| Summary: | Liver transplantation (LT) is a definitive treatment for end-stage liver disease and hepatocellular cancer. As donor-recipient HLA matching is not employed, there is potential for natural killer (NK) cell-mediated alloreactivity. In practise this is not observed, and to date the recipient NK response to LT has not been characterized. This thesis describes a detailed investigation into LT recipient NK cell phenotype, function and activity. Lymphocytes were extracted from peripheral blood samples taken from LT recipients. Expression of activating receptors on NK cells was assessed using flow cytometry assays, and NK function was analysed with functional assays. Recipient NK cells exhibited a downregulated phenotype with reduced expression of activating receptors NKp30 and NKp46. There was associated hypofunctionality, with impaired NK cell cytotoxicity, degranulation and IFNγ production. These changes were found only within the differentiated CD56dim subset, and not in CD56bright cells, implying a maturation defect between the two stages of development. Similar findings were not observed in LT recipients infected with hepatitis C virus (HCV), indicating a counteracting activating effect of HCV. To explore a mechanism for the downregulation observed a microarray experiment was performed, with subsequent qPCR analysis. In LT there was downregulation of STAT-4 with associated reduction in miR-155, a microRNA target of STAT-4 and a key regulator of NK differentiation. Functional assays demonstrated impairment of the IL-12/STAT-4 pathway in LT recipients. The altered NK phenotype and gene expression were not recapitulated in vitro with immunosuppressants. The influence of HLA mismatching on LT outcome remains controversial, and this was addressed by analysing donor HLA and recipient HLA and KIR typing. No associations between HLA and HLA/KIR mismatching, NK cell activation, and clinical outcomes were found. Taken together, the data presented in this thesis indicate that LT induces recipient NK cell tolerance through altered peripheral maturation at a step prior to the acquisition of inhibitory receptors for HLA class I. Consistent with this, HLA-C matching does not influence NK alloreactivity in LT.
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