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

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• 作者：Xiao-Lei Shi¹ ; ⁴ ; Shanta Mancham¹ ; Bettina E. Hansen¹ ; Robert J. de Knegt¹ ; Jeroen de Jonge³ ; Luc J.W. van der Laan³ ; Fernando Rivadeneira² ; Herold J. Metselaar¹ ; Jaap Kwekkeboom¹ ; ^{j.kwekkeboom@erasmusmc.nl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CFSE ; carboxyfluorescein succinimidyl ester ; CNI ; calcineurin inhibitor ; CTLA-4 ; cytotoxic T lymphocyte antigen 4 ; DC ; dendritic cell ; HWE ; Hardy Weinberg Equilibrium ; LT ; liver transplantation ; PBMC ; peripheral blood mononuclear cells ; PD-1 ; programmed death 1 receptor ; SNP ; single nucleotide polymorphism
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：64
• 期：6
• 页码：1274-1282
• 全文大小：2187 K

文摘

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.