Mesenchymal Stem Cells Induce Functionally Active T-Regulatory Lymphocytes in a Paracrine Fashion and Ameliorate Experimental Autoimmune Uveitis
Mesenchymal Stem Cells Induce Functionally Active T-Regulatory Lymphocytes in a Paracrine Fashion and Ameliorate Experimental Autoimmune Uveitis
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DOI：
10.1167/iovs.11-8211
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发表时间：
2012-02-01
影响因子：
4.4
通讯作者：
Pennesi, Giuseppina
中科院分区：
文献类型：
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作者：
Tasso, Roberta;Ilengo, Cristina;Pennesi, Giuseppina
目的。间充质干细胞/祖细胞（MSCs）具有再生和免疫调节特性，通过细胞间接触并以旁分泌方式发挥作用。它们的部分免疫抑制活性归因于它们能够促进诱导具有调节功能的CD4(+)CD25(+)FoxP3(+) T淋巴细胞（Treg）。本研究作者研究了MSCs对Treg诱导和自身免疫发展的影响，并探讨了MSCs介导Treg诱导可能归因于可溶性因子的分泌。作者利用光受体结合蛋白1-20肽免疫诱导小鼠实验性自身免疫性葡萄膜炎（EAU）。同时，部分动物腹腔注射同种间充质干细胞。作者通过细胞增殖和阻断试验，在细胞-细胞接触和transwell环境下检查t细胞反应和体外Treg转化。实时荧光定量pcr检测TGF β及TGF β受体基因表达。作者发现，单次腹腔注射间充质干细胞能够显著减弱EAU，并且与未注射间充质干细胞的动物相比，接受间充质干细胞治疗的小鼠中存在明显更高比例的适应性Treg。在体外，主要组织相容性复合体II类阻断抗原呈递可阻止抗原特异性Treg的引物和克隆扩增，而TGF β阻断可损害FoxP3的表达，阻止CD4(+) T细胞转化为具有功能活性的Treg。作者证明MSCs可以抑制EAU，其免疫调节功能至少部分是由于通过分泌TGF β以旁分泌方式诱导抗原特异性Treg。（中国眼科杂志，2012;53:786-793）DOI: 10.1167/iovs.11-8211
PURPOSE. Mesenchymal stem/progenitor cells (MSCs) have regenerative and immunomodulatory properties, exerted by cell-cell contact and in a paracrine fashion. Part of their immunosuppressive activity has been ascribed to their ability to promote the induction of CD4(+)CD25(+)FoxP3(+) T lymphocytes with regulatory functions (Treg). Here the authors studied the effect of MSCs on the induction of Treg and on the development of autoimmunity, and they examined the possibility that MSC-mediated Treg induction could be attributed to the secretion of soluble factors.METHODS. The authors induced experimental autoimmune uveitis (EAU) in mice by immunization with the 1-20 peptide of the intraphotoreceptor binding protein. At the same time, some of the animals were treated intraperitoneally with syngeneic MSCs. The authors checked T-cell responses and in vitro Treg conversion by cell proliferation and blocking assays, in cell-cell contact and transwell settings. TGF beta and TGF beta receptor gene expression analyses were performed by real-time PCR.RESULTS. The authors found that a single intraperitoneal injection of MSCs was able to significantly attenuate EAU and that a significantly higher percentage of adaptive Treg was present in MSC-treated mice than in MSC-untreated animals. In vitro blocking of antigen presentation by major histocompatibility complex class II precluded priming and clonal expansion of antigen-specific Treg, whereas blockade of TGF beta impaired the expression of FoxP3, preventing the conversion of CD4(+) T cells into functionally active Treg.CONCLUSIONS. The authors demonstrated that MSCs can inhibit EAU and that their immunomodulatory function is due at least in part to the induction of antigen-specific Treg in a paracrine fashion by secreting TGF beta. (Invest Ophthalmol Vis Sci. 2012; 53: 786-793) DOI: 10.1167/iovs.11-8211