Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase
Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase
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DOI：
10.1038/leu.2010.310
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发表时间：
2011-04-01
期刊：
影响因子：
11.4
通讯作者：
Daeubener, W.
中科院分区：
文献类型：
--
作者：
Meisel, R.;Brockers, S.;Daeubener, W.
人多能间充质基质细胞（MSC）具有多向分化潜能，支持造血，抑制多种免疫细胞的增殖和效应功能。基于这些特性，MSC目前正在一系列治疗应用中进行临床研究，包括组织修复和免疫介导的疾病，如药物免疫抑制难治的移植物抗宿主病。虽然初步的临床结果似乎是有希望的，但有重大的关注，即MSC的应用可能会无意中抑制抗菌免疫力，增加感染的风险。我们在此证明，在用炎性细胞因子刺激时，人MSC表现出针对一系列临床相关细菌、原生动物寄生虫和病毒的广谱抗微生物效应子功能。此外，我们确定色氨酸分解代谢酶吲哚胺2，3-双加氧酶（IDO）作为潜在的分子机制。我们还描述了人和鼠MSC之间的显著差异，即鼠MSC不能表达IDO并抑制细菌生长。相反，只有鼠而不是人MSC在细胞因子刺激下表达诱导型一氧化氮合酶，因此挑战了用于人MSC临床前评价的鼠体内模型的有效性。总的来说，我们的数据确定人MSC作为细胞免疫抑制剂，同时表现出有效的抗菌效应功能，从而鼓励他们在临床试验中进一步评估。Leukemia（2011）25，648-654; doi：10.1038/leu.2010.310; 2011年1月18日在线发表
Human multipotent mesenchymal stromal cells (MSCs) exhibit multilineage differentiation potential, support hematopoiesis, and inhibit proliferation and effector function of various immune cells. On the basis of these properties, MSC are currently under clinical investigation in a range of therapeutic applications including tissue repair and immune-mediated disorders such as graft-versus-host-disease refractory to pharmacological immunosuppression. Although initial clinical results appear promising, there are significant concerns that application of MSC might inadvertently suppress antimicrobial immunity with an increased risk of infection. We demonstrate here that on stimulation with inflammatory cytokines human MSC exhibit broad-spectrum antimicrobial effector function directed against a range of clinically relevant bacteria, protozoal parasites and viruses. Moreover, we identify the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) as the underlying molecular mechanism. We furthermore delineate significant differences between human and murine MSC in that murine MSC fail to express IDO and inhibit bacterial growth. Conversely, only murine but not human MSC express inducible nitric oxide synthase on cytokine stimulation thus challenging the validity of murine in vivo models for the preclinical evaluation of human MSC. Collectively, our data identify human MSC as a cellular immunosuppressant that concurrently exhibits potent antimicrobial effector function thus encouraging their further evaluation in clinical trials. Leukemia (2011) 25, 648-654; doi:10.1038/leu.2010.310; published online 18 January 2011