title: Difference in cytotoxicity against hepatocellular carcinoma between liver and periphery natural killer cells in humans.
abstract: In rodents, liver natural killer (NK) cells have been shown to mediate higher cytotoxic activity against tumor cells than do peripheral blood (PB) NK cells. However, such differences between liver and PB NK cells have not been extensively investigated in humans. The phenotypical and functional properties of NK cells extracted from liver perfusates at the time of living donor liver transplantation were investigated. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a critical molecule for NK cell-mediated anti-tumor cell killing, was not expressed by freshly isolated PB NK cells or by liver NK cells. Stimulation with interleukin (IL)-2, significantly up-regulated the expression of TRAIL on liver NK cells, but this effect was barely observed on PB NK cells. Donor liver NK cells showed the most vigorous cytotoxicity against HepG2, a hepatocellular carcinoma (HCC) cell line, after IL-2 stimulation (90.5% +/- 2.2% at E: T = 10:1), compared with donor and recipient PB NK cells and recipient liver NK cells (64.8% +/- 8.2%, 56.1% +/- 8.9%, and 34.6% +/- 7.5%, respectively). IL-2 stimulation resulted in an increased expression of killing inhibitory receptors on liver NK cells in parallel with TRAIL expression. Consistently, the cytotoxicities of IL-2-stimulated donor liver NK cells against self and recipient lymphoblasts were negligible. In conclusion, adoptive transfer of IL-2-stimulated NK cells extracted from donor liver graft perfusate could mount an anti-tumor response without causing toxicity against 1-haplotype identical recipient intact tissues. These findings present a concept to prevent recurrence of HCC after liver transplantation.
authors.affiliation: Department of Surgery, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Kasumi, Hiroshima, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Ishiyama
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohdan
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ohira
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsuta
authors.forename: Koji
authors.initials: K
authors.lastname: Arihiro
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Asahara
mesh_terms: D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000601:surgery; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology* / Q000601:surgery; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008875:Middle Aged; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D051017:Apoptosis Regulatory Proteins; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha