Improving allogeneic islet transplantation by suppressing Th17 and enhancing Treg with histone deacetylase inhibitors
Improving allogeneic islet transplantation by suppressing Th17 and enhancing Treg with histone deacetylase inhibitors
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DOI：
10.1111/tri.12265
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发表时间：
2014-04-01
影响因子：
3.1
通讯作者：
Matsumoto, Shinichi
中科院分区：
文献类型：
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作者：
Sugimoto, Koji;Itoh, Takeshi;Matsumoto, Shinichi
胰岛移植是治疗重症糖尿病患者胰岛素依赖性的一种新方法。然而，这种治疗的主要缺点是移植物存活时间长、需要免疫抑制药物以及移植的功效。供体特异性输血（DST）已被证明可以减少器官移植后的排斥反应，可能是通过增强调节性T细胞（Treg）活性。然而，最近的研究结果表明，活化的Treg可以转化为Th 17细胞。我们专注于组蛋白脱乙酰酶抑制剂（HDACi），因为据报道，HDAC活性的抑制阻止Treg分化为产生IL 17的细胞。因此，我们试图使用DST与HDACi来增强Treg同时抑制Th 17细胞以延长移植物存活。为了通过DST刺激Treg，我们使用供体脾细胞。DST + HDACi组胸腺和脾脏中Foxp 3 mRNA表达和Treg细胞数增加，而Th 17细胞数减少。淋巴细胞mRNA的qPCR分析表明Foxp 3、IL-10和TGF-β表达增加。而DST+HDACi组IL-17 a、Stat 3（Th 17）和IFN-γ表达较DST组降低。此外，在小鼠胰岛移植中，用HDACi处理的DST相对于对照延长了移植物存活。因此，用HDACi进行DST可能在胰岛移植中具有实用性。
Islet transplantation is a new treatment for achieving insulin independence for patients with severe diabetes. However, major drawbacks of this treatment are the long graft survival, the necessity for immunosuppressive drugs, and the efficacy of transplantation. Donor-specific transfusion (DST) has been shown to reduce rejection after organ transplantation, potentially through enhanced regulatory T-cell (Treg) activity. However, recent findings have shown that activated Treg can be converted into Th17 cells. We focused on histone deacetylase inhibitors (HDACi) because it was reported that inhibition of HDAC activity prevented Treg differentiation into IL17-producing cells. We therefore sought to enhance Treg while suppressing Th17 cells using DST with HDACi to prolong graft survival. To stimulate Treg by DST, we used donor splenocytes. In DST with HDACi group, Foxp3 mRNA expression and Treg population increased in the thymus and spleen, whereas Th17 population decreased. qPCR analysis of lymphocyte mRNA indicated that Foxp3, IL-10, and TGF-b expression increased. However, interleukin 17a, Stat3 (Th17), and IFN-g expression decreased in DST+HDACi group, relative to DST alone. Moreover, DST treated with HDACi prolonged graft survival relative to controls in mice islet transplantation. DST with HDACi may therefore have utility in islet transplantation.