Permanent CNI Treatment for Prevention of Renal Allograft Rejection in Sensitized Hosts Can Be Replaced by Regulatory T Cells
Permanent CNI Treatment for Prevention of Renal Allograft Rejection in Sensitized Hosts Can Be Replaced by Regulatory T Cells
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DOI：
10.1111/j.1600-6143.2012.04143.x
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发表时间：
2012-09-01
影响因子：
8.8
通讯作者：
Reinke, P.
中科院分区：
文献类型：
--
作者：
Siepert, A.;Ahrlich, S.;Reinke, P.
最近的数据表明，供体特异性记忆T细胞（Tmem）是患者排斥和移植物功能差的独立危险因素，也是免疫抑制最小化策略的主要挑战。许多耐受诱导方案在小动物模型中成功证明，如共刺激阻断，T细胞消耗在患者中失败。因此，需要更多的预测移植模型来评估新的有前景的策略，如调节性T细胞（Treg）的过继转移。我们建立了一个临床更相关的、支持生命的大鼠肾移植模型，使用高反应（DA to LEW）受者在移植前接受供体特异性CD4+/ 8+ GFP+ Tmem，以达到与许多患者相似的供体特异性Tmem移植前频率。单独的T细胞耗损诱导初代受者的长期移植存活，但不能防止Tmem+大鼠的急性排斥反应，就像患者一样。只有T细胞清除联合永久性cni治疗，才能长期控制移植物体内炎症和急性/慢性同种异体移植排斥反应。值得注意的是，在Tmem+大鼠中，结合10天的CNI治疗和Treg过继性转移（第3天），而不是单独使用Treg，也能诱导移植物长期存活和植入耐受性（如高TOAG-1）。我们的模型允许在临床相关条件下评估新疗法。
Recent data suggest that donor-specific memory T cells (Tmem) are an independent risk factor for rejection and poor graft function in patients and a major challenge for immunosuppression minimizing strategies. Many tolerance induction protocols successfully proven in small animal models e.g. costimulatory blockade, T cell depletion failed in patients. Consequently, there is a need for more predictive transplant models to evaluate novel promising strategies, such as adoptive transfer of regulatory T cells (Treg). We established a clinically more relevant, life-supporting rat kidney transplant model using a high responder (DA to LEW) recipients that received donor-specific CD4+/ 8+ GFP+ Tmem before transplantation to achieve similar pre-transplant frequencies of donor-specific Tmem as seen in many patients. T cell depletion alone induced long-term graft survival in naive recipients but could not prevent acute rejection in Tmem+ rats, like in patients. Only if T cell depletion was combined with permanent CNI-treatment, the intragraft inflammation, and acute/chronic allograft rejection could be controlled long-term. Remarkably, combining 10 days CNI treatment and adoptive transfer of Tregs (day 3) but not Treg alone also induced long-term graft survival and an intragraft tolerance profile (e.g. high TOAG-1) in Tmem+ rats. Our model allows evaluation of novel therapies under clinically relevant conditions.