Why do some people recover spontaneously after therapy disruption?

What is this research project about?

What is this research project about?

Hepatitis B virus (HBV) is a global clinical challenge. Worldwide more than 250 million people are chronically infected with HBV with 650.000 HBV-related deaths annually. Current treatment options for chronic hepatitis B in industrialized countries are PEG-IFNα or nucleos(t)id-analoga (NA). The therapy with NA can suppress viral replication very efficiently. However, only in a small percentage of patients (less than 1% per year), loss of HBsAg (functional cure of HBV) occurs.

What’s the current status?

NA-treated patients are still at risk of developing liver cirrhosis, liver failure or hepatocellular carcinoma (HCC), since NA therapy only inhibits the generation of new hepatitis B virions, but does not affect the generation of HBsAg and subviral particles. Also, NA therapy does not affect the covalently closed circular HBV DNA (cccDNA), the template of HBV. Therefore, new strategies to induce HBsAg loss are needed.

In previous clinical studies, Cornberg/Kraft proposed a strategy to induce hepatic flares by stopping or interrupting NA therapy. They could show that stop of NA treatment in HBeAg- negative patients is safe and can result in decline of HBsAg levels or even in loss of HBsAg in up to 20 % of the patients. So far, it is still not completely clear, which mechanisms are involved in the increased functional cure in patients with NA treatment interruption. To this end, we have initiated a second prospective study (Terminator 2 study) in order to recruit more patients who will stop long-term NA therapy.

What are the project goals?

The aim of this project is to investigate T cell responses in detail before, during, and after NA treatment interruption. Besides αβ T cells we will also focus on γδ T cells. We also want to identify biomarkers to predict outcome of NA treatment termination. And we want to correlate HBV-specific T cell phenotype, function and TCR repertoire to outcome of NA therapy termination (endpoint HBsAg loss at 4 year after treatment termination).

How do we get there?

The project builds on collecting samples from patients enrolled in the Terminator 2 study. Preliminary results showed that γδ T cell numbers are elevated in HBV patients as compared to healthy controls. So far, nothing is known about the phenotype, TCR repertoire, and antiviral potential of γδ T cells in hepatitis B. While it is known that HBV- specific αβ T cell responses are important for control and clearance of HBV, we hypothesize that γδ T cell responses are also critical for patients which cleared the infection after stop of NA treatment. To monitor T cell responses in the course of infections, we have established NGS technologies that provide comprehensive access to complex antigen receptor repertoires.

This project comprises phenotypical, functional and T cell receptor (TCR) analyses of blood-derived αβ and γδ T cells. Specifically, phenotypical and functional HBV-core specific CD4 and CD8 T cell responses will be analyzed in HLA-typed patients using 16 parameter flow cytometry (e.g. HLA-DRB1 for CD4 and HLA-A2+ for CD8). In parallel we will analyze the TCR repertoire of the dominant CD8 and CD4 T cell responses after FACS-sorting.

To determine and investigate the role of γδ T cells in the Terminator 2 study patient cohort, we use multiplex NGS γδ TCR analyses. In particular, we have set up a pipeline to investigate γδ TCR repertoires by RNA-based multiplex PCR amplicon sequencing and αβ TCR repertoires by RNA-based 5’-RACE PCR amplicon sequencing.

Projectleaders

Project title: Receptor repertoire analysis of HBV-specific T cells and γδ T cells in HBeAg negative patients with chronic hepatitis B after stopping nucleos(t)ide analogue therapy

Prof. Dr. Markus Cornberg

Projekte: B8, B9, B10

 
  Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover
  Carl-Neuberg-Str. 1
30625 Hannover
 
 
 
  Cornberg.Markus
@mh-hannover.de
  DOWNLOAD CV

Prof. Dr. Immo Prinz

Projekte: B5, B8, B9

 
  Institut für Immunologie , Medizinische Hochschule Hannover
  Carl-Neuberg-Str. 1
30625 Hannover
  +49 511 532-9739
  +49 511 532-9722
 
  Prinz.Immo
@mh-hannover.de
  DOWNLOAD CV

Hepatitis E Virus (HEV)-Specific T Cell Receptor Cross-Recognition: Implications for Immunotherapy. Soon CF, Zhang S, Suneetha PV, Antunes DA, Manns MP, Raha S, Schultze-Florey C, Prinz I, Wedemeyer H, Sällberg Chen M, Cornberg M. Front Immunol. 2019 Sep 4;10:2076. doi: 10.3389/fimmu.2019.02076. eCollection 2019.

Hepatitis E virus (HEV)-specific T cell receptor cross-recognition: Implications for immunotherapy. Chai Fen Soon, Shihong Zhang, Pothakamuri Venkata Suneetha, Dinler A. Amaral Antunes, Michael P. Manns, Solaiman Raha, Christian Schultze-Florey, Immo Prinz, Heiner Wedemeyer, Margaret Sallberg Chen and Markus Cornberg.  2019 Front Immunol., doi: 10.3389/fimmu.2019.02076

Single-Cell Transcriptomics Identifies the Adaptation of Scart1(+) Vγ6(+) T Cells to Skin Residency as Activated Effector Cells. Tan L, Sandrock I, Odak I, Aizenbud Y, Wilharm A, Barros-Martins J, Tabib Y, Borchers A, Amado T, Gangoda L, Herold MJ, Schmidt-Supprian M, Kisielow J, Silva-Santos B, Koenecke C, Hovav AH, Krebs C, Prinz I*, Ravens S*. Cell Rep. 2019 Jun 18;27(12):3657-3671.e4.

Project B8
Publications