miR-181a Expression in Donor T Cells Modulates Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation
miR-181a Expression in Donor T Cells Modulates Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation
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DOI：
10.4049/jimmunol.1502152
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发表时间：
2016-05-01
影响因子：
4.4
通讯作者：
Koenecke, Christian
中科院分区：
文献类型：
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作者：
Lee, Chun-Wei;Wohlan, Katharina;Koenecke, Christian
由于miR-181a已被描述为改变T细胞活化，我们假设在供体T细胞中操纵miR-181a表达可能改变同种异体骨髓移植（BMT）后的急性移植物抗宿主病（aGvHD）。因此，我们分别分析了供体T细胞中miR-181a表达增强和降低对慢病毒基因转移到原代T细胞和使用miR-181a/b-1(-/-) T细胞诱导aGvHD的影响。接受miR-181a表达增强的供体T细胞的bmt受体小鼠没有出现aGvHD的迹象，并且在随访期间存活，而缺乏miR-181a/b-1的T细胞加速aGvHD。根据这些数据，对BMT后aGvHD患者血液、次级淋巴器官和靶器官中的供体T细胞的分析显示，与对照组相比，mir -181a转导的T细胞数量显著减少。此外，在体外和体内，miR-181a表达增强的活化T细胞的扩增减少。我们进一步发现，过表达miR-181a后，抗凋亡BCL-2蛋白在小鼠和人T细胞中的表达降低，这表明miR-181a调节BCL-2的表达可能有助于改变aGvHD中T细胞的同种异体反应性。这些数据表明，miR-181a调节的蛋白可能是预防aGvHD的治疗靶点。
Because miR-181a has been described to alter T cell activation, we hypothesized that manipulation of miR-181a expression in donor T cells may alter acute graft-versus-host disease (aGvHD) after allogeneic bone marrow transplantation (BMT). We therefore analyzed the impact of enhanced and reduced miR-181a expression in donor T cells on aGvHD induction by lentiviral gene transfer into primary T cells and using miR-181a/b-1(-/-) T cells, respectively. BMT-recipient mice receiving donor T cells with enhanced miR-181a expression showed no signs of aGvHD and survived for the time of follow-up, whereas T cells lacking miR-181a/b-1 accelerated aGvHD. In line with these data, analysis of donor T cells in blood, secondary lymphoid organs, and target organs of aGvHD after BMT showed significantly reduced numbers of miR-181a-transduced T cells, as compared with controls. In addition, expansion of activated T cells with enhanced miR-181a expression was reduced in vitro and in vivo. We further show that anti-apoptotic BCL-2 protein expression is reduced in murine and human T cells upon overexpression of miR-181a, suggesting that regulation of BCL-2-expression by miR-181a may contribute to altered alloreactivity of T cells in aGvHD. These data indicate that proteins regulated by miR-181a may be therapeutic targets for aGvHD prevention.