title: Characterization of HCV-specific CD4+Th17 immunity in recurrent hepatitis C-induced liver allograft fibrosis.
abstract: Hepatitis C virus (HCV) recurrence with accelerated fibrosis following orthotopic liver transplantation (OLT) is a universal phenomenon. To evaluate mechanisms contributing to HCV induced allograft fibrosis/cirrhosis, we investigated HCV-specific CD4+Th17 cells and their induction in OLT recipients with recurrence utilizing 51 HCV+ OLT recipients, 15 healthy controls and 9 HCV- OLT recipients. Frequency of HCV specific CD4+ Tcells secreting IFN-γ, IL-17 and IL-10 was analyzed by ELISpot. Serum cytokines and chemokines were analyzed by LUMINEX. Recipients with recurrent HCV induced allograft inflammation and fibrosis/cirrhosis demonstrated a significant increase in frequency of HCV specific CD4+Th17 cells. Increased pro-inflammatory mediators (IL-17, IL-1β, IL-6, IL-8 and MCP-1), decreased IFN-γ, and increased IL-4, IL-5 and IL-10 levels were identified. OLT recipients with allograft inflammation and fibrosis/cirrhosis demonstrated increased frequency of Foxp3+ regulatory T cells (Tregs) that inhibited HCV specific CD4+Th1 but not Th17 cells. This suggests that recurrent HCV infection in OLT recipients induces an inflammatory milieu characterized by increased IL-6, IL-1β and decreased IFN-γ which facilitates induction of HCV specific CD4+Th17 cells. These cells are resistant to suppression by Tregs and may mediate an inflammatory cascade leading to cirrhosis in OLT recipients following HCV recurrence.
authors: Surgery Pathology and Immunology Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors: H I
authors: HI
authors: Basha
authors: V
authors: V
authors: Subramanian
authors: A
authors: A
authors: Seetharam
authors: D S
authors: DS
authors: Nath
authors: S
authors: S
authors: Ramachandran
authors: C D
authors: CD
authors: Anderson
authors: S
authors: S
authors: Shenoy
authors: W C
authors: WC
authors: Chapman
authors: J S
authors: JS
authors: Crippin
authors: T
authors: T
authors: Mohanakumar
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D016174:Hepacivirus; D006526:Hepatitis C / Q000150:complications / Q000601:surgery* / Q000821:virology; D006521:Hepatitis, Chronic / Q000209:etiology / Q000601:surgery; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology* / Q000601:surgery; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009500:Neutralization Tests; D012008:Recurrence; D058504:Th17 Cells / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines