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Intrasplenic transplantation of IL-18 gene-modified hepatocytes: an effective approach to reverse hepatic fibrosis in schistosomiasis through induction of dominant Th1 response

Gene Therapy volume 8, pages 1333–1342 (2001)Cite this article

Abstract

Hepatic fibrosis is a common outcome of chronic liver diseases. In schistosomiasis, chronic parasite egg-induced granuloma formation can lead to fibrosis, which is immunologically characterized by the dominant Th2 response. Recently, it has been shown that gene therapy is an attractive approach for the treatment of hepatic fibrosis. To investigate the antifibrotic effects of IL-18 gene transfer, a normal murine liver cell line BNL.CL2 was transfected with recombinant adenovirus encoding mouse IL-18, and then intrasplenically transplanted into mice infected with Schistosoma japonicum (S. japonicum). Our data show that IL-18 gene-modified hepatocytes intrasplenically transplanted into mice can effectively express IL-18 in the liver and in peripheral blood. Intrasplenic transplantation of IL-18 gene-modified hepatocytes into S. japonicum-infected mice could result in a significantly increased IFN-γ and IL-2 but decreased IL-4 and IL-10 concentration both in the liver and in the serum, suggesting that the dominant Th2 response in mice with schistosomiasis could be reversed by this intervention. Consistent with the changes in Th1 and Th2 cytokine production, mice intrasplenically transplanted with IL-18 gene-modified hepatocytes developed much less hepatic fibrosis at 20 weeks after infection, which was evaluated by liver content of hydroxyproline, collagens, and hepatic mRNA expression of procollagens. These data indicate that intrasplenic transplantation of IL-18 gene-modified hepatocytes can be a candidate for therapeutic intervention in hepatic fibrosis through induction of a dominant Th1 response.

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Acknowledgements

This work was supported by a grant from the National Natural Science Foundation of China (No. 39825123). We thank Dr H Hamada (Department of Molecular Medicine, Sapporo Medical University, Japan) for generously providing recombinant adenovirus encoding LacZ, and Prof H Yu for helpful discussion.

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Authors and Affiliations

  1. Institute of Immunology, Zhejiang University, Hangzhou, P.R. China

    LH Zhang, JP Pan, HP Yao, WJ Sun, DJ Xia, QQ Wang, J Wang & X Cao

  2. Institute of Immunology, Second Military Medical University, Shanghai, P.R. China

    L He & X Cao

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Zhang, L., Pan, J., Yao, H. et al. Intrasplenic transplantation of IL-18 gene-modified hepatocytes: an effective approach to reverse hepatic fibrosis in schistosomiasis through induction of dominant Th1 response. Gene Ther 8, 1333–1342 (2001). https://doi.org/10.1038/sj.gt.3301524

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