The role of FasL and IFNγ in a model of AAV-mediated chronic liver injury in the mouse (39.52)

Abstract

As models of chronic liver injury in the mouse are limited, we have developed such a model in the C57B6 mouse that utilizes Adeno-associated viral vectors (AAV) engineered to express both enhanced Green Fluorescent Protein and the CD8+ epitope SIINFEKL. After injection of this vector directly into the liver, 1x104 SIINFEKL-specific OT-1 cells are administered. Injection of these cells results in an increase in OT-1 cell numbers in the liver until Day 20 correlating with liver damage from Days 10-25. Addition of these cells does not cause decreased vector DNA but significantly decreases vector mRNA expression. To define the mechanisms by which OT-1 cells mediate their effect, we focused on both IFNγ and Fas. In looking at the role of these two molecules, we have found that IFNγ is important in the activation and/or recruitment of the OT-1 cells as IFNγR KO hosts have a significant decrease in the number of OT-1 in the liver at Day 20 compared to their WT controls. The same has been found when comparing WT and Faslpr hosts indicating a role of FasL in the same activation or recruitment processes. FasL has been shown by Suzuki et al to play a role in costimulation in a peptide model, but this phenomenon has not been seen in other viral or vector models1. The role of these two molecules in our AAV model may give clues to the molecular events that occur in other types of hepatitis. Suzuki I JI 2000 Nov 15; 165(10):5537-43. Support: NIH RO1 AI064463