Endothelial cells (ECs) are an initial barrier between vascularized organ allografts and the host immune system and are thus well positioned to initiate and influence alloimmune rejection. The mammalian target of rapamycin inhibitor rapamycin is known to inhibit T cell activation and attenuate acute allograft rejection. It also has numerous effects on ECs. We hypothesized that A mammalian target of rapamycin blockade might directly alter EC alloimmunogenicity and reduce alloimmune responses independent of its effects on T cell function. Here we report that rapamycin treatment modulates EC coinhibitory ligand expression and alters cytokine/chemokine production. It alters the EC transcriptome broadly associated with negative regulation of immune responses. Rapamycin-treated ECs suppress EC-specific T cell proliferation independent of programmed cell death 1/programmed death-ligand interaction and inhibit T cells responding to adjacent allogeneic cells in a contact-independent manner via secreted inhibitory mediators above 10 kDa. The T cell hyporesponsiveness induced by rapamycin-pretreated ECs was rescued by exogenous interleukin 2. Preexposing donor hearts to rapamycin improves the effect of B7 costimulation blockade in prolonging heart allograft survival in a major histocompatibility complex-mismatched mouse model. Our results indicate that rapamycin-treated ECs have reduced alloimmunogenicity and created a local, contact-independent environment that limits T cell alloreactivity via anergy induction and improves the efficacy of B7 costimulation blockade.

中文翻译：

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在哺乳动物雷帕霉素阻断靶点下靠近内皮细胞对 T 细胞介导的同种异体免疫进行免疫调节


内皮细胞 （EC） 是血管化器官同种异体移植物与宿主免疫系统之间的初始屏障，因此可以很好地启动和影响同种免疫排斥反应。已知雷帕霉素抑制剂雷帕霉素的哺乳动物靶标可抑制 T 细胞活化并减轻急性同种异体移植物排斥反应。它还对 EC 有许多影响。我们假设雷帕霉素阻断的哺乳动物靶标可能会直接改变 EC 同种免疫原性并减少同种免疫反应，而与其对 T 细胞功能的影响无关。在这里，我们报道了雷帕霉素治疗调节 EC 共抑制配体表达并改变细胞因子/趋化因子的产生。它改变了与免疫反应的负调节广泛相关的 EC 转录组。雷帕霉素处理的 ECs 抑制 EC 特异性 T 细胞增殖，独立于程序性细胞死亡 1/程序性死亡-配体相互作用，并通过分泌的 10 kDa 以上的抑制介质以接触非依赖性方式抑制 T 细胞对相邻同种异体细胞的反应。雷帕霉素预处理的 ECs 诱导的 T 细胞低反应性被外源性白细胞介素 2 挽救。在主要组织相容性复合体不匹配小鼠模型中，将供体心脏预先暴露于雷帕霉素可改善 B7 共刺激阻断在延长心脏同种异体移植物存活方面的作用。我们的结果表明，雷帕霉素处理的 ECs 降低了同种异体免疫原性，并创造了一个局部的、不依赖接触的环境，通过无能诱导限制 T 细胞同种异体反应性，并提高 B7 共刺激阻断的疗效。