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Impaired Plasmacytoid Dendritic Cell Maturation and Differential Chemotaxis in Chronic HCV: Associations with Antiviral Treatment Outcomes
  1. John Andrew Mengshol, MD, PhD (andy.mengshol{at}uchsc.edu)
  1. University of Colorado Denver School of Medicine, United States
    1. Lucy Golden-Mason, PhD (lucy.golden{at}uchsc.edu)
    1. University of Colorado Denver Department of Medicine Division of Gastroenterology and Hepatology, United States
      1. Nicole Castelblanco (nicole.castelblanco{at}uchsc.edu)
      1. University of Colorado Denver Department of Medicine Division of Gastroenterology and Hepatology, United States
        1. KyungAh Im (im{at}edc.pitt.edu)
        1. Graduate School of Public Health, University of Pittsburgh, United States
          1. Stephanie M Dillon, PhD (stephanie.dillon{at}uchsc.edu)
          1. University of Colorado Denver Department of Medicine Division of Infectious Disease, United States
            1. Cara C Wilson, M D (cara.wilson{at}uchsc.edu)
            1. University of Colorado Denver Department of Medicine Division of Infectious Disease, United States
              1. Hugo R Rosen MD (hugo.rosen{at}uchsc.edu)
              1. University of Colorado Denver Department of Medicine Division of Gastroenterology and Hepatology, United States

                Abstract

                Background: 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.

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

                Methods: We analyzed peripheral DCs of 64 HCV genotype 1-infected patients from the Virahep-C study two 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: Pretreatment frequencies of pDC and mDC were significantly lower in HCV patients than controls and successful therapy normalized pDC. Levels of CXCR3 and CXCR4 on pDC 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 on pDC 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 pDC to CXCL12 and CXCL10 predicted failure of antiviral response and correlated with the HAI inflammation score.

                Conclusions: Plasmacytoid DC defects exist in chronic HCV and successful antiviral therapy normalizes many phenotypic and functional abnormalities.

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