Background:The role of checkpoint axes in transplantation has been partially addressed in animal models but not in humans. Occurrence of fulminant myocarditis with allorejection-like immunologic features in patients under anti-PD1 (programmed death cell protein 1) treatment suggests a key role of the PD1/PD-L1 (programmed death ligand 1) axis in cardiac immune homeostasis.Methods:We cross-sectionally studied 23 heart transplant patients undergoing surveillance endomyocardial biopsy. Endomyocardial tissue and peripheral blood mononuclear cells were analyzed by flow cytometry. Multivariate logistic regression analyses including demographic, clinical, and hemodynamic parameters were performed. Murine models were used to evaluate the impact of PD-L1 endothelial graft expression in allorejection.Results:We found that myeloid cells dominate the composition of the graft leukocyte compartment in most patients, with variable T-cell frequencies. The CD (cluster of differentiation) 4:CD8 T-cell ratios were between 0 and 1.5. The proportion of PD-L1 expressing cells in graft endothelial cells, fibroblasts, and myeloid leukocytes ranged from negligible up to 60%. We found a significant inverse logarithmic correlation between the proportion of PD-L1⁺HLA (human leukocyte antigen)-DR⁺ endothelial cells and CD8⁺ T cells (slope, −18.3 [95% CI, −35.3 to −1.3]; P=0.030). PD-L1 expression and leukocyte patterns were independent of demographic, clinical, and hemodynamic parameters. We confirmed the importance of endothelial PD-L1 expression in a murine allogeneic heart transplantation model, in which Tie2^Crepdl1^fl/fl grafts lacking PD-L1 in endothelial cells were rejected significantly faster than controls.Conclusions:Loss of graft endothelial PD-L1 expression may play a role in regulating CD8⁺ T-cell infiltration in human heart transplantation. Murine model results suggest that loss of graft endothelial PD-L1 may facilitate alloresponses and rejection.

中文翻译：

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内皮基质 PD-L1（程序性死亡配体 1）调节心脏移植后 CD8+ T 细胞浸润

背景：检查点轴在移植中的作用已在动物模型中部分得到解决，但在人类中尚未得到解决。接受抗 PD1（程序性死亡细胞蛋白 1）治疗的患者出现具有同种异体排斥样免疫学特征的暴发性心肌炎，表明 PD1/PD-L1（程序性死亡配体 1）轴在心脏免疫稳态中发挥着关键作用。横断面研究了 23 名接受监测心内膜心肌活检的心脏移植患者。通过流式细胞术分析心内膜心肌组织和外周血单核细胞。进行了包括人口统计学、临床和血流动力学参数在内的多变量逻辑回归分析。使用小鼠模型评估 PD-L1 内皮移植物表达对同种异体排斥的影响。结果：我们发现，在大多数患者中，骨髓细胞在移植物白细胞区室的组成中占主导地位，且 T 细胞频率各异。CD（分化簇）4：CD8 T 细胞比率在 0 到 1.5 之间。移植物内皮细胞、成纤维细胞和髓系白细胞中表达 PD-L1 的细胞比例从可忽略不计到高达 60%。^{我们发现 PD-L1 +} HLA（人类白细胞抗原）-DR ⁺内皮细胞与 CD8 ⁺ T 细胞的比例之间存在显着的反对数相关性（斜率，-18.3 [95% CI，-35.3 至 -1.3]；P = 0.030）。PD-L1 表达和白细胞模式独立于人口统计学、临床和血流动力学参数。我们在小鼠同种异体心脏移植模型中证实了内皮 PD-L1 表达的重要性，其中内皮细胞中缺乏 PD-L1 的Tie2 ^Cre pdl1 ^fl/fl移植物的排斥速度明显快于对照。结论：移植物内皮 PD-L1 丢失表达可能在人类心脏移植中调节CD8 ⁺ T细胞浸润中发挥作用。小鼠模型结果表明，移植物内皮细胞 PD-L1 的缺失可能会促进同种异体反应和排斥反应。