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


Journal Article

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-gamma 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-gamma gene (BNL.IFN-gamma) in vitro, and transplanted intrasplenically into Schistosoma japonicum-infected mice. The amounts and distribution of IFN-gamma (which inhibits collagen synthesis), TGF-beta (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-gamma, an increase of IFN-gamma and decrease of TGF-beta1 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-gamma, 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-beta1 and its receptor TGF-betaRII in the liver of BNL.IFN-gamma-treated mice was also observed. Moreover, the decrease in TGF-beta1 and TGF-betaRII protein approximately paralleled the decrease in their mRNA expression, which was detected by RNA dot blotting. The data indicate that intrasplenic transplantation of IFN-gamma gene-modified hepatocyte can be a candidate approach to treat hepatic fibrosis.

Full Text

Cited Authors

  • Zhang, L; Mi, J; Yu, Y; Yao, H; Chen, H; Li, M; Cao, X

Published Date

  • January 2001

Published In

Volume / Issue

  • 23 / 1

Start / End Page

  • 11 - 17

PubMed ID

  • 11136473

Pubmed Central ID

  • 11136473

Electronic International Standard Serial Number (EISSN)

  • 1365-3024

International Standard Serial Number (ISSN)

  • 0141-9838

Digital Object Identifier (DOI)

  • 10.1046/j.1365-3024.2001.00349.x


  • eng