Division of Transplantation, Department of Surgery, University of Alberta, Canada.
J Hepatol. 2011 Dec;55(6):1441-51. doi: 10.1016/j.jhep.2011.06.015. Epub 2011 Jul 23.
The development of calcineurin inhibitors (CNIs) led to marked improvements in patient and graft survival after liver transplantation (LTx). We have been left, however, with a dependence on immunosuppressive agents with nephrotoxicity, neurotoxicity, adverse impacts on cardiac risk profile, and risk for malignancy. These challenges need to be met against a dominance of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) as indications for liver transplant. Unmet needs for immunosuppression (IS) in LTx include: (1) Effective drugs that avoid CNIs toxicities. (2) Agents without adverse impact on HCV recurrence. (3) Compounds that minimize risk of HCC recurrence. New immunosuppressives will need to address the above needs while supporting patient and graft survival equivalent to those achievable with CNIs, ideally without important new toxicities. Two new classes of agents are currently in advanced clinical development: belatacept, and the mammalian target of rapamycin inhibitors (m-TORi). This manuscript will review evidence for a role for m-TORi in LTx in a range of clinical scenarios including patients with CNI nephrotoxicity or neurotoxicity, patients at risk of (or with) HCV recurrence, and patients at risk of HCC recurrence.
钙调磷酸酶抑制剂（CNIs）的发展显著提高了肝移植（LTx）后患者和移植物的存活率。然而，我们仍然依赖于具有肾毒性、神经毒性、对心脏风险状况有不良影响以及致癌风险的免疫抑制剂。这些挑战需要在丙型肝炎病毒（HCV）和肝细胞癌（HCC）成为肝移植指征的情况下得到解决。LTx 中免疫抑制（IS）的未满足需求包括：（1）避免 CNI 毒性的有效药物。（2）对 HCV 复发无不良影响的药物。（3）最大限度降低 HCC 复发风险的化合物。新型免疫抑制剂需要在支持患者和移植物存活率与 CNI 相当的情况下满足上述需求，理想情况下不会产生重要的新毒性。目前有两类新型药物处于临床开发的后期阶段：巴利昔单抗和雷帕霉素靶蛋白抑制剂（mTORi）。本文将综述 mTORi 在 LTx 中在一系列临床情况下的作用证据，包括有 CNI 肾毒性或神经毒性的患者、有（或有）HCV 复发风险的患者和有 HCC 复发风险的患者。
