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dc.contributor.authorCebula, Marcin
dc.contributor.authorOchel, Aaron
dc.contributor.authorHillebrand, Upneet
dc.contributor.authorPils, Marina C
dc.contributor.authorSchirmbeck, Reinhold
dc.contributor.authorHauser, Hansjörg
dc.contributor.authorWirth, Dagmar
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.
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
refterms.dateFOA2018-06-13T14:14:30Z
html.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.


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