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Title: Toll-like receptor 3 and 7/8 function is impaired in hepatitis C rapid fibrosis progression post-liver transplantation.
Austin Authors: Howell, Jessica;Sawhney, R;Skinner, N;Gow, Paul J ;Angus, Peter W ;Ratnam, D;Visvanathan, K
Affiliation: Medicine (University of Melbourne)
Victorian Liver Transplant Unit
Issue Date: 20-Feb-2013
Publication information: American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2013; 13(4): 943-53
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.
DOI: 10.1111/ajt.12165
Journal: American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
Type: Journal Article
Subjects: Adult
Cross-Sectional Studies
Disease Progression
Hepatitis C.metabolism.physiopathology
Killer Cells, Natural.cytology
Leukocytes, Mononuclear.cytology
Liver Cirrhosis.physiopathology.virology
Liver Failure.therapy
Liver Transplantation
Middle Aged
Prospective Studies
Toll-Like Receptor 3.metabolism
Toll-Like Receptor 7.metabolism
Toll-Like Receptor 8.metabolism
Appears in Collections:Journal articles

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