Active participation of CCR5(+)CD8(+) T lymphocytes in the pathogenesis of liver injury in graft-versus-host disease.
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.
Murai
M
M
Department of Molecular Preventive Medicine and CREST, School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Yoneyama
H
H
Harada
A
A
Yi
Z
Z
Vestergaard
C
C
Guo
B
B
Suzuki
K
K
Asakura
H
H
Matsushima
K
K
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016827:CD8 Antigens / Q000032:analysis; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D002761:Cholangitis / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation / Q000187:drug effects; D006086:Graft vs Host Disease / Q000150:complications* / Q000276:immunology / Q000517:prevention & control; D006520:Hepatitis, Animal / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D008107:Liver Diseases / Q000276:immunology* / Q000517:prevention & control; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000235:genetics; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D012333:RNA, Messenger / Q000096:biosynthesis; D011828:Radiation Chimera; D019713:Receptors, CCR5 / Q000032:analysis / Q000276:immunology / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000911:Antibodies, Monoclonal; D016827:CD8 Antigens; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019713:Receptors, CCR5