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

比较采用 CsA 或依维莫司自下而上免疫抑制方案治疗的肝移植受者的早期免疫反应

• 批准号: 181841433
• 负责人: Professor Dr. James Hutchinson, Ph.D.
• 金额: --
• 依托单位: Klinik und Poliklinik für Chirurgie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/181841433?language=en
• 关键词: Comparing; early; immunological; responses; liver

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.

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反应的发展。历史上，人们设计了各种据称有利于调节过程的治疗方案，尽管没有一个方案被令人满意地证明具有“促耐受性”。在这方面，目前的观点主张使用淋巴细胞耗竭诱导疗法、避免 CNI 和延长类固醇治疗、使用 mTOR 抑制剂以及相对逐渐停止维持治疗 (1,2)。这种方法几乎在所有方面都与以前的方式相反，即以最小的免疫抑制开始治疗，然后迅速撤除维持治疗。事实上，甚至有人认为早期免疫激活对于诱导后期的免疫调节过程至关重要 (3,4)。支持这两种一般方法的证据并不是压倒性的，需要立即重新解决，因为随着旨在促进同种异体移植耐受的新药物（包括基于细胞的疗法）的出现，必须定义优化的促进耐受的免疫抑制方案。在该项目中，将对根据标准方案治疗的肝移植受者与基于延迟引入 CsA 或依维莫司的自下而上方案治疗的患者进行比较。患者的结果将根据其免疫学特征进行临床评估，通过标记物分析和功能测定来定义。重点将放在移植后早期对患者进行系列检查，假设自下而上，而不是自上而下，免疫抑制促进调节细胞类型的早期扩增。在当前资助期之后，该项目的未来前景之一是为肝移植患者建立临床方案，该方案可用作测试新型基于细胞的免疫抑制疗法的合适平台。

项目成果

Early Enrichment and Restitution of the Peripheral Blood Treg Pool Is Associated With Rejection-Free Stable Immunosuppression After Liver Transplantation.

外周血 Treg 库的早期富集和恢复与肝移植后无排斥的稳定免疫抑制相关

• DOI: 10.1097/tp.0000000000001190
• 发表时间: 2016
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Haarer J;Riquelme P;Hoffmann P;Schnitzbauer A;Schlitt HJ;Sawitzki B;Geissler EK;Hutchinson JA
• 通讯作者: Hutchinson JA