title: Counter-regulation of rejection activity against human liver grafts by donor PD-L1 and recipient PD-1 interaction.
abstract: 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.
  
  
  
  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 (⩽6months) and late (>6months) 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.
  
  
  
  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.
  
  
  
  Our data suggest that interplay between donor PD-L1 and recipient PD-1 counter-regulates rejection activity against liver grafts in humans.
authors.affiliation: 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.
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Shi
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center, Rotterdam, The Netherlands.
authors.forename: Shanta
authors.initials: S
authors.lastname: Mancham
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center, Rotterdam, The Netherlands.
authors.forename: Bettina E
authors.initials: BE
authors.lastname: Hansen
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center, Rotterdam, The Netherlands.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: de Knegt
authors.affiliation: Department of Surgery, Erasmus MC - University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: de Jonge
authors.affiliation: Department of Surgery, Erasmus MC - University Medical Center, Rotterdam, The Netherlands.
authors.forename: Luc J W
authors.initials: LJ
authors.lastname: van der Laan
authors.affiliation: Department of Internal Medicine, Erasmus MC - University Medical Center, Rotterdam, The Netherlands.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center, Rotterdam, The Netherlands.
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center, Rotterdam, The Netherlands. Electronic address: j.kwekkeboom@erasmusmc.nl.
authors.forename: Jaap
authors.initials: J
authors.lastname: Kwekkeboom
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000209:etiology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D016031:Liver Transplantation / Q000009:adverse effects*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D055815:Young Adult
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma
keywords: Co-inhibition; Genetic polymorphism; Graft rejection; Liver transplantation; PD-1; PD-L1; T lymphocytes; Tolerance