Suppression of experimental autoimmune myasthenia gravis by autologous T regulatory cells
Suppression of experimental autoimmune myasthenia gravis by autologous T regulatory cells
复制标题
自体调节性T细胞对实验性自身免疫性重症肌无力的抑制作用
DOI：
10.1016/j.jaut.2015.09.005
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发表时间：
2016-02-01
影响因子：
12.8
通讯作者：
Souroujon, Miriam C.
中科院分区：
文献类型：
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作者：
Aricha, Revital;Reuveni, Debby;Souroujon, Miriam C.
调节性T(Treg)细胞过继转移已被有效地用于抑制几种自身免疫性疾病的动物模型。为了在患者中使用Treg细胞治疗，有必要从患者自身的细胞(自体)中产生Treg细胞，当它们重新引入患者体内时，这些细胞将能够有效地抑制体内的疾病。为了达到这一目标，我们在本研究中报道了一种通过体外产生的自体Treg细胞对实验性自身免疫性重症肌无力(EAMG)进行成功免疫调节的方案。为此，首先在GM-CSF的存在下培养骨髓(BM)细胞，产生CD11c(+)MHCII(+)C-D45RA(+)CD8(-)DC(BMDCs)。然后，将脾中的CD4(+)T细胞与分化的BM细胞共培养，并扩增至90%的Foxp3(+)Treg细胞。体外实验显示，无论是健康供者还是患病供者，Treg细胞对T效应细胞增殖的抑制作用具有相似的剂量依赖关系。此外，两种Treg细胞对活化的脾细胞分泌干扰素-γ的抑制作用相似。给EAMG大鼠静脉注射1×10(6)体外产生的Treg细胞，在疾病诱导后3天或3周进行单一治疗，对疾病进行调节。当从健康或患病的捐赠者身上提取CD4细胞时，也实现了类似的疾病抑制。伴随着疾病抑制的是血清中总AChR特异性抗体水平的降低。此外，由于所描述的Treg细胞的多克隆性，我们已经研究了这种治疗方法是否也可以用于治疗其他涉及Treg细胞的自身免疫性疾病。事实上，我们证明了体外产生的自体Treg细胞可以抑制大鼠佐剂性关节炎(AA)。这项研究为诱导自体Treg细胞疗法在重症肌无力以及其他涉及Treg细胞的人类自身免疫性疾病中的应用开辟了道路。(C)2015爱思唯尔有限公司。保留所有权利。
Adoptive transfer of regulatory T (Treg) cells have been employed effectively for suppression of several animal models for autoimmune diseases. In order to employ Treg cell therapy in patients, it is necessary to generate Treg cells from the patient's own cells (autologous) that would be able to suppress effectively the disease in vivo, upon their reintroduction to the patient. Towards this objective, we report in the present study on a protocol for a successful immune-regulation of experimental autoimmune myasthenia gravis (EAMG) by ex vivo - generated autologous Treg cells. For this protocol bone marrow (BM) cells, are first cultured in the presence of GM-CSF, giving rise to a population of CD11c(+)MHCII(+)C-D45RA(+)CD8(-) DCs (BMDCs). Splenic CD4(+) T cells are then co-cultured with the differentiated BM cells and expand to 90% of Foxp3(+) Treg cells. In vitro assay exhibits a similar dose dependent manner in the suppression of T effector cells proliferation between Treg cells obtained from either healthy or sick donors. In addition, both Treg cells inhibit similarly the secretion of IFN-gamma from activated splenocytes. Administration of 1 x 10(6) ex-vivo generated Treg cells, I.V, to EAMG rats, modulates the disease following a single treatment, given 3 days or 3 weeks after disease induction. Similar disease inhibition was achieved when CD4 cells were taken from either healthy or sick donors. The disease suppression was accompanied by reduced levels of total AChR specific antibodies in the serum. Moreover, due to the polyclonality of the described Treg cell, we have examined whether this treatment approach could be also employed for the treatment of other autoimmune diseases involving Treg cells. Indeed, we demonstrated that the ex-vivo generated autologous Treg cells suppress Adjuvant Arthritis (AA) in rats. This study opens the way for the application of induced autologous Treg cell therapy for myasthenia gravis, as well as for other human autoimmune diseases involving Treg cells. (C) 2015 Elsevier Ltd. All rights reserved.