Article first published online: 26 JUN 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 2, pages 586–596, August 2011
How to Cite
Bansal, R., Prakash, J., Post, E., Beljaars, L., Schuppan, D. and Poelstra, K. (2011), Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice. Hepatology, 54: 586–596. doi: 10.1002/hep.24395
Potential conflict of interest: Dr. Poelstra owns stock in, is a consultant for, and received grants from Biorion Technology. Dr. Schuppan advises and received grants from Gilead and Pfizer. He also advises Takeda, Sanofi-Adventis, Stromedix, and GlaxoSmithKline.
Supported by VICI grant-in-aid from Netherlands Organization for Scientific Research (NWO) and the Technical foundation (STW).
- Issue published online: 25 JUL 2011
- Article first published online: 26 JUN 2011
- Accepted manuscript online: 29 APR 2011 11:10AM EST
- Manuscript Accepted: 19 APR 2011
- Manuscript Received: 9 FEB 2011
Liver fibrogenesis is a process tightly controlled by endogenous anti- and pro-fibrogenic factors. Interferon gamma (IFNγ) is a potent antifibrogenic cytokine in vitro and might therefore represent a powerful therapeutic entity. However, its poor pharmacokinetics and adverse effects, due to the presence of IFNγ receptors on nearly all cells, prevented its clinical application so far. We hypothesized that delivery of IFNγ specifically to the disease-inducing cells and concurrently avoiding its binding to nontarget cells might increase therapeutic efficacy and avoid side effects. We conjugated IFNγ to a cyclic peptide recognizing the platelet-derived growth factor beta receptor (PDGFβR) which is strongly up-regulated on activated hepatic stellate cells (HSC), the key effector cells responsible for hepatic fibrogenesis. The IFNγ conjugates were analyzed in vitro for PDGFβR-specific binding and biological effects and in vivo in acute (early) and chronic (progressive and established) carbon-tetrachloride-induced liver fibrosis in mice. The targeted-IFNγ construct showed PDGFβR-specific binding to fibroblasts and HSC and inhibited their activation in vitro. In vivo, the targeted-IFNγ construct attenuated local HSC activation in an acute liver injury model. In the established liver fibrosis model, it not only strongly inhibited fibrogenesis but also induced fibrolysis. In contrast, nontargeted IFNγ was ineffective in both models. Moreover, in contrast to unmodified IFNγ, our engineered targeted-IFNγ did not induce IFNγ-related side effects such as systemic inflammation, hyperthermia, elevated plasma triglyceride levels, and neurotropic effects. Conclusion: This study presents a novel HSC-targeted engineered-IFNγ, which in contrast to systemic IFNγ, blocked liver fibrogenesis and is devoid of side effects, by specifically acting on the key pathogenic cells within the liver. (HEPATOLOGY 2011;)