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

Liver-targeted gene therapy using hepatocyte a 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 antiprel iferative and antifibrogenic activity in a variety of mesenchymal cells, in cluding hepatic satellite cells. To investigate the antifibrogenic response of liver gene therapy mediated by intrasplenic transplantation of gene-mod ified hepatocytes, normal mouse liver cell line BNL CL2 cells were transfec ted with murine IFN-gamma gene (BNL-IFN-gamma) in vitro, and transplanted i ntrasplenically into Schistosoma japonicum-infected mice. The amounts and d istribution of IFN-gamma (which inhibits collagen synthesis), TGF-beta (whi ch stimulates collagen synthesis) and extracellular matrix, including type I and III collagen, were detected. In the mice infected with S. japonicum a nd then treated wit BNL.IFN-gamma, an increase of IFN-gamma and decrease of TGF-beta (1) were detected at 20 weeks post-infection compared to untreate d S. japonicum-infected mice. Immunohistochemical analysis showed that S. j aponicum infection indued a marked increase of type I and III collagen synt hesis Whereas, 4 weeks after treatment with BNL-IFN-gamma, net synthesis ra tes of type I and II collagen were markedly decreased in the liver of infec ted mice. In addition, a decreased expression of TGF-beta (1) and its recep tor TGF-beta RII in the liver of BNL.IFN-gamma -treated mice was also obser ved. Moreover, the decrease in TGF-beta (1) and TGF-beta RII protein approx imately paralleled the decrease in their mRNA expression, which was detecte d 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.