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.

中文翻译：

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调节性 T 细胞疗法在肝移植中的适用性、安全性和生物活性。

调节性 T 细胞 (Treg) 是一种具有内在免疫抑制特性的淋巴细胞亚群，可以在体外大量扩增，并已被证明可以防止同种异体移植物排斥并促进动物模型的耐受性。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、剂量递增的 I 期临床试验。患者在等待肝移植时或移植后 6-12 个月时入组。循环 Tregs 从血液或白细胞分离术中分离出来，在良好生产规范 (GMP) 条件下进行扩增，并以 0.5-1 百万 Tregs/kg 或 3-450 万 Tregs/kg 静脉内给药。主要终点是输注后 4 周内发生剂量限制性毒性的发生率。除非将患者招募推迟到移植后 6-12 个月，否则临床方案的适用性很差。因此，在等待肝移植时同意的 17 名患者中只有 3 名接受了给药。相比之下，所有六名同意移植后 6-12 个月的患者都接受了细胞输注。Treg 转移是安全的，短暂地增加了循环 Tregs 池并减少了抗供体 T 细胞反应。我们的研究为采用 Treg 免疫疗法来促进肝移植后减少或完全停止免疫抑制打开了大门。所有六名同意移植后 6-12 个月的患者都接受了细胞输注。Treg 转移是安全的，短暂地增加了循环 Tregs 池并减少了抗供体 T 细胞反应。我们的研究为采用 Treg 免疫疗法来促进肝移植后减少或完全停止免疫抑制打开了大门。所有六名同意移植后 6-12 个月的患者都接受了细胞输注。Treg 转移是安全的，短暂地增加了循环 Tregs 池并减少了抗供体 T 细胞反应。我们的研究为采用 Treg 免疫疗法来促进肝移植后减少或完全停止免疫抑制打开了大门。