Ye Qing, Zhang Mingjian, Wang Yang, Fu Shangxi, Han Shu, Wang Liming, Wang Quanxing
Institute of Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai, China.
National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, China.
Cell Biosci. 2017 Oct 27;7:55. doi: 10.1186/s13578-017-0182-2. eCollection 2017.
Current immunosuppressive medications used after transplantation induce significant toxicity , and a new medication regimen is needed. Based on recent research, Sirt1 exerts a proinflammatory effect on the immune response. Sirtinol is a Sirt1 inhibitor, but its impact on allograft rejection and its molecular mechanisms of action have not yet been reported.
In this study, we examined the effect of sirtinol on prolonging allograft survival in a mouse cervical heterotopic heart transplantation model. Based on an examination of the allograft, allografts from sirtinol-treated recipients show significantly lower levels of IL-17A expression and higher levels of Foxp3 expression. In vivo, sirtinol reduces the proportion of Th17 cells and increases the proportion of Treg cells in splenocytes from recipients. In vitro, sirtinol reduces the proportion of Th17 cells and decreases the expression of IL-17A and RORγt in an isolated CD4 T cell population. Moreover, we identified synergistic effects of sirtinol and FK506 on prolonging allograft survival, and sirtinol synergizes with FK506 to promote Foxp3 expression.
Sirtinol, a Sirt1 inhibitor, may be a promising immunosuppressive drug to prevent the rejection reaction in combination with FK506.
目前移植后使用的免疫抑制药物会引发显著毒性，因此需要新的药物治疗方案。基于近期研究，沉默调节蛋白1（Sirt1）对免疫反应具有促炎作用。Sirtinol是一种Sirt1抑制剂，但其对同种异体移植排斥反应的影响及其分子作用机制尚未见报道。
在本研究中，我们在小鼠颈部异位心脏移植模型中检测了Sirtinol对延长同种异体移植物存活时间的作用。基于对同种异体移植物的检测，接受Sirtinol治疗的受体的同种异体移植物显示白细胞介素-17A（IL-17A）表达水平显著降低，叉头框蛋白3（Foxp3）表达水平升高。在体内，Sirtinol降低了受体脾细胞中辅助性T细胞17（Th17）细胞的比例，增加了调节性T细胞（Treg）的比例。在体外，Sirtinol降低了分离的CD4 T细胞群体中Th17细胞的比例，并降低了IL-17A和维甲酸相关孤儿受体γt（RORγt）的表达。此外，我们确定了Sirtinol和他克莫司（FK506）在延长同种异体移植物存活时间方面的协同作用，并且Sirtinol与FK506协同促进Foxp3表达。
Sirt1抑制剂Sirtinol可能是一种有前景的免疫抑制药物，可与FK506联合用于预防排斥反应。
