title: Toll-like receptor 3 and 7/8 function is impaired in hepatitis C rapid fibrosis progression post-liver transplantation.
abstract: 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 (F0-4; R=fibrosis stage/year posttransplant; rapid fibrosis defined as >0.4 units/year). Thirty of 70 (43%) patients had rapid fibrosis progression. PBMCs from HCV rapid-fibrosers produced less IFNα 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 IFNγ was impaired in HCV rapid fibrosis (p=0.006) independently of IFNα 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.
authors: Liver Transplant Unit, Austin Hospital, Melbourne, Australia.|Department of Medicine, University of Melbourne, Australia.
authors: J
authors: J
authors: Howell
authors: Liver Transplant Unit, Austin Hospital, Melbourne, Australia.|Department of Medicine, University of Melbourne, Australia.
authors: R
authors: R
authors: Sawhney
authors: Innate Immune Laboratory, Monash University, Melbourne, Australia.
authors: N
authors: N
authors: Skinner
authors: Liver Transplant Unit, Austin Hospital, Melbourne, Australia.|Department of Medicine, University of Melbourne, Australia.
authors: P
authors: P
authors: Gow
authors: Liver Transplant Unit, Austin Hospital, Melbourne, Australia.|Department of Medicine, University of Melbourne, Australia.
authors: P
authors: P
authors: Angus
authors: Innate Immune Laboratory, Monash University, Melbourne, Australia.
authors: D
authors: D
authors: Ratnam
authors: Innate Immune Laboratory, Monash University, Melbourne, Australia.
authors: K
authors: K
authors: Visvanathan
mesh_terms: D000328:Adult; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D016174:Hepacivirus; D006526:Hepatitis C / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008024:Ligands; D008103:Liver Cirrhosis / Q000503:physiopathology / Q000821:virology; D017093:Liver Failure / Q000628:therapy; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012008:Recurrence; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D016898:Interferon-alpha; D015850:Interleukin-6; D008024:Ligands; C495344:TLR3 protein, human; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D007371:Interferon-gamma