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

Abstract

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.

TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells

“…We have previously reported that gene modification of Th1 cytokines (e.g., IL-18 and IFN-c) can efficiently induce a T cell response to treat immunological disorders, including cancer and chronic infection. 12,13,39 Moreover, a CEA 576-669 -HSP70L1 fusion protein promotes the secretion of Th1 cytokines (such as IL-12 and IFN-c) and stimulates an anti-tumor cytotoxic T lymphocyte response to a DC vaccine. 40 Thus, certain types of chemotherapy can kill tumor cells through efficient cytotoxic effects while enhancing the induction of an anti-tumor immune response.…”

Intrasplenic transplantation of syngenic hepatocytes modified by IFN-gamma gene ameliorates hepatic fibrosis in rats

“…By contrast, cytokines produced by genetically modified hepatocytes are biologically sound, and, thus, may minimize their adverse effects [lo, 181. Moreover, IFN-y produced by gene transfection has a lower affinity with heparan sulfate and avoids localization of the cytokine [40]. Secondly, the optimal therapeutic effect of IFN-y relies on constant release of the cytokine, but administrated recombinant IFN-y lasts for a short duration only [2S].…”

“…In addition, IFN-y inhibited the transformation of hepatic stellate cells into myofibroblasts, which is primarily responsible for collagen production in fibrotic livers [ 151. Moreover, the inhibitory effects of IFN-y on collagen synthesis are also associated with the downregulating of profibrogenic growth factors, such as TGF-P1 [40].…”

Current concepts in radiation enteritis and implications for future clinical trials

“…When mouse liver cells line were transfected with the IFN-␥ gene in vitro and transplanted into the spleen of SJ-infected mice, TGF-␤1 expression was inhibited markedly in the liver. 106 The synthesis of Type I and III collagen also decreased. Therefore, IFN-␥ is a potential therapeutic agent for the reduction of liver fibrosis.…”

“…Ramos et al 69 Human IPF ELISA, RT-PCR Increased Ziesche et al 70 Human IPF ELISA, RT-PCR Increased, inhibited by IFN-␥ Gauldie et al 72 Rat EPF IH, CGT Increased Querfeld et al 74 Human SS IH, ISH Increased Ihn et al 75 Human SS ELISA, IB Increased, inhibited by TGF-␤ Ab Oh et al 83 Rat DN NB, MLEC Increased, inhibited by TGF-␤ Ab Hong et al 86 Mouse DN IH, ISH, SH Increased Sharma et al 87 Human DN ELISA Increased, inhibited by, captopril Helmich et al 88 Human DN SEI Increased Mezzano et al 90 Human MN IH, ISH Increased Honkanen et al 91 Human MN EIA Increased Diamond et al 92 Rat ON NB, IL Increased Isaka et al 96 Rat ON IH, NB, ISH, AODN transfer Increased, inhibited by TGF-␤ AODN Kaneto et al 97 Human ON IH, RT-PCR Increased Sharma et al 100 Human CAN RT-PCR Increased Cuhaci et al 101 Human CAN IH Increased Qi et al 104 Rat LC NB, AdCAT␤-TR transfection Inhibited by AdCAT␤-TR transfection Ueno et al 105 Rat LC IF, ELISA, AdT␤-ExR Inhibited by AdT␤-ExR injection Zhang et al 106 Rat LC ELISA Increased, inhibited by IFN-␥ gene transfer Bacr et al 107 Human LC NB, IH Increased …”