Conferring alloantigen-specificity to ex vivo expanded CD4+CD25+FOXP3+ regulatory T cells (Tregs) increases their capacity to counteract effector alloimmune responses following adoptive transfer into transplant recipients. Three strategies are currently undergoing clinical development, which involve the following: (1) expanding Tregs in the presence of donor B cells (donor alloantigen-reactive [DAR] Tregs); (2) culturing Tregs with donor cells in the presence of costimulation blockade (CSB-Tregs); and (3) transducing Tregs with an human leukocyte antigen A2–specific chimeric antigen receptor (CAR-Tregs). Our goal in this study was to assess the relative potency of each of these manufactured Treg products both in vitro and in vivo. When compared with polyclonal Tregs, all 3 manufacturing strategies increased the precursor frequency of alloreactive Tregs, and this was proportional to the overall in vitro immunosuppressive properties of the cell products. Accordingly, CAR-Tregs, which contained the highest frequency of donor-reactive Tregs, exhibited the strongest suppressive effects on a cell-per-cell basis. Similarly, in an in vivo mouse model of graft-vs-host disease, infusion of CAR-Tregs conferred a significantly longer recipient survival than any other Treg product. Our results highlighting the alloantigen-reactivity and associated immunosuppressive properties of different manufactured Treg products have implications for the mechanistic interpretation of currently ongoing clinical trials in transplantation.

中文翻译：

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赋予调节性 T 细胞同种异体抗原特异性：移植中正在进行临床开发的细胞制剂的比较分析


赋予离体扩增的 CD4+CD25+FOXP3+ 调节性 T 细胞 （Tregs） 同种异体抗原特异性可增加它们在过继转移到移植受者后抵消效应同种免疫反应的能力。目前有三种策略正在进行临床开发，涉及以下内容：（1） 在供体 B 细胞存在的情况下扩增 Tregs（供体同种异体抗原反应 [DAR] Tregs）;（2） 在共刺激阻断 （CSB-Tregs） 存在下用供体细胞培养 Tregs;（3） 用人白细胞抗原 A2 特异性嵌合抗原受体 （CAR-Tregs） 转导 Treg。我们在这项研究中的目标是评估这些制造的 Treg 产品中每一种在体外和体内的相对效力。与多克隆 Treg 相比，所有 3 种制造策略都增加了同种异体反应性 Treg 的前体频率，这与细胞产品的整体体外免疫抑制特性成正比。因此，包含最高频率的供体反应性 Treg 的 CAR-Tregs 在每细胞基础上表现出最强的抑制作用。同样，在移植物抗宿主病的体内小鼠模型中，输注 CAR-Tregs 的受体存活时间明显长于任何其他 Treg 产品。我们的结果强调了不同制造的 Treg 产品的同种异体抗原反应性和相关的免疫抑制特性，对目前正在进行的移植临床试验的机制解释具有重要意义。