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An Inducible Transgenic Mouse Model for Immune Mediated Hepatitis Showing Clearance of Antigen Expressing Hepatocytes by CD8+ T Cells

The liver has the ability to prime immune responses against neo antigens provided upon infections. However, T cell immunity in liver is uniquely modulated by the complex tolerogenic property of this organ that has to also cope with foreign agents such as endotoxins or food antigens. In this respect,...

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Detalles Bibliográficos
Autores principales: Cebula, Marcin, Ochel, Aaron, Hillebrand, Upneet, Pils, Marina C., Schirmbeck, Reinhold, Hauser, Hansjörg, Wirth, Dagmar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711822/
https://www.ncbi.nlm.nih.gov/pubmed/23869228
http://dx.doi.org/10.1371/journal.pone.0068720
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author Cebula, Marcin
Ochel, Aaron
Hillebrand, Upneet
Pils, Marina C.
Schirmbeck, Reinhold
Hauser, Hansjörg
Wirth, Dagmar
author_facet Cebula, Marcin
Ochel, Aaron
Hillebrand, Upneet
Pils, Marina C.
Schirmbeck, Reinhold
Hauser, Hansjörg
Wirth, Dagmar
author_sort Cebula, Marcin
collection PubMed
description The liver has the ability to prime immune responses against neo antigens provided upon infections. However, T cell immunity in liver is uniquely modulated by the complex tolerogenic property of this organ that has to also cope with foreign agents such as endotoxins or food antigens. In this respect, the nature of intrahepatic T cell responses remains to be fully characterized. To gain deeper insight into the mechanisms that regulate the CD8+ T cell responses in the liver, we established a novel OVA_X_CreER(T2) mouse model. Upon tamoxifen administration OVA antigen expression is observed in a fraction of hepatocytes, resulting in a mosaic expression pattern. To elucidate the cross-talk of CD8+ T cells with antigen-expressing hepatocytes, we adoptively transferred K(b)/OVA257-264-specific OT-I T cells to OVA_X_CreER(T2) mice or generated triple transgenic OVA_X CreER(T2)_X_OT-I mice. OT-I T cells become activated in OVA_X_CreER(T2) mice and induce an acute and transient hepatitis accompanied by liver damage. In OVA_X_CreER(T2)_X_OT-I mice, OVA induction triggers an OT-I T cell mediated, fulminant hepatitis resulting in 50% mortality. Surviving mice manifest a long lasting hepatitis, and recover after 9 weeks. In these experimental settings, recovery from hepatitis correlates with a complete loss of OVA expression indicating efficient clearance of the antigen-expressing hepatocytes. Moreover, a relapse of hepatitis can be induced upon re-induction of cured OVA_X_CreER(T2)_X_OT-I mice indicating absence of tolerogenic mechanisms. This pathogen-free, conditional mouse model has the advantage of tamoxifen inducible tissue specific antigen expression that reflects the heterogeneity of viral antigen expression and enables the study of intrahepatic immune responses to both de novo and persistent antigen. It allows following the course of intrahepatic immune responses: initiation, the acute phase and antigen clearance.
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spelling pubmed-37118222013-07-18 An Inducible Transgenic Mouse Model for Immune Mediated Hepatitis Showing Clearance of Antigen Expressing Hepatocytes by CD8+ T Cells Cebula, Marcin Ochel, Aaron Hillebrand, Upneet Pils, Marina C. Schirmbeck, Reinhold Hauser, Hansjörg Wirth, Dagmar PLoS One Research Article The liver has the ability to prime immune responses against neo antigens provided upon infections. However, T cell immunity in liver is uniquely modulated by the complex tolerogenic property of this organ that has to also cope with foreign agents such as endotoxins or food antigens. In this respect, the nature of intrahepatic T cell responses remains to be fully characterized. To gain deeper insight into the mechanisms that regulate the CD8+ T cell responses in the liver, we established a novel OVA_X_CreER(T2) mouse model. Upon tamoxifen administration OVA antigen expression is observed in a fraction of hepatocytes, resulting in a mosaic expression pattern. To elucidate the cross-talk of CD8+ T cells with antigen-expressing hepatocytes, we adoptively transferred K(b)/OVA257-264-specific OT-I T cells to OVA_X_CreER(T2) mice or generated triple transgenic OVA_X CreER(T2)_X_OT-I mice. OT-I T cells become activated in OVA_X_CreER(T2) mice and induce an acute and transient hepatitis accompanied by liver damage. In OVA_X_CreER(T2)_X_OT-I mice, OVA induction triggers an OT-I T cell mediated, fulminant hepatitis resulting in 50% mortality. Surviving mice manifest a long lasting hepatitis, and recover after 9 weeks. In these experimental settings, recovery from hepatitis correlates with a complete loss of OVA expression indicating efficient clearance of the antigen-expressing hepatocytes. Moreover, a relapse of hepatitis can be induced upon re-induction of cured OVA_X_CreER(T2)_X_OT-I mice indicating absence of tolerogenic mechanisms. This pathogen-free, conditional mouse model has the advantage of tamoxifen inducible tissue specific antigen expression that reflects the heterogeneity of viral antigen expression and enables the study of intrahepatic immune responses to both de novo and persistent antigen. It allows following the course of intrahepatic immune responses: initiation, the acute phase and antigen clearance. Public Library of Science 2013-07-15 /pmc/articles/PMC3711822/ /pubmed/23869228 http://dx.doi.org/10.1371/journal.pone.0068720 Text en © 2013 Cebula et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Cebula, Marcin
Ochel, Aaron
Hillebrand, Upneet
Pils, Marina C.
Schirmbeck, Reinhold
Hauser, Hansjörg
Wirth, Dagmar
An Inducible Transgenic Mouse Model for Immune Mediated Hepatitis Showing Clearance of Antigen Expressing Hepatocytes by CD8+ T Cells
title An Inducible Transgenic Mouse Model for Immune Mediated Hepatitis Showing Clearance of Antigen Expressing Hepatocytes by CD8+ T Cells
title_full An Inducible Transgenic Mouse Model for Immune Mediated Hepatitis Showing Clearance of Antigen Expressing Hepatocytes by CD8+ T Cells
title_fullStr An Inducible Transgenic Mouse Model for Immune Mediated Hepatitis Showing Clearance of Antigen Expressing Hepatocytes by CD8+ T Cells
title_full_unstemmed An Inducible Transgenic Mouse Model for Immune Mediated Hepatitis Showing Clearance of Antigen Expressing Hepatocytes by CD8+ T Cells
title_short An Inducible Transgenic Mouse Model for Immune Mediated Hepatitis Showing Clearance of Antigen Expressing Hepatocytes by CD8+ T Cells
title_sort inducible transgenic mouse model for immune mediated hepatitis showing clearance of antigen expressing hepatocytes by cd8+ t cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711822/
https://www.ncbi.nlm.nih.gov/pubmed/23869228
http://dx.doi.org/10.1371/journal.pone.0068720
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