Ex vivo generated regulatory T cells modulate experimental autoimmune myasthenia gravis
Ex vivo generated regulatory T cells modulate experimental autoimmune myasthenia gravis
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DOI：
10.4049/jimmunol.180.4.2132
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发表时间：
2008-02-15
影响因子：
4.4
通讯作者：
Souroujon, Miriam C.
中科院分区：
文献类型：
--
作者：
Aricha, Revital;Feferman, Tali;Souroujon, Miriam C.
天然存在的CD 4（+）CD 25（+）调节性T（Treg）细胞是免疫耐受的关键参与者，因此被认为是“自身免疫性疾病”的潜在治疗工具。在重症肌无力（MG）中，已经报道了Treg细胞数量减少或功能受损。我们已经观察到，与来自健康对照的PBL相比，来自肌无力大鼠的PBL含有减少数量的CD 4（+）CD 25（高）Foxp 3（+）细胞，并且我们已经测试了来自健康供体的Treg细胞是否可以抑制大鼠的实验性自身免疫性MG。由于天然存在的Treg细胞的数量很低，我们使用了一种从健康供体大鼠的CD 4（+）脾细胞大规模离体产生功能性Treg细胞的方法。Treg细胞通过在TGF-β和IL-2存在下用抗CD 3和抗CD 28 Ab刺激从CD 4（+）细胞离体产生。获得的细胞表达高水平的CD 25、CTLA-4和Foxp 3，并且它们能够抑制肌无力大鼠的T细胞对肌无力中的主要自身抗原乙酰胆碱受体应答的体外增殖。给予重症肌无力大鼠体外产生的Treg细胞可抑制实验性自身免疫性MG的进展，并导致不道德乙酰胆碱受体特异性反应的下调，以及IL-18和IL-10表达的降低。治疗组大鼠脾脏中的CD 4（+）CD 25（+）细胞数量保持不变，但表达Foxp 3的CD 4（+）CD 25（+）细胞亚群显著升高。我们的研究结果表明，Treg细胞在控制肌无力中起着关键作用，因此可以被认为是治疗MG患者的潜在药物。
Naturally occurring CD4(+)CD25(+) regulatory T (Treg) cells are key players in immune tolerance and have therefore been suggested as potential therapeutic tools for 'autoimmune diseases. In myasthenia gravis (MG), reduced numbers or functionally impaired Treg cells have been reported. We have observed that PBL from myasthenic rats contain decreased numbers of CD4(+)CD25(high) Foxp3(+) cells as compared with PBL from healthy controls, and we have tested whether Treg cells from healthy donors can suppress experimental autoimmune MG in rats. Because the number of naturally occurring Treg cells is low, we used an approach for a large-scale ex vivo generation of functional Treg cells from CD4(+) splenocytes of healthy donor rats. Treg cells were generated ex vivo from CD4(+) cells by stimulation with anti-CD3 and anti-CD28 Abs in the presence of TGF-beta and IL-2. The obtained cells expressed high levels of CD25, CTLA-4, and Foxp3, and they were capable of suppressing in vitro proliferation of T cells from myasthenic rats in response to acetylcholine receptor, the major antoantigen in myasthenia. Administration of ex vivo-generated Treg cells to myasthenic rats inhibited the progression of experimental autoimmune MG and led to down-regulation of Immoral acetylcholine receptor-specific responses, and to decreased IL-18 and IL-10 expression. The number of CD4(+)CD25(+) cells in the spleen of treated rats remained unchanged, but the subpopulation of CD4(+)CD25(+) cells expressing Foxp3 was significantly elevated. Our findings imply that Treg cells play a critical role in the control of myasthenia and could thus be considered as potential agents for the treatment of MG patients.