| Summary: | Infection with chronic hepatitis C virus (HCV) is the leading indication for liver transplantation. Recurrence, however of HCV is universal after liver transplantation and subsequent fibrosis rates after transplantation are accelerated leading to significant morbidity and mortality. In addition, treatment of recurrent HCV after transplantation with pegylated-interferon (PEG) and ribavirin (RBV) are poorly tolerated and are associated with inferior treatment outcomes. The ability to therefore understand the mechanisms that relate to disease recurrence and therefore develop markers of fast fibrosis and treatment response would be beneficial for clinicians caring for these patients. The role of donor and recipient rs12979860 IL-28B genotype was examined first. My results demonstrated recipient non-CC IL-28B genotype was associated with a rapid fibrosis (F≥2) progression at 12 months and increased risk of F≥4 post transplantation. The donor/recipient CC IL-28B combination was associated with attenuated fibrosis progression post transplantation. Next, the role of CXCL10 in predicting fibrosis rates and treatment response was examined. My results that CXCL10 levels taken 6 months following liver transplantation correlated with fibrosis rates at 12 months and were predictive of rapid fibrosis progression at 12 months and F≥4. CXCL10 levels pre-treatment with PEG and RBV were predictive of successful treatment outcomes. Finally, the role of microRNAs (miRNAs) were examined to delineate their role in predicting HCV recurrence. My results demonstrated intragraft expression of miRNA- 146a, miRNA-19a, miRNA-20a and miRNA-let7e in patients with slow fibrosis progression (F < 2) at 12 months. These miRNAs regulated the expression of cardinal genes implicated in promoting antifibrotic, antiangiogenic and anti-inflammatory pathways. miRNA-19a and miRNA-20a may also be possible serum biomarkers of fibrosis progression in patients with HCV post transplantation. These experiments demonstrate and identify further predictors of fibrosis progression in patients with HCV recurrence after liver transplantation.
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