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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Programmed death-1/B7-H1 negative costimulation protects mouse liver against ischemia and reperfusion injury.
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Programmed death-1/B7-H1 negative costimulation protects mouse liver against ischemia and reperfusion injury.

机译：程序性死亡-1 / B7-H1阴性共刺激可保护小鼠肝脏免受缺血和再灌注损伤。

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摘要

Programmed death-1 (PD-1)/B7-H1 costimulation acts as a negative regulator of host alloimmune responses. Although CD4 T cells mediate innate immunity-dominated ischemia and reperfusion injury (IRI) in the liver, the underlying mechanisms remain to be elucidated. This study focused on the role of PD-1/B7-H1 negative signaling in liver IRI. We used an established mouse model of partial liver warm ischemia (90 minutes) followed by reperfusion (6 hours). Although disruption of PD-1 signaling after anti-B7-H1 monoclonal antibody treatment augmented hepatocellular damage, its stimulation following B7-H1 immunoglobulin (B7-H1Ig) fusion protected livers from IRI, as evidenced by low serum alanine aminotransferase levels and well-preserved liver architecture. The therapeutic potential of B7-H1 engagement was evident by diminished intrahepatic T lymphocyte, neutrophil, and macrophage infiltration/activation; reduced cell necrosis/apoptosis but enhanced anti-necrotic/apoptotic Bcl-2/Bcl-xl; and decreased proinflammatory chemokine/cytokine gene expression in parallel with selectively increased interleukin (IL)-10. Neutralization of IL-10 re-created liver IRI and rendered B7-H1Ig-treated hosts susceptible to IRI. These findings were confirmed in T cell-macrophage in vitro coculture in which B7-H1Ig diminished tumor necrosis factor-alpha/IL-6 levels in an IL-10-dependent manner. Our novel findings document the essential role of the PD-1/B7-H1 pathway in liver IRI. CONCLUSION: This study is the first to demonstrate that stimulating PD-1 signals ameliorated liver IRI by inhibiting T cell activation and Kupffer cell/macrophage function. Harnessing mechanisms of negative costimulation by PD-1 upon T cell-Kupffer cell cross-talk may be instrumental in the maintenance of hepatic homeostasis by minimizing organ damage and promoting IL-10-dependent cytoprotection.
机译：程序性死亡1（PD-1）/ B7-H1共刺激充当宿主同种免疫反应的负调节剂。尽管CD4 T细胞介导肝脏中固有的以免疫力为主的局部缺血和再灌注损伤（IRI），但其潜在机制仍有待阐明。这项研究的重点是PD-1 / B7-H1阴性信号在肝脏IRI中的作用。我们使用已建立的部分肝温暖局部缺血（90分钟）然后再灌注（6小时）的小鼠模型。尽管抗B7-H1单克隆抗体治疗后PD-1信号的破坏增加了肝细胞损伤，但B7-H1免疫球蛋白（B7-H1Ig）融合后的刺激可保护肝脏免受IRI，这可通过低血清丙氨酸氨基转移酶水平和良好保存来证明肝建筑。 B7-H1参与的治疗潜力通过减少肝内T淋巴细胞，嗜中性粒细胞和巨噬细胞浸润/激活来证明。减少细胞坏死/凋亡，但增强抗坏死/凋亡Bcl-2 / Bcl-xl;并与选择性增加白介素（IL）-10平行的促炎趋化因子/细胞因子基因表达降低。 IL-10的中和重建了肝脏IRI，并使B7-H1Ig处理的宿主易患IRI。这些发现在T细胞巨噬细胞体外共培养中得到了证实，其中B7-H1Ig以IL-10依赖的方式降低了肿瘤坏死因子α/ IL-6的水平。我们的新发现证明了PD-1 / B7-H1通路在肝脏IRI中的重要作用。结论：本研究首次证明刺激PD-1信号通过抑制T细胞活化和库普弗细胞/巨噬细胞功能而改善了肝脏IRI。 PD-1对T细胞-Kupffer细胞串扰的负共刺激的调节机制可能通过最小化器官损伤并促进IL-10依赖性细胞保护来维持肝脏稳态。

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