Active participation of CCR5(+)CD8(+) T lymphocytes in the pathogenesis ofliver injury in graft-versus-host disease

We examined the molecular pathogenesis of graft-versus-host disease-associa ted (GVHD-associated) liver injury in mice, focusing on the role of chemoki nes. At the second week after cell transfer in the parent-into-F1 model of GVHD, CD8(+) T cells - especially donor-derived CD8(+) T cells - infiltrate d the liver, causing both portal hepatitis and nonsuppurative destructive c holangitis (NSDC). These migrating cells expressed CCR5. Moreover, macropha ge inflammatory protein-1 alpha (MIP-1 alpha), one of the ligands for CCR5, was selectively expressed an intralobular bile duct epithelial cells, endo thelial cells, and infiltrating macrophages and lymphocytes. Administration of anti-CCR5 antibody dramatically reduced the infiltration of CCR5(+)CD8( +) T lymphocytes into the liver, and consequently protected against liver d amage in GVHD. The levels of Fas ligand (FasL) mRNA expression in the liver were also decreased by anti-CCR5 antibody treatment. Anti-MIP-1 alpha anti body treatment also reduced liver injury. These results suggest that MIP-1 alpha-induced migration of CCR5-expressing CD8(+) T cells into the portal a reas of the liver plays a significant role in causing liver injury in GVHD; thus, CCR5 and its ligand may be the novel target molecules of therapeutic intervention of hepatic GVHD.