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.
Department of Molecular Preventive Medicine and CREST, School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
M
M
Murai
H
H
Yoneyama
A
A
Harada
Z
Z
Yi
C
C
Vestergaard
B
B
Guo
K
K
Suzuki
H
H
Asakura
K
K
Matsushima
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