Toll-Like Receptor 3 and 7/8 Function Is Impaired in Hepatitis C Rapid Fibrosis Progression Post-Liver Transplantation

Recurrence of hepatitis C (HCV) postliver transplant is universal, with a subgroup developing rapid hepatic fibrosis. Toll-like receptors (TLRs) are critical to innate antiviral responses and HCV alters TLR function to evade immune clearance. Whether TLRs play a role in rapid HCV recurrence posttransplant is unknown. We stimulated peripheral blood mononuclear cells (PBMCs) from 70 patients with HCV postliver transplant with TLR subclass-specific ligands and measured cytokine production, TLR expression and NK cell function. Rate of fibrosis progression was calculated using posttransplant liver biopsies graded by Metavir scoring (F04; R= fibrosis stage/year posttransplant; rapid fibrosis defined as >0.4units/year). Thirty of 70 (43%) patients had rapid fibrosis progression. PBMCs from HCV rapid-fibrosers produced less IFN with TLR7/8 stimulation (p= 0.039), less IL-6 at baseline (p= 0.027) and with TLR3 stimulation (p= 0.008) and had lower TLR3-mediated monocyte IL-6 production (p= 0.028) compared with HCV slow fibrosers. TLR7/8-mediated NKCD56 dim cell secretion of IFN was impaired in HCV rapid fibrosis (p= 0.006) independently of IFN secretion and TLR7/8 expression, while cytotoxicity remained preserved. Impaired TLR3 and TLR7/8-mediated cytokine responses may contribute to aggressive HCV recurrence postliver transplantation through impaired immune control of HCV and subsequent activation of fibrogenesis.