IFN-gamma 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-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.
Zhang
L
L
Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, PR China.
Mi
J
J
Yu
Y
Y
Yao
H
H
Chen
H
H
Li
M
M
Cao
X
X
D000818:Animals; D003094:Collagen / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D022781:Hepatocytes / Q000637:transplantation*; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012549:Schistosoma japonicum / Q000472:pathogenicity; D012554:Schistosomiasis japonica / Q000150:complications*; D013154:Spleen / Q000601:surgery; D016212:Transforming Growth Factor beta / Q000097:blood; D016042:Transplantation, Heterotopic
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D003094:Collagen