Pachiadakis, I.; (2009) Dendritic cell function in the setting of chronic hepatitis c infection and changes during antiviral treatment. Masters thesis , UCL (University College London).

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Abstract

The role of the innate immune system and in particular of dendritic cells, in the establishment of chronic hepatitis C has been studied quite extensively over the last few years but controversy remains as to whether a potential virus-induced defect in DC function leads to sub-optimal initiation of adaptive immune responses and finally to the establishment of chronic infection. In the present thesis we examined monocyte-derived DC (MDDC), generated from patients with chronic hepatitis C (CHC), and healthy subjects in order to gain a better understanding of dendritic cell functions in the setting of hepatitis C infection. We initially observed a defect in CHC patients’ DC capacity to stimulate ‘naïve’ CD4+ T-cells into proliferation. Investigating for factors potentially contributing to this defect we demonstrated that HCV genome (both positive strand HCV RNA and the replicative intermediate negative strand HCV RNA) and HCV protein products (HCV core protein) are present in DC without though any obvious correlation to DC functions. We further proccedeed to investigate for potential influence of other, host-related, parameters on DC and tested liver fibrosis, ethanol consumption, HCV viraemia levels and HCV protein products’ concentration in the serum demonstarting significant influences of HCV viraemia / HCV core serum concentration and ethanol consumption on DC functional and phenotypic output. After successful antiviral treatment (with pegylated interferon α and ribavirin) our patients restored their DC functions (allostimulatory capacity, HCV-specific immune-reactivity and IL-12production). Performing ‘cross-over’ experiments we suggest that antiviral treatment exerted its effect by improving mainly DC capacities and not effector CD4+ T-cell reactivity. We also tested plasmacytoid dendritic cell cytokine output after HCV infection and we observed a controversial effect of the virus on the Th1-skewing capacity of this DC subset.

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