Xiao-Lei Shi1, Shanta Mancham2, Bettina E Hansen2, Robert J de Knegt2, Jeroen de Jonge3, Luc J W van der Laan3, Fernando Rivadeneira4, Herold J Metselaar2, Jaap Kwekkeboom5. 1. 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. 2. Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center, Rotterdam, The Netherlands. 3. Department of Surgery, Erasmus MC - University Medical Center, Rotterdam, The Netherlands. 4. Department of Internal Medicine, Erasmus MC - University Medical Center, Rotterdam, The Netherlands. 5. Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center, Rotterdam, The Netherlands. Electronic address: j.kwekkeboom@erasmusmc.nl.
Abstract
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 (⩽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. 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.
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 (⩽6months) and late (>6months) acute rejection were analyzed using Cox proportional-hazards regression model. The effect of PD-L1rs4143815 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, donorPD-L1rs4143815 (CC/CG vs. GG; HR=0.230; p=0.002) and recipient PD-1rs11568821 (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-1rs11568821 A allele who were transplanted with liver grafts of PD-L1rs4143815 GG homozygous donors showed the highest risk for late acute rejection. PD-L1rs4143815 is associated with differential PD-L1 expression on donor hepatic dendritic cells upon IFN-γ stimulation. CONCLUSION: Our data suggest that interplay between donorPD-L1 and recipient PD-1 counter-regulates rejection activity against liver grafts in humans.
Authors: Yoshihiro Ono; Angelica Perez-Gutierrez; Toshimasa Nakao; Helong Dai; Geoffrey Camirand; Osamu Yoshida; Shinichiro Yokota; Donna Beer Stolz; Mark A Ross; Adrian E Morelli; David A Geller; Angus W Thomson Journal: Hepatology Date: 2018-02-18 Impact factor: 17.425
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