Adoptive transfer of splenic T cells restores the hepatic fibrogenic response to chronic cholestasis in severe combined immunodeficient mice

Abstract

Chronic cholestasis induces significant periportal T cell accumulation and hepatic fibrosis. Given recent experimental studies demonstrating a role for T cells in the initiation of hepatic fibrosis, we hypothesized that T cells were responsible for the development of cholestasis-induced hepatic fibrosis. Male C57Bl/6 wild type (wt) mice, severe combined immunodeficient (SCID) mice which lack mature T and B cells or SCID mice reconstituted with 1x107 wt T cells were subjected to ligation of the common bile duct (BDL) or sham surgery for a period of 14 days after which serum and tissue were collected to determine liver injury and hepatic fibrosis. Wt mice subjected to BDL showed significant increases in serum aspartate aminotransferase (AST) levels (79±14 vs. 1092±426 for sham vs. BDL; p<0.05), periportal CD3+ T cell accumulation and collagen gene expression (5.64-fold increase over sham). SCID mice subjected to BDL showed similar serum AST levels but significant reductions in hepatic collagen gene expression (5.64-fold vs. 2.87-fold for wt vs. SCID respectively). T cell reconstituted SCID mice showed nearly complete restoration of the BDL-induced collagen expression (5.64-fold vs 4.26-fold for wt vs reconstituted SCID respectively) without significantly affecting liver injury. In summary, CD3+ T cells play a significant role in the development of cholestasis-induced hepatic fibrosis. Modulation of the T cell response clinically may prove useful in treating the various forms of cholestatic liver disease. This work was supported by NIAAA grants AA014243 and F32-AA015005.