Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation
Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation
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DOI：
10.1111/ajt.15700
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发表时间：
2020-02-03
影响因子：
8.8
通讯作者：
Lombardi, Giovanna
中科院分区：
文献类型：
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作者：
Sanchez-Fueyo, Alberto;Whitehouse, Gavin;Lombardi, Giovanna
调节性T细胞（Regulatory T cells，Tcells）是具有内在免疫抑制特性的淋巴细胞亚群，其可以在体外大量扩增，并且已经显示出在动物模型中防止同种异体移植物排斥和促进耐受。为了研究人类自体Treg过继转移的安全性、适用性和生物活性，我们在肝移植中进行了一项开放标签、剂量递增、I期临床试验。患者在等待肝移植或移植后6-12个月入组。从血液或白细胞分离术中分离循环TcR，在良好生产规范（GMP）条件下扩增，并以0.5-1百万TcR/kg或3-4.5百万TcR/kg静脉内施用。主要终点是输注后4周内发生的剂量限制性毒性的发生率。临床方案的适用性较差，除非患者招募推迟到移植后6-12个月。因此，在17例同意等待肝移植的患者中，仅3例接受了给药。相比之下，所有6名同意移植后6-12个月的患者都接受了细胞输注。Treg转移是安全的，短暂增加循环T细胞库并降低抗供体T细胞应答。我们的研究为采用Treg免疫疗法促进肝移植后免疫抑制的减少或完全停止打开了大门。
Regulatory T cells (Tregs) are a lymphocyte subset with intrinsic immunosuppressive properties that can be expanded in large numbers ex vivo and have been shown to prevent allograft rejection and promote tolerance in animal models. To investigate the safety, applicability, and biological activity of autologous Treg adoptive transfer in humans, we conducted an open-label, dose-escalation, Phase I clinical trial in liver transplantation. Patients were enrolled while awaiting liver transplantation or 6-12 months posttransplant. Circulating Tregs were isolated from blood or leukapheresis, expanded under good manufacturing practices (GMP) conditions, and administered intravenously at either 0.5-1 million Tregs/kg or 3-4.5 million Tregs/kg. The primary endpoint was the rate of dose- limiting toxicities occurring within 4 weeks of infusion. The applicability of the clinical protocol was poor unless patient recruitment was deferred until 6-12 months posttransplant. Thus, only 3 of the 17 patients who consented while awaiting liver transplantation were dosed. In contrast, all six patients who consented 6-12 months posttransplant received the cell infusion. Treg transfer was safe, transiently increased the pool of circulating Tregs and reduced anti-donor T cell responses. Our study opens the door to employing Treg immunotherapy to facilitate the reduction or complete discontinuation of immunosuppression following liver transplantation.