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.

Co-inhibition, Genetic polymorphism, Graft rejection, Liver transplantation, PD-1, PD-L1, T lymphocytes, Tolerance,
Journal of Hepatology
Department of Internal Medicine

Shi, X-L, Mancham, S, Hansen, B.E, de Knegt, R.J, de Jonge, J, van der Laan, L.J.W, … Kwekkeboom, J. (2016). Counter-regulation of rejection activity against human liver grafts by donor PD-L1 and recipient PD-1 interaction. Journal of Hepatology, 64(6), 1274–1282. doi:10.1016/j.jhep.2016.02.034