Counter-regulation of rejection activity against human liver grafts by donor PD-L1 and recipient PD-1 interaction
Counter-regulation of rejection activity against human liver grafts by donor PD-L1 and recipient PD-1 interaction
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DOI：
10.1016/j.jhep.2016.02.034
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发表时间：
2016-06-01
影响因子：
25.7
通讯作者：
Kwekkeboom, Jaap
中科院分区：
文献类型：
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作者：
Shi, Xiao-Lei;Mancham, Shanta;Kwekkeboom, Jaap
背景与目的：共抑制受体-配体相互作用通过负性调节T细胞功能来微调免疫应答。我们的目的是研究参与共同抑制受体-配体对PD-1/PD-L1在调节排斥反应后，在humans liver transplantation（LT）.Methods：PD-L1/PD-1在肝移植物中的表达通过免疫组织化学或流式细胞术测定，并使用移植物浸润T细胞体外研究阻断的效果。对528例肝移植受者和410例供者进行PD-1和PD-L1基因5个单核苷酸多态性基因分型，采用考克斯比例风险回归模型分析其与早期（66个月）和晚期（> 6个月）急性排斥反应的关系。结果：PD-L1在肝移植后肝细胞、胆管细胞和沿着血窦表达，PD-1在移植物浸润的T细胞上大量表达。PD-L1阻断增强了移植物浸润性T细胞的同种异体增殖反应。在遗传关联分析中，供体PD-L1 rs 4143815（CC/CG vs. GG; HR = 0.230; p = 0.002）和受体PD-1 rs 11568821（AA/AG vs. GG; HR = 3.739; p = 0.004）在多变量分析中与LT后晚期急性排斥反应相关。携带PD-1 rs 11568821 A等位基因的受体，移植PD-L1 rs 4143815 GG纯合子供体的肝移植物，显示晚期急性排斥反应的风险最高。PD-L1 rs 4143815与IFN-gamma stimulation.Conclusion供体PD-L1和受体PD-1之间的相互作用对人类肝移植物的排斥反应活性起反调节作用。(C)2016年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
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 (66 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-gamma stimulation.Conclusion: Our data suggest that interplay between donor PD-L1 and recipient PD-1 counter-regulates rejection activity against liver grafts in humans. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.