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

Cebula, M., Riehn, M., Hillebrand, U., Kratzer, R. F., Kreppel, F., Koutsoumpli, G., Daemen, T., Hauser, H. & Wirth, D., 4-Oct-2017, In : Molecular Therapy. 25, 10, p. 2289-2298 10 p.

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

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DOI

  • Marcin Cebula
  • Mathias Riehn
  • Upneet Hillebrand
  • Ramona F Kratzer
  • Florian Kreppel
  • Georgia Koutsoumpli
  • Toos Daemen
  • Hansjörg Hauser
  • Dagmar Wirth

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.

Original languageEnglish
Pages (from-to)2289-2298
Number of pages10
JournalMolecular Therapy
Volume25
Issue number10
Publication statusPublished - 4-Oct-2017

    Keywords

  • CD8(+) T-CELLS, C VIRUS-INFECTION, IMMUNE-RESPONSES, HEPATITIS-B, THERAPEUTIC VACCINATION, ADENOVIRUS VECTORS, CERVICAL-CANCER, CD8+T CELLS, ANTIGEN, HEPATOCYTES

ID: 46954894