结果经处理的MSC在体外抑制诱导的T淋巴细胞增殖方面的效力高达5倍。我们表明，这种效果可能是由于在预处理过程中MSC对药物的吸附，随后以足以抑制T细胞增殖的浓度扩散到共培养物中。MSC在暴露15分钟后含有可测量量的雷帕霉素，并且增强作用被药物的中和抗体阻断。通过使用急性移植物抗宿主病的临床前模型，我们证明了低剂量的雷帕霉素处理的但非未处理的脐带来源的MSC显著抑制疾病的发作。结论.使用经处理的MSC可以实现未经处理的MSC无法达到的临床终点，并允许输注更少的细胞以降低成本并使潜在的副作用最小化。
Background aims. Multipotent mesenchymal stromal cells (MSCs) are distinguished by their ability to differentiate into a number of stromal derivatives of interest for regenerative medicine, but they also have immunoregulatory properties that are being tested in a number of clinical settings. Methods. We show that brief incubations with rapamycin, everolimus, FK506 or cyclosporine A increase the immunosuppressive potency of MSCs and other cell types. Results. The treated MSCs are up to 5-fold more potent at inhibiting the induced proliferation of T lymphocytes in vitro. We show that this effect probably is due to adsorption of the drug by the MSCs during pre-treatment, with subsequent diffusion into co-cultures at concentrations sufficient to inhibit T-cell proliferation. MSCs contain measurable amounts of rapamycin after a 15-min exposure, and the potentiating effect is blocked by a neutralizing antibody to the drug. With the use of a pre-clinical model of acute graft-versus-host disease, we demonstrate that a low dose of rapamycin-treated but not untreated umbilical cord derived MSCs significantly inhibit the onset of disease. Conclusions. The use of treated MSCs may achieve clinical end points not reached with untreated MSCs and allow for infusion of fewer cells to reduce costs and minimize potential side effects.