TLR9-Mediated Conditioning of Liver Environment Is Essential for Successful Intrahepatic Immunotherapy and Effective Memory Recall.

2.50
Hdl Handle:
http://hdl.handle.net/10033/621120
Title:
TLR9-Mediated Conditioning of Liver Environment Is Essential for Successful Intrahepatic Immunotherapy and Effective Memory Recall.
Authors:
Cebula, Marcin; Riehn, Mathias; Hillebrand, Upneet; Kratzer, Ramona F; Kreppel, Florian; Koutsoumpli, Georgia; Daemen, Toos; Hauser, Hansjörg ( /0000-0002-4418-9859 ) ; Wirth, Dagmar ( 0000-0002-2541-6251 )
Abstract:
Immune defense against hepatotropic viruses such as hepatitis B (HBV) and hepatitis C (HCV) poses a major challenge for therapeutic approaches. Intrahepatic cytotoxic CD8 T cells that are crucial for an immune response against these viruses often become exhausted resulting in chronic infection. We elucidated the T cell response upon therapeutic vaccination in inducible transgenic mouse models in which variable percentages of antigen-expressing hepatocytes can be adjusted, providing mosaic antigen distribution and reflecting the varying viral antigen loads observed in patients. Vaccination-induced endogenous CD8 T cells could eliminate low antigen loads in liver but were functionally impaired if confronted with elevated antigen loads. Strikingly, only by conditioning the liver environment with TLR9 ligand prior and early after peripheral vaccination, successful immunization against high intrahepatic antigen density with its elimination was achieved. Moreover, TLR9 immunomodulation was also indispensable for functional memory recall after high frequency antigen challenge. Together, the results indicate that TLR9-mediated conditioning of liver environment during therapeutic vaccination or antigen reoccurrence is crucial for an efficacious intrahepatic T cell response.
Affiliation:
Helmholtz -Zentrum für Infektionsforschung GmbH. Inhoffenstr. 7, 38124 Braunschweig, Germany.
Citation:
TLR9-Mediated Conditioning of Liver Environment Is Essential for Successful Intrahepatic Immunotherapy and Effective Memory Recall. 2017 Mol. Ther.
Journal:
Molecular therapy : the journal of the American Society of Gene Therapy
Issue Date:
14-Jul-2017
URI:
http://hdl.handle.net/10033/621120
DOI:
10.1016/j.ymthe.2017.06.018
PubMed ID:
28716576
Type:
Article
Language:
en
ISSN:
1525-0024
Appears in Collections:
publications of the research group modell systems for infections and immunity (MSYS); publications of the scientific administration (GFW)

Full metadata record

DC FieldValue Language
dc.contributor.authorCebula, Marcinen
dc.contributor.authorRiehn, Mathiasen
dc.contributor.authorHillebrand, Upneeten
dc.contributor.authorKratzer, Ramona Fen
dc.contributor.authorKreppel, Florianen
dc.contributor.authorKoutsoumpli, Georgiaen
dc.contributor.authorDaemen, Toosen
dc.contributor.authorHauser, Hansjörgen
dc.contributor.authorWirth, Dagmaren
dc.date.accessioned2017-09-25T14:24:23Z-
dc.date.available2017-09-25T14:24:23Z-
dc.date.issued2017-07-14-
dc.identifier.citationTLR9-Mediated Conditioning of Liver Environment Is Essential for Successful Intrahepatic Immunotherapy and Effective Memory Recall. 2017 Mol. Ther.en
dc.identifier.issn1525-0024-
dc.identifier.pmid28716576-
dc.identifier.doi10.1016/j.ymthe.2017.06.018-
dc.identifier.urihttp://hdl.handle.net/10033/621120-
dc.description.abstractImmune defense against hepatotropic viruses such as hepatitis B (HBV) and hepatitis C (HCV) poses a major challenge for therapeutic approaches. Intrahepatic cytotoxic CD8 T cells that are crucial for an immune response against these viruses often become exhausted resulting in chronic infection. We elucidated the T cell response upon therapeutic vaccination in inducible transgenic mouse models in which variable percentages of antigen-expressing hepatocytes can be adjusted, providing mosaic antigen distribution and reflecting the varying viral antigen loads observed in patients. Vaccination-induced endogenous CD8 T cells could eliminate low antigen loads in liver but were functionally impaired if confronted with elevated antigen loads. Strikingly, only by conditioning the liver environment with TLR9 ligand prior and early after peripheral vaccination, successful immunization against high intrahepatic antigen density with its elimination was achieved. Moreover, TLR9 immunomodulation was also indispensable for functional memory recall after high frequency antigen challenge. Together, the results indicate that TLR9-mediated conditioning of liver environment during therapeutic vaccination or antigen reoccurrence is crucial for an efficacious intrahepatic T cell response.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleTLR9-Mediated Conditioning of Liver Environment Is Essential for Successful Intrahepatic Immunotherapy and Effective Memory Recall.en
dc.typeArticleen
dc.contributor.departmentHelmholtz -Zentrum für Infektionsforschung GmbH. Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalMolecular therapy : the journal of the American Society of Gene Therapyen

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