Increased Expression of Inhibitory B7 Family Members Associated with Chronic Hepatitic Necroinflammatory Disease
MW Cruise, R Kassel, TL Pruett, YS Hahn, JC Iezzoni. University of Virginia, Charlottesville; University of Virgina, Charlottesville
Background: Several of the chronic hepatitic diseases are characterized by infiltrating lymphocytes, which are thought to be a key component in the pathophysiology of the disease. Recent data has demonstrated that PBL from patients with HCV and HBV express increased levels of PD-1 and regulation of this pathway may contribute to treatment failure and inability to resolve the infection. The immunomodulatory PD-1 along with its receptors, B7-H1 and B7-DC, induces tolerance and dampens the immune response. However the expression of these proteins within the liver is not well studied. We examined the expression profiles of PD-1 and its ligands to determine the utility of these molecules as markers of clinical disease.
Design: Liver biopsy from 74 patients were examined: HBV(n=11), HCV(n=17), AIH(n=14), NAFLD(n=13), and normal(n=19). Study exclusion criteria included: HIV+, acute HAV, antiviral therapy, cirrhosis, and EtOH abuse. Normal patients demonstrate elevated LFTs with normal histology. Blinded analyses was performed on the biopsies utilizing the Ishak modified HAI and fibrosis score or the NAS system, as appropriate. The biopsies were stained for CD3, PD-1, B7-H1, B7-DC and MHC I and graded by quartiles, reflecting frequency and intensity of expression.
Results: Liver biopsies from patients with HBV, HCV, and AIH demonstrated an increase in intrahepatic PD-1 positive lymphocytes, as compared to NAFLD and normal biopsies. While the PD-1 is expressed on primarily CD3 cells, the PD-1 ligands are expressed on Kupffer cells, LSECs, leukocytes, and hepatocytes. HBV, HCV, and AIH demonstrate increased B7-H1 and B7-DC expression by liver parenchymal cells and leukocytes. The increase is statistically significant and demonstrates a positive correlation with the Ishak scores.
Conclusions: The biopsies demonstrate an increase in the hepatic expression of B7-H1 and B7-DC along with increased numbers of infiltrating PD-1 positive lymphocytes in chronic viral and autoimmune hepatitic diseases. These increases correlate with the level of inflammation and fibrosis across these etiologies, however they do not correlate with damage in NAFLD. These findings document the expression profile of this class of molecules and may suggest a possible target for therapy (humanized antibody recently released for phase I trial) as well as a marker for treatment outcomes.
Category: Liver & Pancreas
Tuesday, March 10, 2009 9:30 AM
Poster Session III # 153, Tuesday Morning