title: Alloimmune activation promotes anti-cancer cytotoxicity after rat liver transplantation.
abstract: Liver transplantation for hepatocellular carcinoma (HCC) results in a specific condition where the immune response is potentially directed against both allogeneic and cancer antigens. We have investigated the level of anti-cancer immunity during allogeneic immune response. Dark Agouti-to-Lewis and Lewis-to-Lewis rat liver transplantations were performed and the recipients anti-cancer immunity was analysed at the time of alloimmune activation. The occurrence of rejection in the allogeneic recipients was confirmed by a shorter survival (p<0.01), increased liver function tests (p<0.01), the presence of signs of rejection on histology, and a donor-specific ex vivo mixed lymphocyte reaction. At the time of alloimmune activation, blood mononuclear cells of the allogeneic group demonstrated increased anti-cancer cytotoxicity (p<0.005), which was related to an increased natural killer (NK) cell frequency (p<0.05) and a higher monocyte/macrophage activation level (p<0.01). Similarly, liver NK cell anti-cancer cytotoxicity (p<0.005), and liver monocyte/macrophage activation levels (p<0.01) were also increased. The alloimmune-associated cytotoxicity was mediated through the NKG2D receptor, whose expression was increased in the rejected graft (p<0.05) and on NK cells and monocyte/macrophages. NKG2D ligands were expressed on rat HCC cells, and its inhibition prevented the alloimmune-associated cytotoxicity. Although waiting for in vivo validation, alloimmune-associated cytotoxicity after rat liver transplantation appears to be linked to increased frequencies and levels of activation of NK cells and monocyte/macrophages, and is at least in part mediated through the NKG2D receptor.
authors.affiliation: Department of Surgery, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Lacotte
authors.affiliation: Department of Surgery, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
authors.forename: Graziano
authors.initials: G
authors.lastname: Oldani
authors.affiliation: Department of Surgery, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
authors.forename: Florence
authors.initials: F
authors.lastname: Slits
authors.affiliation: Department of Surgery, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Orci
authors.affiliation: Hepato-pancreato-biliary Centre, Geneva University Hospitals, University of Geneva, Geneva, Switzerland; Department of Pathology, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Rubbia-Brandt
authors.affiliation: Department of Surgery, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Morel
authors.affiliation: Department of Surgery, Geneva University Hospitals, University of Geneva, Geneva, Switzerland; Department of Pathology, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
authors.forename: Gilles
authors.initials: G
authors.lastname: Mentha
authors.affiliation: Department of Surgery, Geneva University Hospitals, University of Geneva, Geneva, Switzerland; Department of Pathology, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Toso
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000601:surgery*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D006084:Graft Rejection / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000276:immunology* / Q000601:surgery*; D016031:Liver Transplantation; D008297:Male; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000473:pathology; D014184:Transplantation, Homologous
chemical_list: D055655:NK Cell Lectin-Like Receptor Subfamily K