Impaired plasmacytoid dendritic cell maturation and differential chemotaxis in chronic hepatitis C virus: associations with antiviral treatment outcomes.
BACKGROUND
Dendritic cell (DC) defects may contribute to chronicity in hepatitis C virus (HCV) infection and determine response to PEG-interferon and ribavirin therapy via poor T cell stimulation. Studies to date have produced inconsistent results regarding DC maturation and function: no large study has examined DCs before and after therapy.


OBJECTIVE
We examined if DC defects in maturation and chemotaxis are present by comparing therapeutic responders to non-responders.


METHODS
We analysed peripheral DCs of 64 HCV genotype 1-infected patients from the Virahep-C study 2 weeks before and 24 weeks after therapy. We used flow cytometry to enumerate plasmacytoid DC (pDC) and myeloid DCs (mDC) and quantify expression of chemokine receptors and maturation markers. Chemotaxis was measured with an in vitro assay.


RESULTS
Pre-treatment frequencies of pDCs and mDCs were significantly lower in HCV patients than controls and successful therapy normalised pDCs. Levels of CXCR3 and CXCR4 on pDCs were higher at baseline compared to normal controls and decreased with therapy. Pre-therapy levels of co-stimulatory marker CD40 and the maturation marker CD83 were higher in pDCs of patients chronically infected with HCV compared to normal patients, and levels of both markers dropped significantly with therapy in the SVR+ group only. Other maturation markers (CD86 and CCR7) were not elevated suggesting a partially activated phenotype. Baseline chemotaxis of pDCs to CXCL12 and CXCL10 predicted failure of antiviral response and correlated with the histological activity index inflammation score.


CONCLUSIONS
Plasmacytoid DC defects exist in chronic HCV and successful antiviral therapy normalises many phenotypic and functional abnormalities.
Mengshol
J A
JA
Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Denver, Colorado, USA.
Golden-Mason
L
L
Castelblanco
N
N
Im
K A
KA
Dillon
S M
SM
Wilson
C C
CC
Rosen
H R
HR
D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D019707:Receptors, Chemokine / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016896:Treatment Outcome
D000998:Antiviral Agents; D019707:Receptors, Chemokine