Pigs expressing the human inhibitory ligand PD-L1 (CD 274) provide a new source of xenogeneic cells and tissues with low immunogenic properties
Pigs expressing the human inhibitory ligand PD-L1 (CD 274) provide a new source of xenogeneic cells and tissues with low immunogenic properties
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DOI：
10.1111/xen.12387
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发表时间：
2018-09-01
影响因子：
3.9
通讯作者：
Schwinzer, Reinhard
中科院分区：
文献类型：
--
作者：
Buermann, Anna;Petkov, Stoyan;Schwinzer, Reinhard
程序性细胞死亡-1 (PD-1, CD279)/ pd -配体-1 （PD-L1, CD274）受体系统通过产生抑制信号来控制免疫激活和诱导耐受之间的平衡是至关重要的。PD-L1的表达与免疫原性降低有关，并使细胞和组织进入免疫特权/耐受原状态。方法为了将这一概念应用于临床异种移植，我们培育了人(h)PD-L1转基因猪，并在细胞水平上表征了该转基因猪的表达和生物学功能。结果肾、心、胰腺组织均检测到hPD-L1。此外，外周血单核细胞（PBMC）、培养成纤维细胞和内皮细胞hPD-L1阳性（hPD-L1(+)）。用人细胞因子（如TNF-）处理转基因细胞后，hPD-L1的表达水平升高，表明转基因表达具有可调控的模式。与野生型猪细胞相比，hPD-L1(+) PBMC刺激人CD4(+) T细胞增殖的能力显著降低。此外，hPD-L1转基因猪的成纤维细胞被人细胞毒性效应细胞部分保护，不受细胞介导的裂解。结论这些数据表明来自hPD-L1转基因猪的细胞具有低免疫原性和免疫保护状态。将hPD-L1概念整合到现有的多转基因猪中，有望实现猪异种移植物在非人灵长类动物受体中的长期存活。
BackgroundThe programmed cell death-1 (PD-1, CD279)/PD-Ligand1 (PD-L1, CD274) receptor system is crucial for controlling the balance between immune activation and induction of tolerance via generation of inhibitory signals. Expression of PD-L1 is associated with reduced immunogenicity and renders cells and tissues to an immune-privileged/tolerogenic state.MethodsTo apply this concept for clinical xenotransplantation, we generated human (h)PD-L1 transgenic pigs and characterized expression and biological function of the transgene at the cellular level.ResultsThe hPD-L1 was detected in kidney, heart, and pancreas. In addition, peripheral blood mononuclear cells (PBMC), cultured fibroblasts, and endothelial cells were hPD-L1 positive (hPD-L1(+)). The hPD-L1 levels were increased by the treatment of transgenic cells with human cytokines (eg, TNF-), suggesting a regulatable mode of transgene expression. Compared to cells from wild-type pigs, hPD-L1(+) PBMC had a significantly reduced capacity to stimulate proliferation of human CD4(+) T cells. Moreover, fibroblasts from hPD-L1 transgenic pigs were partially protected from cell-mediated lysis by human cytotoxic effector cells.ConclusionsThese data indicate a low immunogenic, immune-protected status of cells from hPD-L1 transgenic pigs. The integration of the hPD-L1 concept into existing multi-transgenic pigs is promising to achieve long-term survival of porcine xenografts in non-human primate recipients.