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

2.50
Hdl Handle:
http://hdl.handle.net/10033/297227
Title:
An Inducible Transgenic Mouse Model for Immune Mediated Hepatitis Showing Clearance of Antigen Expressing Hepatocytes by CD8+ T Cells.
Authors:
Cebula, Marcin; Ochel, Aaron; Hillebrand, Upneet; Pils, Marina C; Schirmbeck, Reinhold; Hauser, Hansjörg; Wirth, Dagmar
Abstract:
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.
Affiliation:
Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Citation:
An Inducible Transgenic Mouse Model for Immune Mediated Hepatitis Showing Clearance of Antigen Expressing Hepatocytes by CD8+ T Cells. 2013, 8 (7):e68720 PLoS ONE
Journal:
PloS one
Issue Date:
2013
URI:
http://hdl.handle.net/10033/297227
DOI:
10.1371/journal.pone.0068720
PubMed ID:
23869228
Type:
Article
Language:
en
ISSN:
1932-6203
Appears in Collections:
publications of the research group modell systems for infections and immunity (MSYS)

Full metadata record

DC FieldValue Language
dc.contributor.authorCebula, Marcinen_GB
dc.contributor.authorOchel, Aaronen_GB
dc.contributor.authorHillebrand, Upneeten_GB
dc.contributor.authorPils, Marina Cen_GB
dc.contributor.authorSchirmbeck, Reinholden_GB
dc.contributor.authorHauser, Hansjörgen_GB
dc.contributor.authorWirth, Dagmaren_GB
dc.date.accessioned2013-08-01T14:20:49Z-
dc.date.available2013-08-01T14:20:49Z-
dc.date.issued2013-
dc.identifier.citationAn Inducible Transgenic Mouse Model for Immune Mediated Hepatitis Showing Clearance of Antigen Expressing Hepatocytes by CD8+ T Cells. 2013, 8 (7):e68720 PLoS ONEen_GB
dc.identifier.issn1932-6203-
dc.identifier.pmid23869228-
dc.identifier.doi10.1371/journal.pone.0068720-
dc.identifier.urihttp://hdl.handle.net/10033/297227-
dc.description.abstractThe 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.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to PloS oneen_GB
dc.titleAn Inducible Transgenic Mouse Model for Immune Mediated Hepatitis Showing Clearance of Antigen Expressing Hepatocytes by CD8+ T Cells.en
dc.typeArticleen
dc.contributor.departmentModel Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig, Germany.en_GB
dc.identifier.journalPloS oneen_GB

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