Cell therapy with autologous donor-specific regulatory T cells (Tregs) is a promising strategy to minimize immunosuppression in transplant recipients. Chimeric antigen receptor (CAR) technology has recently been used successfully to generate donor-specific Tregs and overcome the limitations of enrichment protocols based on repetitive stimulations with alloantigens. However, the ability of CAR-Treg therapy to control alloreactivity in immunocompetent recipients is unknown. We first analyzed the effect of donor-specific CAR Tregs on alloreactivity in naive, immunocompetent mice receiving skin allografts. Tregs expressing an irrelevant or anti-HLA-A2-specific CAR were administered to Bl/6 mice at the time of transplanting an HLA-A2+ Bl/6 skin graft. Donor-specific CAR-Tregs, but not irrelevant-CAR Tregs, significantly delayed skin rejection and diminished donor-specific antibodies (DSAs) and frequencies of DSA-secreting B cells. Donor-specific CAR-Treg-treated mice also had a weaker recall DSA response, but normal responses to an irrelevant antigen, demonstrating antigen-specific suppression. When donor-specific CAR Tregs were tested in HLA-A2-sensitized mice, they were unable to delay allograft rejection or diminish DSAs. The finding that donor-specific CAR-Tregs restrain de novo but not memory alloreactivity has important implications for their use as an adoptive cell therapy in transplantation.

中文翻译：

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供体特异性嵌合抗原受体 Tregs 限制了幼稚但未致敏的同种异体移植物受者的排斥反应。

用自体供体特异性调节性 T 细胞 (Tregs) 进行细胞治疗是一种有前途的策略，可以最大限度地减少移植受者的免疫抑制。嵌合抗原受体 (CAR) 技术最近已成功用于生成供体特异性 Treg，并克服了基于同种异体抗原重复刺激的富集方案的局限性。然而，CAR-Tr​​eg 疗法在免疫功能正常的接受者中控制同种异体反应的能力尚不清楚。我们首先分析了供体特异性 CAR Tregs 对接受同种异体皮肤移植的幼稚免疫活性小鼠同种异体反应性的影响。在移植 HLA-A2+ Bl/6 皮肤移植物时，将表达无关或抗 HLA-A2 特异性 CAR 的 Tregs 施用于 Bl/6 小鼠。供体特异性 CAR-Tr​​egs，但不是不相关的 CAR-Tr​​egs，显着延迟皮肤排斥并减少供体特异性抗体 (DSA) 和分泌 DSA 的 B 细胞的频率。供体特异性 CAR-Tr​​eg 处理的小鼠也有较弱的回忆 DSA 反应，但对不相关抗原的正常反应，表明抗原特异性抑制。当在 HLA-A2 致敏小鼠中测试供体特异性 CAR Tregs 时，它们无法延迟同种异体移植排斥反应或减少 DSA。供体特异性 CAR-Tr​​egs 从头抑制而非记忆同种异体反应性的发现对于它们在移植中用作过继细胞疗法具有重要意义。当在 HLA-A2 致敏小鼠中测试供体特异性 CAR Tregs 时，它们无法延迟同种异体移植排斥反应或减少 DSA。供体特异性 CAR-Tr​​egs 从头抑制而非记忆同种异体反应性的发现对于它们在移植中用作过继细胞疗法具有重要意义。当在 HLA-A2 致敏小鼠中测试供体特异性 CAR Tregs 时，它们无法延迟同种异体移植排斥反应或减少 DSA。供体特异性 CAR-Tr​​egs 从头抑制而非记忆同种异体反应性的发现对于它们在移植中用作过继细胞疗法具有重要意义。