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人类肝脏移植供体的PD-L1及移植受体的PD-1相互作用可反向调节排斥活性

Counter-regulation of rejection activity against human liver grafts by donor PD-L1 and recipient PD-1 interaction.

来源:Scopus 发布时间:2016-7-8
作者:Shi XL1, Mancham S, Hansen BE, de Knegt RJ, de Jonge J, van der Laan LJ, Rivadeneira F, Metselaar HJ, Kwekkeboom J.
机构: Erasmus MC大学医学中心胃肠病及肝病科;上海交通大学医学院附属仁济医院肝外科
期刊: J HEPATOL 2016年6月6期64卷

Background & Aims Co-inhibitory receptor-ligand interactions fine-tune immune responses by negatively regulating T cell functions. Our aim is to examine the involvement of co-inhibitory receptor-ligand pair PD-1/PD-L1 in regulating rejection after liver transplantation (LT) in humans. Methods PD-L1/PD-1 expression in liver allograft was determined by immunohistochemistry or flow cytometry, and the effect of blockade was studied using graft-infiltrating T cells ex vivo. Five single nucleotide polymorphisms within PD-1 and PD-L1 genes were genotyped in 528 LT recipients and 410 donors, and associations with both early (≤6 months) and late (>6 months) acute rejection were analyzed using Cox proportional-hazards regression model. The effect of PD-L1 rs4143815 on PD-L1 expression was analyzed using donor hepatic leukocytes. Results PD-L1 was expressed by hepatocytes, cholangiocytes and along the sinusoids in post-transplant liver allografts, and PD-1 was abundantly expressed on allograft-infiltrating T cells. PD-L1 blockade enhanced allogeneic proliferative responses of graft-infiltrating T cells. In the genetic association analysis, donor PD-L1 rs4143815 (CC/CG vs. GG; HR = 0.230; p = 0.002) and recipient PD-1 rs11568821 (AA/AG vs. GG; HR = 3.739; p = 0.004) were associated with acute rejection late after LT in multivariate analysis. Recipients carrying the PD-1 rs11568821 A allele who were transplanted with liver grafts of PD-L1 rs4143815 GG homozygous donors showed the highest risk for late acute rejection. PD-L1 rs4143815 is associated with differential PD-L1 expression on donor hepatic dendritic cells upon IFN-γ stimulation. Conclusion Our data suggest that interplay between donor PD-L1 and recipient PD-1 counter-regulates rejection activity against liver grafts in humans. © 2016 European Association for the Study of the Liver.

通讯作者:Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center, Rotterdam, The Netherlands; Department of Liver Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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