IN-SITU IMMUNOPHENOTYPING STUDY OF HEPATIC-INFILTRATING CYTOTOXIC-CELLS IN CHRONIC ACTIVE HEPATITIS-C

Objective: Beside the hypothesis of a direct viral cytopathy, several lines of evidence argue in favour of hepatic damage triggered by immun e-mediated mechanisms in hepatitis C virus (HCV) infection. The intrah epatic localization of HCV antigen-specific cytotoxic T-lymphocytes (C TLs) to disease sites has been described; however, very few data are a vailable about the degree and the role of hepatic-infiltrating natural killer (NK) cells in chronically HCV-infected subjects. Design: In a series of percutaneous needle liver biopsies obtained from 35 consecut ive untreated patients with chronic active hepatitis C, we performed a n in-situ immunophenotyping study to evaluate the degree of cytotoxic NK cell infiltration as compared to CTLs, the hepatocyte expression of human major histocompatibility complex antigens class I and class II (HLA-I and HLA-II), and cell adhesion molecules (CAM) in the context o f liver inflammatory infiltrates. The data were correlated with the hi stological activity index (HAI) of disease.Results: In-situ immunophen otyping analysis of CAM provided evidence for the intrahepatic express ion of leucocyte adhesion molecules (CD11a and CD2) and their correspo nding ligands on hepatocytes (CD54 and CD58) in all cases. A significa nt parallel expression of CD11a and CD54 as well as CD2 and CD58 struc tures, restricted to hepatic lobules within the disease sites, was als o observed, even if their induction exhibited different degrees of cor relation with biological and/or histological activities. A membranous pattern of HLA-I and HLA-II antigen expression on hepatocyte clusters was found in all tissue samples, although HLA-I expression was signifi cantly higher than HLA-II. Moreover, lymphocyte subset analysis displa yed a CD8(+) T-cell lobular infiltration within inflammatory and/or sp otty necrosis areas in all cases, while CD4(+) T-cells were confined t o the portal and periportal levels. A few scattered CD56(+) and CD16() NK cells, mainly distributed at periportal areas within inflammatory and/or necrotic foci, were detected in 7/35 (20%) and in 5/35 (14.2%) cases, respectively. On the other hand, CD8(+) T-cell lobular express ion exhibited a linear correlation with HAI (r:0.698, P<0.01). Finally , cytotoxic cell infiltration degree did not correlate with HCV seroty pes. Conclusion: Our findings suggest a limited role for NK cells in t he immune mechanism of liver injury in chronic active hepatitis C, whi le providing further support for the involvement of CD8(+) T-cells at disease sites.