Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye
Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye
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DOI：
10.1073/pnas.1522905113
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发表时间：
2016-01-05
影响因子：
11.1
通讯作者：
Oh, Joo Youn
中科院分区：
文献类型：
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作者：
Ko, Jung Hwa;Lee, Hyun Ju;Oh, Joo Youn
骨髓间充质干/基质细胞（MSCs）的植入只是暂时的，但在免疫疾病患者中具有长期的治疗益处。这表明MSC通过对受体免疫调节系统的持久作用诱导免疫耐受。在这里，我们证明了静脉输注的MSC预处理肺单核细胞/巨噬细胞朝着免疫调节表型在TNF-α刺激的基因/蛋白（TSG）-6依赖的方式。结果，小鼠在两种同种异体和自身免疫性眼部炎症模型中受到保护，免受随后的免疫攻击：角膜同种异体移植和实验性自身免疫性葡萄膜炎（EAU）。MSC诱导的单核/巨噬细胞表达高水平的MHC II类、B220、CD 11b和IL-10，并表现出独立于FoxP 3（+）调节性T细胞的T细胞抑制活性。MSC诱导的B220（+）CD 11b（+）单核/巨噬细胞的连续转移可预防角膜移植排斥反应和EAU。删除单核细胞/巨噬细胞消除MSC诱导的耐受性。然而，TSG-6敲低的MSC不能诱导MHC II+ B220（+）CD 11b（+）细胞，并且不能减弱EAU。因此，结果证明了MSC介导的免疫调节的机制，通过诱导涉及单核细胞/巨噬细胞的先天免疫耐受。
Intravenously administered mesenchymal stem/stromal cells (MSCs) engraft only transiently in recipients, but confer long-term therapeutic benefits in patients with immune disorders. This suggests that MSCs induce immune tolerance by long-lasting effects on the recipient immune regulatory system. Here, we demonstrate that i.v. infusion of MSCs preconditioned lung monocytes/macrophages toward an immune regulatory phenotype in a TNF-alpha-stimulated gene/protein (TSG)-6-dependent manner. As a result, mice were protected against subsequent immune challenge in two models of alloand autoimmune ocular inflammation: corneal allotransplantation and experimental autoimmune uveitis (EAU). The monocytes/macrophages primed by MSCs expressed high levels of MHC class II, B220, CD11b, and IL-10, and exhibited T-cell-suppressive activities independently of FoxP3(+) regulatory T cells. Adoptive transfer of MSC-induced B220(+) CD11b(+) monocytes/macrophages prevented corneal allograft rejection and EAU. Deletion of monocytes/macrophages abrogated the MSC-induced tolerance. However, MSCs with TSG-6 knockdown did not induce MHC II+ B220(+) CD11b(+) cells, and failed to attenuate EAU. Therefore, the results demonstrate a mechanism of the MSC-mediated immune modulation through induction of innate immune tolerance that involves monocytes/macrophages.