Prevention of intrahepatic metastasis of liver cancer by suicide gene therapy and chemokine ligand 2/monocyte chemoattractant protein-1 delivery in mice.

BACKGROUND: The prognosis of patients with hepatocellular carcinoma (HCC) remains poor, largely as a result of intrahepatic metastasis. Using a mouse model of intrahepatic metastasis, we investigated whether chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) could potentiate the antitumor effects of the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system. METHODS: Mouse hepatoma cells infected with recombinant adenovirus vectors expressing HSV-tk, CCL2/MCP-1 and LacZ at multiplicities of infection of Ad-tk/Ad-MCP1 = 3/0.03 (T/M(Low)), 3/3 (T/M(High)) and Ad-tk/Ad-LacZ = 3/3 (T/L) were injected into BALB/c mice. RESULTS: Intrahepatic tumor growth was significantly lower in T/M(Low) mice. By contrast, no tumor suppression was observed in T/M(High) mice. The tumor-specific cytolytic activities of splenocytes from T/M(Low) and T/M(High) mice were comparable. Immunohistochemical analysis of liver tissues showed similar infiltration by Mac-1(+) and T cells in these animals, whereas the proportions of classical activated (M1) monocytes/macrophages were significantly higher in T/M(Low) mice. In addition, interleukin-12 production was elevated in these tissues. Vascular endothelial growth factor-A expression and CD31(+) microvessels were increased in T/M(High) mice. CONCLUSIONS: Collectively, these results demonstrate that an adequate amount of CCL2/MCP-1, together with the HSV-tk/GCV system, may induce T helper 1-polarized antitumor effects without inducing tumor angiogenesis in the microenvironment of intrahepatic HCC progression.

Autoimmune hepatitis associated with bile duct injury resembling chronic non-suppurative destructive cholangitis.

Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are representative autoimmune liver diseases in which hepatocytes and intrahepatic bile ducts, respectively, are selectively damaged by autoimmune mechanisms. Bile duct injury and loss is characteristic of PBC and chronic non-suppurative destructive cholangitis (CNSDC), in particular, is a histological hallmark of PBC. In this report, we present an unusual case of AIH accompanied by CNSDC-like bile duct injury in a 46-year-old woman. The patient's serum aminotransferase level was abnormally high. The serum levels of alkaline phosphatase, gamma-GTP and IgG were also elevated, but the IgM level was within normal limits. The titer of antismooth muscle antibody (SMA) was 1:80, while antinuclear autoantibody (ANA) and the M2 fraction of antimitochondrial antibody (AMA) were both negative. Liver biopsy disclosed CNSDC-like bile duct injuries and severe interface hepatitis and lobular hepatitis with perivenular zonal necrosis were observed. The aggregate score of the International Autoimmune Hepatitis Group corresponded to the category of probable AIH. Immunohistochemically, histocompatibility leukocyte antigen-DR, which is aberrantly expressed in the damaged bile ducts of PBC, was not found in the injured bile ducts of this case. Laboratory data were much improved by treatment with prednisone, but ursodeoxycholic acid was not effective. Although the possibility of an overlapping syndrome of AIH- and AMA-negative PBC could not be excluded, this case was diagnosed as AIH with CNSDC-like bile duct lesions.