Comparing the early immunological responses of liver transplant recipients treated under a bottom-up immunosuppressive regimen utilising either CsA or Everolimus

虽然传统的普通免疫抑制剂在预防排斥反应方面非常有效，但它们也可以抑制调节性反应的发展。从历史上看，已经设计出了各种据称有利于调节过程的治疗方案，尽管没有一种疗法被令人满意地证明是“有利于耐受的”。在这方面，目前的意见主张使用淋巴细胞耗尽诱导疗法，避免CNI和长期类固醇治疗，使用mTOR抑制剂和相对渐进的维持疗法(1，2)。这种方法几乎在各个方面都与以前的方式背道而驰，即以最低限度的免疫抑制开始治疗，然后迅速停止维持治疗；事实上，甚至有人建议，早期免疫激活对于诱导后来的免疫调节过程至关重要(3，4)。支持任何一种一般方法的证据都不是压倒性的，需要紧急改头换面，因为随着旨在促进同种移植耐受性的新药物的出现，包括基于细胞的疗法，必须定义优化的促进耐受性的免疫抑制方案。在这个项目中，将比较按标准方案治疗的肝移植受者和基于延迟引入CsA或Everolimus的自下而上方案治疗的患者。患者的预后将在临床上进行评估，并根据他们的免疫学特征，通过标志物分析和功能分析来确定。重点将放在移植后早期患者的系列检查上，假设自下而上而不是自上而下的免疫抑制促进了调节性细胞类型的早期扩张。该项目的一个未来前景是，在当前的资助期之后，为肝移植患者建立一个临床方案，该方案可以作为测试新型细胞免疫抑制疗法的合适平台。

Whilst conventional general immunosuppressive agents are superbly effective in preventing rejection responses, they can also suppress the development of regulatory responses. Historically, various therapeutic regimens have been devised which purportedly favour regulatory processes, although none has been satisfactorily shown to be “pro-tolerogenic”. In this regard, current opinion advocates the use of lymphocyte-depleting induction therapies, avoidance of CNIs and prolonged steroid treatment, the use of mTOR inhibitors and a relatively gradual weaning of maintenance therapy (1,2). This approach runs contrary, in almost every respect, to the previous fashion of initiating treatment with minimal immunosuppression and then weaning maintenance therapy rapidly; indeed, it has even been suggested that early immunological activation is essential to induce later immunoregulatory processes (3,4). Evidence in favour of either general approach is not overwhelming and needs to be urgently readdressed because, with the advent of novel agents intended to promote tolerance to allografts, including cell-based therapies, an optimised tolerance-promoting immunosuppressive protocol must be defined. In this project, comparisons will be drawn between liver transplant recipients treated according to a standard protocol and patients treated with a bottom-up regimen based on the delayed introduction of either CsA or Everolimus. Patient outcomes will be assessed clinically and in terms of their immunological profile, defined by marker analyses and functional assays. Emphasis will be placed on serial examination of patients in the early time-period after transplantation on the hypothesis that bottom-up, as opposed to top-down, immunosuppression promotes the early expansion of regulatory cell types. One future perspective of this project, beyond the immediate funding period, is the establishment of a clinical protocol for liver transplant patients that could be used as a suitable platform for testing novel, cell-based immunosuppressive therapies.