Active participation of CCR5+CD8+ T lymphocytes in the pathogenesis of liver injury in graft-versus-host disease
Masako Murai, … , Hitoshi Asakura, Kouji Matsushima
Masako Murai, … , Hitoshi Asakura, Kouji Matsushima
Published July 1, 1999
Citation Information: J Clin Invest. 1999;104(1):49-57. https://doi.org/10.1172/JCI6642.
View: Text | PDF
Article

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

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-1α (MIP-1α), 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-1α antibody treatment also reduced liver injury. These results suggest that MIP-1α–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.

Authors

Masako Murai, Hiroyuki Yoneyama, Akihisa Harada, Zhang Yi, Christian Vestergaard, Baoyu Guo, Kenji Suzuki, Hitoshi Asakura, Kouji Matsushima

×

Figure 5

Options: View larger image (or click on image) Download as PowerPoint
(a) Kinetics of MIP-1α, MIP-1β, and RANTES mRNA expression in the liver....
(a) Kinetics of MIP-1α, MIP-1β, and RANTES mRNA expression in the liver. Total RNA was isolated from liver tissues of untreated and GVHD-induced mice during the second week after induction. RT-PCR cDNA products were generated and amplified using oligonucleotide primers specific to MIP-1α, MIP-1β, RANTES, or the housekeeping gene GAPDH. (b) The amount of MIP-1α was normalized to the level of GAPDH at each time point. Each normalized MIP-1α value of untreated liver was designated as the calibrator, and final relative quantity of mRNA was expressed relative to the calibrator. PCR was performed in triplicate for each experiment. (c) Effect of anti–MIP-1α antibody on intrahepatic infiltration of mononuclear cells. The number of CD4+ (dotted bars) and CD8+ (filled bars) cells was determined by multiplying the total leukocyte number (open bars) by the fraction of CD4+ and CD8+ cells. Liver-infiltrating leukocytes were prepared from untreated mice and GVHD-induced mice treated with either control antibody or anti–MIP-1α antibody. (d) Effect of anti–MIP-1α on serum ALT levels. Shown are serum ALT levels of untreated mice and GVHD-induced mice treated with either control antibody or anti–MIP-1α antibody, at the second week after induction. The data represent the mean ± SD of 6 mice. Graph is representative of results obtained from 3 independent experiments. *P < 0.05.