Human MSC Suppression Correlates With Cytokine Induction of Indoleamine 2,3-Dioxygenase and Bystander M2 Macrophage Differentiation
Human MSC Suppression Correlates With Cytokine Induction of Indoleamine 2,3-Dioxygenase and Bystander M2 Macrophage Differentiation
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DOI：
10.1038/mt.2011.189
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发表时间：
2012-01-01
影响因子：
12.4
通讯作者：
Galipeau, Jacques
中科院分区：
文献类型：
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作者：
Francois, Moira;Romieu-Mourez, Raphaelle;Galipeau, Jacques
使用自体或同种异体人骨髓间充质干细胞(MSC)作为细胞药物抑制自身免疫和同种免疫疾病的临床试验正在进行中。已完成试验的报告结果在研究内部和研究之间的有效性各不相同，没有任何明确的机制解释。我们认为，这些差异可能源于每个MSC供体来源的免疫抑制潜力的内在变异性。在这里，我们证明了来自正常成人志愿者的肿瘤坏死因子-α(肿瘤坏死因子-α)和干扰素-γ(干扰素-γ)激活的MSC在体外以一种不同的方式抑制T细胞增殖，这一观察与干扰素介导的吲哚胺2，3-双加氧酶(IDO)上调有关。我们还证明MSC IDO活性与单核细胞分化为分泌IL-10的M2免疫抑制巨噬细胞(CD14(+)/CD206(+))有关。这些单核细胞来源的M2反过来以IL-10非依赖的方式参与抑制T细胞的增殖，从而放大MSC产生的免疫抑制效应。综上所述，MSC的干扰素-γ和肿瘤坏死因子-α许可否决功能的免疫可塑性因供者不同而不同，并定义了诱导IDO活性及其对淋巴瘤免疫效应器的旁观者效应的核心作用。
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-alpha (TNF-alpha) and interferon-gamma (IFN-gamma)-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-gamma and TNF-alpha 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.