Targeting Sirtuin-1 prolongs murine renal allograft survival and function.
Targeting Sirtuin-1 prolongs murine renal allograft survival and function.
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DOI：
10.1016/j.kint.2015.12.051
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发表时间：
2016-05
影响因子：
19.6
通讯作者：
Beier UH
中科院分区：
文献类型：
--
作者：
Levine MH;Wang Z;Xiao H;Jiao J;Wang L;Bhatti TR;Hancock WW;Beier UH
目前移植后使用的免疫抑制药物具有显着的毒性。 Foxp3+ T 调节 (Treg) 细胞可以防止同种异体移植排斥，而不损害宿主的保护性免疫。有趣的是，抑制 III 类组蛋白/蛋白脱乙酰酶 Sirtuin-1 可以通过增加 Foxp3 乙酰化来增强 Foxp3+ Treg 抑制功能。在这里，我们确定了 Sirtuin-1 靶向是否可以稳定生物同种异体移植功能。将 BALB/c 肾同种异体移植物移植到 CD4 条件性删除 Sirtuin-1 (Sirt1fl/flCD4cre) 的 C57BL/6 受体中或用 Sirtuin-1 特异性抑制剂 (EX-527) 治疗的小鼠中，并切除天然肾脏。每周跟踪血液化学和血细胞比容。 Sirt1fl/flCD4cre 接受者表现出明显更长的生存期和改善的肾功能。 Sirt1fl/flCD4cre 受体表现出供体特异性耐受性，接受 BALB/c，但拒绝第三方 C3H 心脏同种异体移植物。使用 EX-527 治疗的 BALB/c 同种异体肾移植物的 C57BL/6 接受者在 1 毫克/公斤/天（但不是 10 毫克/公斤/天）时显示出生存率和肾功能的改善。 Sirtuin-1 的药理学抑制还可以改善肾同种异体移植物的存活和功能，且剂量效应与结果相关。因此，抑制 Sirtuin-1 可以有效控制 T 细胞介导的排斥反应。然而，对非 T 细胞的影响可能会对同种异体移植物的存活和功能产生不利影响，值得考虑。
Current immunosuppressive medications used after transplantation have significant toxicities. Foxp3+ T-regulatory (Treg) cells can prevent allograft rejection without compromising protective host immunity. Interestingly, inhibiting the class III histone/protein deacetylase Sirtuin-1 can augment Foxp3+ Treg suppressive function through increasing Foxp3 acetylation. Here we determined whether Sirtuin-1 targeting can stabilize biological allograft function. BALB/c kidney allografts were transplanted into C57BL/6 recipients with a CD4-conditional deletion of Sirtuin-1 (Sirt1fl/flCD4cre) or mice treated with a Sirtuin-1 specific inhibitor (EX-527), and the native kidneys removed. Blood chemistries and hematocrit were followed weekly. Sirt1fl/flCD4cre recipients showed markedly longer survival and improved kidney function. Sirt1fl/flCD4cre recipients exhibited donor specific tolerance, accepted BALB/c, but rejected third-party C3H cardiac allografts. C57BL/6 recipients of BALB/c renal allografts that were treated with EX-527 showed improved survival and renal function at 1, but not 10 mg/kg/day. Pharmacologic inhibition of Sirtuin-1 also improved renal allograft survival and function with dosing effects having relevance to outcome. Thus, inhibiting Sirtuin-1 can be a useful asset in controlling T-cell mediated rejection. However, effects on non-T cells that could adversely affect allograft survival and function merit consideration.