Active Participation of CCR5(+)CD8(+) T Lymphocytes in the Pathogenesis of Liver Injury in Graft-Versus-Host Disease

J Clin Invest. 1999 Jul;104(1):49-57. doi: 10.1172/JCI6642.

Abstract

We examined the molecular pathogenesis of graft-versus-host disease-associated (GVHD-associated) liver injury in mice, focusing on the role of chemokines. At the second week after cell transfer in the parent-into-F1 model of GVHD, CD8(+) T cells -- especially donor-derived CD8(+) T cells -- infiltrated the liver, causing both portal hepatitis and nonsuppurative destructive cholangitis (NSDC). These migrating cells expressed CCR5. Moreover, macrophage inflammatory protein-1alpha (MIP-1alpha), one of the ligands for CCR5, was selectively expressed on intralobular bile duct epithelial cells, endothelial 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 damage in GVHD. The levels of Fas ligand (FasL) mRNA expression in the liver were also decreased by anti-CCR5 antibody treatment. Anti-MIP-1alpha antibody treatment also reduced liver injury. These results suggest that MIP-1alpha-induced migration of CCR5-expressing CD8(+) T cells into the portal areas 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.

MeSH terms

  • Acute Disease
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • CD8 Antigens / analysis
  • Chemokine CCL3
  • Chemokine CCL4
  • Chemokine CCL5 / biosynthesis
  • Chemokine CCL5 / genetics
  • Chemotaxis, Leukocyte / drug effects*
  • Cholangitis / etiology
  • Cholangitis / immunology
  • Cholangitis / prevention & control
  • Fas Ligand Protein
  • Gene Expression Regulation / drug effects
  • Graft vs Host Disease / complications*
  • Graft vs Host Disease / immunology
  • Graft vs Host Disease / prevention & control
  • Hepatitis, Animal / etiology
  • Hepatitis, Animal / immunology
  • Hepatitis, Animal / prevention & control
  • Liver Diseases / immunology*
  • Liver Diseases / prevention & control
  • Macrophage Inflammatory Proteins / biosynthesis
  • Macrophage Inflammatory Proteins / genetics
  • Membrane Glycoproteins / biosynthesis
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • RNA, Messenger / biosynthesis
  • Radiation Chimera
  • Receptors, CCR5 / analysis
  • Receptors, CCR5 / immunology
  • Receptors, CCR5 / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes, Cytotoxic / immunology*

Substances

  • Antibodies, Monoclonal
  • CD8 Antigens
  • Chemokine CCL3
  • Chemokine CCL4
  • Chemokine CCL5
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Macrophage Inflammatory Proteins
  • Membrane Glycoproteins
  • RNA, Messenger
  • Receptors, CCR5