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TLR9-Mediated Conditioning of Liver Environment Is Essential for Successful Intrahepatic Immunotherapy and Effective Memory Recall.
Cebula, Marcin Riehn, Mathias Hillebrand, Upneet Kratzer, Ramona F Kreppel, Florian Koutsoumpli, Georgia Daemen, Toos Hauser, Hansjoerg Wirth, Dagmar
Cebula, Marcin
Riehn, Mathias
Hillebrand, Upneet
Kratzer, Ramona F
Kreppel, Florian
Koutsoumpli, Georgia
Daemen, Toos
Hauser, Hansjoerg
Wirth, Dagmar
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2017-07-14
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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.
Citation
TLR9-Mediated Conditioning of Liver Environment Is Essential for Successful Intrahepatic Immunotherapy and Effective Memory Recall. 2017 Mol. Ther.
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Article
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en
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ISSN
1525-0024