Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
Mol Ther. 2012 Jan;20(1):187-95. doi: 10.1038/mt.2011.189. Epub 2011 Sep 20.
Clinical trials testing the use of either autologous or allogeneic human bone marrow-derived mesenchymal stromal cells (MSC) as a cell-based pharmaceutical for suppression of autoimmune and alloimmune ailments are underway. Reported results from completed trials vary in effectiveness within and between studies without any clear mechanistic explanation. We propose that these discrepancies may arise from intrinsic variability in the immunosuppressive potential of each MSC donor source. Here, we demonstrate that tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)-activated MSC derived from normal adult volunteers suppress T cell proliferation in vitro in a variegated manner, an observation linked to IFN-mediated indoleamine 2,3-dioxygenase (IDO) upregulation. We also demonstrate that MSC IDO activity is implicated in the differentiation of monocytes into interleukin (IL)-10-secreting M2 immunosuppressive macrophages (CD14(+)/CD206(+)). Those monocyte-derived M2 are in turn implicated in the suppression of T cell proliferation in an IL-10-independent manner, thus amplifying the immunosuppressive effect generated by MSC. In summary, the immune plasticity of IFN-γ and TNF-α licensed veto function of MSC vary among donors and defines a central role to inducible IDO activity and its bystander effect on lymphomyeloid immune effectors.
正在进行临床试验，以测试自体或同种异体人骨髓间充质基质细胞（MSC）作为基于细胞的药物用于抑制自身免疫和同种免疫疾病的用途。已完成试验的报告结果在有效性方面在研究内和研究之间存在差异，没有任何明确的机制解释。我们提出，这些差异可能源于每个 MSC 供体来源的免疫抑制潜力的固有可变性。在这里，我们证明肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）激活的源自正常成年志愿者的 MSC 以不同的方式体外抑制 T 细胞增殖，这一观察结果与 IFN 介导的吲哚胺 2,3-双加氧酶（IDO）上调有关。我们还证明 MSC IDO 活性参与单核细胞分化为白细胞介素（IL）-10 分泌的 M2 免疫抑制巨噬细胞（CD14(+)/CD206(+))。这些单核细胞衍生的 M2 继而以 IL-10 非依赖性方式参与 T 细胞增殖的抑制，从而放大 MSC 产生的免疫抑制作用。总之，IFN-γ 和 TNF-α 许可 MSC 否决功能的免疫可塑性在供体之间存在差异，并定义了诱导型 IDO 活性及其对淋巴髓样免疫效应物的旁观者效应的核心作用。
