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Interferon-γ-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice

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Interferon-γ-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice. / Ravichandran, Gevitha; Neumann, Katrin; Berkhout, Laura K; Weidemann, Sören; Langeneckert, Annika E; Schwinge, Dorothee; Poch, Tobias; Huber, Samuel; Schiller, Birgit; Hess, Leonard U; Ziegler, Annerose E; Oldhafer, Karl J; Barikbin, Roja; Schramm, Christoph; Altfeld, Marcus; Tiegs, Gisa.

in: J HEPATOL, Jahrgang 71, Nr. 4, 10.2019, S. 773-782.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Ravichandran, G, Neumann, K, Berkhout, LK, Weidemann, S, Langeneckert, AE, Schwinge, D, Poch, T, Huber, S, Schiller, B, Hess, LU, Ziegler, AE, Oldhafer, KJ, Barikbin, R, Schramm, C, Altfeld, M & Tiegs, G 2019, 'Interferon-γ-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice', J HEPATOL, Jg. 71, Nr. 4, S. 773-782. https://doi.org/10.1016/j.jhep.2019.05.023

APA

Ravichandran, G., Neumann, K., Berkhout, L. K., Weidemann, S., Langeneckert, A. E., Schwinge, D., Poch, T., Huber, S., Schiller, B., Hess, L. U., Ziegler, A. E., Oldhafer, K. J., Barikbin, R., Schramm, C., Altfeld, M., & Tiegs, G. (2019). Interferon-γ-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice. J HEPATOL, 71(4), 773-782. https://doi.org/10.1016/j.jhep.2019.05.023

Vancouver

Ravichandran G, Neumann K, Berkhout LK, Weidemann S, Langeneckert AE, Schwinge D et al. Interferon-γ-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice. J HEPATOL. 2019 Okt;71(4):773-782. https://doi.org/10.1016/j.jhep.2019.05.023

Bibtex

@article{cfecefc250594265bf75b536251913a8,
title = "Interferon-γ-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice",
abstract = "BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is an idiopathic, chronic cholestatic liver disorder characterized by biliary inflammation and fibrosis. Increased numbers of intrahepatic interferon-γ- (IFNγ) producing lymphocytes have been documented in patients with PSC, yet their functional role remains to be determined.METHODS: Liver tissue samples were collected from patients with PSC. The contribution of lymphocytes to liver pathology was assessed in Mdr2-/- x Rag1-/- mice, which lack T and B cells, and following depletion of CD90.2+ or natural killer (NK)p46+ cells in Mdr2-/- mice. Liver pathology was also determined in Mdr2-/- x Ifng-/- mice and following anti-IFNγ antibody treatment of Mdr2-/- mice. Immune cell composition was analysed by multi-colour flow cytometry. Liver injury and fibrosis were determined by standard assays.RESULTS: Patients with PSC showed increased IFNγ serum levels and elevated numbers of hepatic CD56bright NK cells. In Mdr2-/- mice, hepatic CD8+ T cells and NK cells were the primary source of IFNγ. Depletion of CD90.2+ cells reduced hepatic Ifng expression, NK cell cytotoxicity and liver injury similar to Mdr2-/- x Rag1-/- mice. Depletion of NK cells resulted in reduced CD8+ T cell cytotoxicity and liver fibrosis. The complete absence of IFNγ in Mdr2-/-x Ifng-/- mice reduced NK cell and CD8+ T cell frequencies expressing the cytotoxic effector molecules granzyme B and TRAIL and prevented liver fibrosis. The antifibrotic effect of IFNγ was also observed upon antibody-dependent neutralisation in Mdr2-/- mice.CONCLUSION: IFNγ changed the phenotype of hepatic CD8+ T cells and NK cells towards increased cytotoxicity and its absence attenuated liver fibrosis in chronic sclerosing cholangitis. Therefore, unravelling the immunopathogenesis of PSC with a particular focus on IFNγ might help to develop novel treatment options.LAY SUMMARY: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and fibrosis, whose current medical treatment is hardly effective. We observed an increased interferon (IFN)-γ response in patients with PSC and in a mouse model of sclerosing cholangitis. IFNγ changed the phenotype of hepatic CD8+ T lymphocytes and NK cells towards increased cytotoxicity, and its absence decreased liver cell death, reduced frequencies of inflammatory macrophages in the liver and attenuated liver fibrosis. Therefore, IFNγ-dependent immune responses may disclose checkpoints for future therapeutic intervention strategies in sclerosing cholangitis.",
author = "Gevitha Ravichandran and Katrin Neumann and Berkhout, {Laura K} and S{\"o}ren Weidemann and Langeneckert, {Annika E} and Dorothee Schwinge and Tobias Poch and Samuel Huber and Birgit Schiller and Hess, {Leonard U} and Ziegler, {Annerose E} and Oldhafer, {Karl J} and Roja Barikbin and Christoph Schramm and Marcus Altfeld and Gisa Tiegs",
note = "Copyright {\textcopyright} 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.",
year = "2019",
month = oct,
doi = "10.1016/j.jhep.2019.05.023",
language = "English",
volume = "71",
pages = "773--782",
journal = "J HEPATOL",
issn = "0168-8278",
publisher = "Elsevier",
number = "4",

}

RIS

TY - JOUR

T1 - Interferon-γ-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice

AU - Ravichandran, Gevitha

AU - Neumann, Katrin

AU - Berkhout, Laura K

AU - Weidemann, Sören

AU - Langeneckert, Annika E

AU - Schwinge, Dorothee

AU - Poch, Tobias

AU - Huber, Samuel

AU - Schiller, Birgit

AU - Hess, Leonard U

AU - Ziegler, Annerose E

AU - Oldhafer, Karl J

AU - Barikbin, Roja

AU - Schramm, Christoph

AU - Altfeld, Marcus

AU - Tiegs, Gisa

N1 - Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

PY - 2019/10

Y1 - 2019/10

N2 - BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is an idiopathic, chronic cholestatic liver disorder characterized by biliary inflammation and fibrosis. Increased numbers of intrahepatic interferon-γ- (IFNγ) producing lymphocytes have been documented in patients with PSC, yet their functional role remains to be determined.METHODS: Liver tissue samples were collected from patients with PSC. The contribution of lymphocytes to liver pathology was assessed in Mdr2-/- x Rag1-/- mice, which lack T and B cells, and following depletion of CD90.2+ or natural killer (NK)p46+ cells in Mdr2-/- mice. Liver pathology was also determined in Mdr2-/- x Ifng-/- mice and following anti-IFNγ antibody treatment of Mdr2-/- mice. Immune cell composition was analysed by multi-colour flow cytometry. Liver injury and fibrosis were determined by standard assays.RESULTS: Patients with PSC showed increased IFNγ serum levels and elevated numbers of hepatic CD56bright NK cells. In Mdr2-/- mice, hepatic CD8+ T cells and NK cells were the primary source of IFNγ. Depletion of CD90.2+ cells reduced hepatic Ifng expression, NK cell cytotoxicity and liver injury similar to Mdr2-/- x Rag1-/- mice. Depletion of NK cells resulted in reduced CD8+ T cell cytotoxicity and liver fibrosis. The complete absence of IFNγ in Mdr2-/-x Ifng-/- mice reduced NK cell and CD8+ T cell frequencies expressing the cytotoxic effector molecules granzyme B and TRAIL and prevented liver fibrosis. The antifibrotic effect of IFNγ was also observed upon antibody-dependent neutralisation in Mdr2-/- mice.CONCLUSION: IFNγ changed the phenotype of hepatic CD8+ T cells and NK cells towards increased cytotoxicity and its absence attenuated liver fibrosis in chronic sclerosing cholangitis. Therefore, unravelling the immunopathogenesis of PSC with a particular focus on IFNγ might help to develop novel treatment options.LAY SUMMARY: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and fibrosis, whose current medical treatment is hardly effective. We observed an increased interferon (IFN)-γ response in patients with PSC and in a mouse model of sclerosing cholangitis. IFNγ changed the phenotype of hepatic CD8+ T lymphocytes and NK cells towards increased cytotoxicity, and its absence decreased liver cell death, reduced frequencies of inflammatory macrophages in the liver and attenuated liver fibrosis. Therefore, IFNγ-dependent immune responses may disclose checkpoints for future therapeutic intervention strategies in sclerosing cholangitis.

AB - BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is an idiopathic, chronic cholestatic liver disorder characterized by biliary inflammation and fibrosis. Increased numbers of intrahepatic interferon-γ- (IFNγ) producing lymphocytes have been documented in patients with PSC, yet their functional role remains to be determined.METHODS: Liver tissue samples were collected from patients with PSC. The contribution of lymphocytes to liver pathology was assessed in Mdr2-/- x Rag1-/- mice, which lack T and B cells, and following depletion of CD90.2+ or natural killer (NK)p46+ cells in Mdr2-/- mice. Liver pathology was also determined in Mdr2-/- x Ifng-/- mice and following anti-IFNγ antibody treatment of Mdr2-/- mice. Immune cell composition was analysed by multi-colour flow cytometry. Liver injury and fibrosis were determined by standard assays.RESULTS: Patients with PSC showed increased IFNγ serum levels and elevated numbers of hepatic CD56bright NK cells. In Mdr2-/- mice, hepatic CD8+ T cells and NK cells were the primary source of IFNγ. Depletion of CD90.2+ cells reduced hepatic Ifng expression, NK cell cytotoxicity and liver injury similar to Mdr2-/- x Rag1-/- mice. Depletion of NK cells resulted in reduced CD8+ T cell cytotoxicity and liver fibrosis. The complete absence of IFNγ in Mdr2-/-x Ifng-/- mice reduced NK cell and CD8+ T cell frequencies expressing the cytotoxic effector molecules granzyme B and TRAIL and prevented liver fibrosis. The antifibrotic effect of IFNγ was also observed upon antibody-dependent neutralisation in Mdr2-/- mice.CONCLUSION: IFNγ changed the phenotype of hepatic CD8+ T cells and NK cells towards increased cytotoxicity and its absence attenuated liver fibrosis in chronic sclerosing cholangitis. Therefore, unravelling the immunopathogenesis of PSC with a particular focus on IFNγ might help to develop novel treatment options.LAY SUMMARY: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and fibrosis, whose current medical treatment is hardly effective. We observed an increased interferon (IFN)-γ response in patients with PSC and in a mouse model of sclerosing cholangitis. IFNγ changed the phenotype of hepatic CD8+ T lymphocytes and NK cells towards increased cytotoxicity, and its absence decreased liver cell death, reduced frequencies of inflammatory macrophages in the liver and attenuated liver fibrosis. Therefore, IFNγ-dependent immune responses may disclose checkpoints for future therapeutic intervention strategies in sclerosing cholangitis.

U2 - 10.1016/j.jhep.2019.05.023

DO - 10.1016/j.jhep.2019.05.023

M3 - SCORING: Journal article

C2 - 31173810

VL - 71

SP - 773

EP - 782

JO - J HEPATOL

JF - J HEPATOL

SN - 0168-8278

IS - 4

ER -