Z Gastroenterol 2018; 56(01): E2-E89
DOI: 10.1055/s-0037-1612843
Poster Visit Session V Viral Hepatitis and Immunology – Saturday, January 27, 2018, 11:00am – 11:45am, Foyer area East Wing
Georg Thieme Verlag KG Stuttgart · New York

Hepatitis B virus-specific T cell receptors with high functional redirect T cells to eliminate HBV

J Kah
1   University Medical Center Hamburg-Eppendorf, I. Medical Department, Center for Internal Medicine, Hamburg
,
K Wisskirchen
2   Technische Universität München/Helmholtz Zentrum München, Institute of Virology, München
,
A Malo
2   Technische Universität München/Helmholtz Zentrum München, Institute of Virology, München
,
K Metzger
2   Technische Universität München/Helmholtz Zentrum München, Institute of Virology, München
,
L Allweiss
1   University Medical Center Hamburg-Eppendorf, I. Medical Department, Center for Internal Medicine, Hamburg
,
L Weigand
3   Technische Universität München, Klinikum Rechts der Isar, III. Medical Clinic, München
,
M Schiemann
4   Technische Universität München, Institute for Medical Microbiology, Immunology and Hygiene, München
,
T Volz
1   University Medical Center Hamburg-Eppendorf, I. Medical Department, Center for Internal Medicine, Hamburg
,
A Krackhardt
3   Technische Universität München, Klinikum Rechts der Isar, III. Medical Clinic, München
,
M Dandri
1   University Medical Center Hamburg-Eppendorf, I. Medical Department, Center for Internal Medicine, Hamburg
5   German Center for Infection Research, Hamburg-Lübeck-Borstel Partner Site
,
U Protzer
5   German Center for Infection Research, Hamburg-Lübeck-Borstel Partner Site
2   Technische Universität München/Helmholtz Zentrum München, Institute of Virology, München
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2018 (online)

 
 

    Adoptive T-cell therapy of chronic hepatitis B or hepatitis B virus (HBV)-induced hepatocellular carcinoma intends to restore antiviral T-cell immunity to clear the infection or control tumor growth. Question: to identify T-cell receptors (TCR) with high functional avidity to redirect T cells and to test their potential to cure HBV infection in vitro and in vivo. We isolated a series of HLA-A*02 restricted TCRs specific for HBV S or core protein derived peptides from patients with acute and resolved HBV infection. Primary human T cells were genetically modified by retroviral transduction to express these HBV-specific TCRs. One S20- and one C18-specific TCR each with high functional avidity were selected for further analysis. Upon TCR grafting, CD8 as well as CD4 T cells became polyfunctional HBV-specific effector T cells recognizing even picomolar concentrations of cognate peptide. TCR-grafted T cells secreted IFN gamma, TNF alpha and interleukin-2, controlled HBV replication and effectively killed hepatoma cells with an integrated HBV genome as well as HBV-infected cells. Notably, these HBV-specific TCRs recognized peptide of different HBV genotypes and presented on different HLA-A*02 subtypes common in areas with high HBV prevalence.When co-cultured with HBV-infected HepaRG or HepG2-NTCP cells, TCR-transduced T cells stopped viral replication, killed approximately 80% of plated cells and eliminated viral antigens as well as cccDNA from the cell culture. Importantly, TCRs also mediated elimination of HBV when expressed on CD4 T cells or on T cells from patients with chronic hepatitis B. In vivo, TCR-redirected T cells targeted the liver when transferred into HBV-infected uPA-SCID/beige/IL2rg-/- (USG) mice repopulated with HLA-A*02-matched primary human hepatocytes. After 5 days, alanine amino transferase levels were moderately increased. Subsequently, viremia decreased more than 4 – 5 log and HBsAg as well as HBeAg dropped to the level of detection. Intrahepatic analysis after three weeks revealed strong reduction of cccDNA loads (> 95%), and HBcAg staining in the liver had become negative. HBV rebound was not observed till the end of the experiment.

    Our experiments indicate that T cells stably transduced with TCRs of high functional avidity allow adoptive T-cell therapy of chronic hepatitis B and HBV-induced hepatocellular carcinoma, because they have a remarkable cytotoxic potential and may mediate clearance of the virus.Moreover, HBV-specific TCRs represent an interesting tool for elucidating mechanisms of TCR-MHC interaction and dissecting specific anti-HBV mechanisms exerted by T cells.


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