Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Division of Lung Transplantation and Thoracic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Int Immunopharmacol. 2023 Dec;125(Pt B):111172. doi: 10.1016/j.intimp.2023.111172. Epub 2023 Nov 9.
Inhibition of mammalian target of rapamycin (mTOR), which is a component of both mTORC1 and mTORC2, leads to clinical benefits for organ transplant recipients. Pathways to inhibit mTOR include strengthening the association of FKBP12-mTOR or competing with ATP at the active site of mTOR, which have been applied to the design of first- and second-generation mTOR inhibitors, respectively. However, the clinical efficacy of these mTOR inhibitors may be limited by side effects, compensatory activation of kinases and attenuation of feedback inhibition of receptor expression. A new generation of mTOR inhibitors possess a core structure similar to rapamycin and covalently link to mTOR kinase inhibitors, resulting in moderate selectivity and potent inhibition of mTORC1. Since the immunosuppressive potential of this class of compounds remains unknown, our goal is to examine the therapeutic efficacy of a third-generation mTOR inhibitor in organ transplantation. In this study, RapaLink-1 outperformed rapamycin in inhibiting T-cell proliferation and significantly prolonged graft survival time. Mechanistically, the ameliorated rejection induced by RapaLink-1 is associated with a reduction in p-4E-BP1 in T cells, resulting in an elevation in Treg cells alongside a decline in Th1 and Th17 cells. For the first time, these studies demonstrate the effectiveness of third-generation mTOR inhibitors in inhibiting allograft rejection, highlighting the potential of this novel class of mTOR inhibitors for further investigation.
哺乳动物雷帕霉素靶蛋白（mTOR）的抑制作用，它是 mTORC1 和 mTORC2 的组成部分，为器官移植受者带来了临床获益。抑制 mTOR 的途径包括增强 FKBP12-mTOR 的结合或在 mTOR 的活性位点与 ATP 竞争，这分别被应用于第一代和第二代 mTOR 抑制剂的设计中。然而，这些 mTOR 抑制剂的临床疗效可能受到副作用、激酶的代偿性激活和受体表达反馈抑制的衰减的限制。新一代的 mTOR 抑制剂具有与雷帕霉素相似的核心结构，并与 mTOR 激酶抑制剂共价连接，导致对 mTORC1 的中等选择性和强效抑制。由于这类化合物的免疫抑制潜力尚不清楚，我们的目标是研究第三代 mTOR 抑制剂在器官移植中的治疗效果。在这项研究中，RapaLink-1 在抑制 T 细胞增殖方面优于雷帕霉素，并显著延长了移植物的存活时间。从机制上讲，RapaLink-1 引起的排斥反应的改善与 T 细胞中 p-4E-BP1 的减少有关，导致 Treg 细胞的增加和 Th1 和 Th17 细胞的减少。这些研究首次证明了第三代 mTOR 抑制剂在抑制同种异体移植排斥反应方面的有效性，突出了这类新型 mTOR 抑制剂的潜力，值得进一步研究。
