IFN-γ gene therapy by intrasplenic hepatocyte transplantation: a novel strategy for reversing hepatic fibrosis in Schistosoma japonicum-infected mice.

Liver-targeted gene therapy using hepatocyte as recipient cells has recently been documented to be effective in treatment of numerous hepatic diseases, such as metabolic diseases and liver carcinoma. IFN-γ elicits antipreliferative and antifibrogenic activity in a variety of mesenchymal cells, including hepatic satellite cells. To investigate the antifibrogenic response of liver gene therapy mediated by intrasplenic transplantation of gene-modified hepatocytes, normal mouse liver cell line BNL CL.2 cells were transfected with murine IFN-γ gene (BNL.IFN-γ) in vitro, and transplanted intrasplenically into Schistosoma japonicum-infected mice. The amounts and distribution of IFN-γ (which inhibits collagen synthesis), TGF-β (which stimulates collagen synthesis) and extracellular matrix, including type I and III collagen, were detected. In mice infected with S. japonicum and then treated with BNL.IFN-γ, an increase of IFN-γ and decrease of TGF-β1 were detected at 20 weeks postinfection compared to untreated S. japonicum-infected mice. Immunohistochemical analysis showed that S. japonicum infection induced a marked increase of type I and III collagen synthesis. Whereas, 4 weeks after treatment with BNL.IFN-γ, net synthesis rates of type I and III collagen were markedly decreased in the liver of infected mice. In addition, a decreased expression of TGF-β1 and its receptor TGF-βRII in the liver of BNL.IFN-γ-treated mice was also observed. Moreover, the decrease in TGF-β1 and TGF-βRII protein approximately paralleled the decrease in their mRNA expression, which was detected by RNA dot blotting. The data indicate that intrasplenic transplantation of IFN-γ gene-modified hepatocyte can be a candidate approach to treat hepatic fibrosis. [ABSTRACT FROM AUTHOR]