Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice

Ruchi Bansal*, Jai Prakash, Eduard Post, Leonie Beljaars, Detlef Schuppan, Klaas Poelstra

*Corresponding author for this work

Research output: Contribution to journalReview articleAcademicpeer-review

56 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)586-596
Number of pages11
JournalHepatology
Volume54
Issue number2
DOIs
Publication statusPublished - 1 Aug 2011
Externally publishedYes

Fingerprint

Interferon-gamma
Liver
Hepatic Stellate Cells
Platelet-Derived Growth Factor beta Receptor
Liver Cirrhosis
Cyclic Peptides
Carbon Tetrachloride
Hepatocytes
Triglycerides
Fever
Pharmacokinetics
Fibroblasts
Cytokines
Inflammation
Wounds and Injuries

Cite this

Bansal, R., Prakash, J., Post, E., Beljaars, L., Schuppan, D., & Poelstra, K. (2011). Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice. Hepatology, 54(2), 586-596. https://doi.org/10.1002/hep.24395
Bansal, Ruchi ; Prakash, Jai ; Post, Eduard ; Beljaars, Leonie ; Schuppan, Detlef ; Poelstra, Klaas. / Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice. In: Hepatology. 2011 ; Vol. 54, No. 2. pp. 586-596.
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Bansal, R, Prakash, J, Post, E, Beljaars, L, Schuppan, D & Poelstra, K 2011, 'Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice', Hepatology, vol. 54, no. 2, pp. 586-596. https://doi.org/10.1002/hep.24395

Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice. / Bansal, Ruchi; Prakash, Jai; Post, Eduard; Beljaars, Leonie; Schuppan, Detlef; Poelstra, Klaas.

In: Hepatology, Vol. 54, No. 2, 01.08.2011, p. 586-596.

Research output: Contribution to journalReview articleAcademicpeer-review

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T1 - Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice

AU - Bansal, Ruchi

AU - Prakash, Jai

AU - Post, Eduard

AU - Beljaars, Leonie

AU - Schuppan, Detlef

AU - Poelstra, Klaas

PY - 2011/8/1

Y1 - 2011/8/1

N2 - 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.

AB - 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.

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Bansal R, Prakash J, Post E, Beljaars L, Schuppan D, Poelstra K. Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice. Hepatology. 2011 Aug 1;54(2):586-596. https://doi.org/10.1002/hep.24395