Mouse Mesenchymal Stem Cells Suppress Antigen-Specific TH Cell Immunity Independent of Indoleamine 2,3-Dioxygenase 1 (IDO1)
Mouse Mesenchymal Stem Cells Suppress Antigen-Specific TH Cell Immunity Independent of Indoleamine 2,3-Dioxygenase 1 (IDO1)
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DOI：
10.1089/scd.2009.0385
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发表时间：
2010-05-01
影响因子：
4
通讯作者：
Platten, Michael
中科院分区：
文献类型：
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作者：
Lanz, Tobias V.;Opitz, Christiane A.;Platten, Michael
人骨髓间充质干细胞(HMSC)具有免疫抑制作用，有望用于多发性硬化症(MS)等自身免疫性疾病的细胞治疗。在实验性自身免疫性脑脊髓炎(EAE)等自身免疫性疾病的小鼠模型中，小鼠骨髓间充质干细胞(MMSC)已被广泛用于表征和优化给药途径、运动性、细胞靶点和免疫抑制机制。由吲哚胺-2，3-双加氧酶1(IDO1)分解色氨酸(Trp)是一条主要的内源性代谢途径，通过消耗Trp和产生免疫抑制犬尿氨酸(Kyn)来密切调节不必要的免疫反应。IDO1活性与hMSC的免疫抑制表型有关。在这里，我们证明，虽然IDO1可以被促炎刺激，如干扰素-g和Toll样受体的配体(TLR)诱导在骨髓来源的MMSC中，但它不会在体外导致色氨酸的分解代谢。这种不能分解色氨酸的原因不是由于TLR信号的缺陷，而是TLR激活诱导了白介素6(IL-6)。当MMSC在共培养中抑制抗原特异性髓鞘少突胶质细胞糖蛋白(MOG)-反应性T细胞受体(TCR)转基因T辅助细胞(TH)的激活时，药物抑制或基因消融IDO1都不能逆转这种抑制作用。最后，系统地给药，熟练的IDO1和表型相同的IDO1缺乏的MMSC，同样可以改善EAE。与hMSC不同，MMSC不显示IDO1介导的对抗原特异性T细胞反应的抑制。
Due to their immunosuppressive properties, human mesenchymal stem cells (hMSC) represent a promising tool for cell-based therapies of autoimmune diseases such as multiple sclerosis (MS). Mouse MSC (mMSC) have been used extensively to characterize and optimize route of administration, motility, cellular targets, and immunosuppressive mechanisms in mouse models of autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE). Tryptophan (trp) catabolism by indolamine-2,3-dioxygenase 1 (IDO1) is a chief endogenous metabolic pathway that tightly regulates unwanted immune responses through depletion of trp and generation of immunosuppressive kynurenines (kyn). IDO1 activity contributes to the immunosuppressive phenotype of hMSC. Here, we demonstrate that although IDO1 is inducible in bone marrow-derived mMSC by proinflammatory stimuli such as interferon-g (IFN-g) and ligands of toll-like receptors (TLR), it does not lead to catabolism of trp in vitro. This failure to catabolize trp is not due to defective TLR signaling as demonstrated by induction of interleukin 6 (IL-6) by TLR activation. While mMSC suppressed the activation of antigen-specific myelin oligodendrocyte glycoprotein (MOG)-reactive T-cell receptor (TCR) transgenic T-helper (TH) cells in co-culture, neither pharmacologic inhibition nor genetic ablation of IDO1 reversed this suppressive effect. Finally, systemic administration of both, IDO1-proficient and phenotypically identical IDO1-deficient mMSC, equally resulted in amelioration of EAE. mMSC, unlike hMSC, do not display IDO1-mediated suppression of antigen-specific T-cell responses.