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Klinik für Innere Medizin IIGastroenterologie, Hepatologie, Endokrinologie und Infektiologie

The Liver Immunology Lab

Members

Group leaders Phone/Fax*
Prof. Robert Thimme 34040 / 36100
Dr. Maike Hofmann 35090 / 35091

Lab Manager
 
Dr. Ulrike Burk  39110
Özlem Sogukpinar (Dipl. Biol.) 35090

Group members
 
Franziska Daul (PhD Stud.) 35110 / 37250
Kathrin Heim (PhD Stud.) 37580 / 37250
Nina Hensel (PhD Stud.) 37580 / 37250
Sabine Mac Nelly (TA) 35090
Charlotte Rohrer (MD student)  35090
Dr. Catrin Tauber (PhD Stud.) 35110 / 37250
Hildegard Vingerhoet (MTA) 35090
*Dial +49-761-270-34040

Research Topics

Innate and adaptive immunity in viral hepatitis and hepatocellular carcinoma

T cell responses play an important role in the outcome of hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus and hepatitis E virus (HEV) infection, e.g. viral elimination versus persistence. However, multiple mechanisms can lead to the failure of the virus-specific T cell response. These mechanisms include primary T cell failure, T cell exhaustion, the emergence of viral escape mutants, as well as T cell dysfunction. Furthermore, genetic factors such as the individual HLA allele background play an important role in the outcome of infection. Once viral persistence has been established, HBV or HCV infection can progress to liver fibrosis and cirrhosis with an enhanced risk for HCC. Tumor-specific T cells are thought to contribute to cancer control.

The focus of our group is the identification and characterization of virus-specific CD4+ and CD8+ T cell responses during acute and chronic HBV, HCV, HDV and HEV infection and the analysis of adaptive and innate immune responses against cancer. A specific focus is on the identification of the molecular determinants of T cell exhaustion and how this can be reversed in the setting of chronic viral infection and cancer. Indeed, in own previous work we could recently show that antigen-specific CD8+ T cells are heterogenous consisting of memory-like and terminally exhausted cells and that removal of antigen, for example by direct acting antiviral therapy leads to a disappearance of highly exhausted, but maintenance of a memory-like CD8+ T cell population. This memory-like population is characterized by specific phenotypical functional metabolic and transcriptional characteristics. On the CD4+ T cell level, we are interested in the lineage commitment of virus-specific CD4 helper T cells in different phases of viral hepatitis. Overall, these translational studies should give novel targets for immune therapy and help to identify biomarkers for prediction of response of different antiviral or immunotherapeutic therapies, such as checkpoint blockade. Another focus in our group is the analysis of innate immune responses in viral hepatitis and cancer with a specific focus on NK cells and gamma delta T cells. For example, we could recently show the expansion of adaptive/memory-like NK cells in chronic HBV virus infection. A further detailed understanding of the biological role of these innate subsets and their interaction with adaptive immune responses will be essential for the development of novel immunotherapeutic approaches.

Methodology

  • Cell culture
  • Immuno spot assays (e.g. FACS, ELISpot)
  • Molecular assays (e.g. RNA seq, single cell analyses)

We currently co-operate with the groups of

  • Prof. Dr. D. Zehn, München (School of Life Sciences Weihenstephan)
  • Prof. Dr. H. Pircher, Freiburg (Institute of Immunology)
  • Dr. Paul Klenerman, Oxford (Nuffield Department of Medicine)
  • Dr. Volker Lohmann and Prof. Dr. Ralf Bartenschlager, Heidelberg (Institute of Molecular Virology)
  • Prof. Dr. Thomas Baumert, Strassbourg (INSERM Strassbourg)
  • Dr. David Price, Cardiff (School of Medicine)
  • Dr. Dominic Grün, Freiburg (Max-Planck-Institute of Immunobiology and Epigenetics)
  • Prof. Dr. Jörg Timm, Düsseldorf (Institute for Virology)
  • E. John Wherry, PhD, University of Pennsylvania (Penn Institute for Immunology)
  • Naveed Ishaque, Heidelberg (Heidelberg Center for Personalized Oncology at the German Research Center) and Christian Conrad, Heidelberg (Alfred-Weber-Institute for Economics)
  • Manching Ku, Freiburg (Clinic for Pediatric Hematology & Oncology) and Melanie Börries, Freiburg (Institute for Molecular Medicine)

Our studies are currently sponsored by:

  • Sonderforschungsbereich-TRR179 (Deutsche Forschungsgemeinschaft, DFG)
  • Sonderforschungsbereich 1160: IMPATH (Deutsche Forschungsgemeinschaft, DFG)
  • Else Kröner-Fresenius-Stiftung: MOTI-VATE
  • Europäische Union: Horizon 2020: HEP-CAR
  • Deutsches Zentrum für Infektionsforschung DZIF (BMBF)

Selected Publications

  1. Schuch A, Salimi Alizei E, Heim K, Wieland D, Kiraithe MM, Kemming J, Llewellyn-Lacey S, Sogukpinar Ö, Ni Y, Urban S, Zimmermann P, Nassal M, Emmerich F, Price DA, Bengsch B, Luxenburger H, Neumann-Haefelin C, Hofmann M, Thimme R. Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load. Gut. 2019 May;68(5):905-915
  2. Wieland D, Kemming J, Schuch A, Emmerich F, Knolle P, Neumann-Haefelin C, Held W, Zehn D, Hofmann M, Thimme R. TCF1(+) hepatitis C virus-specific CD8(+) T cells are maintained after cessation of chronic antigen stimulation. Nat Commun. 2017; May 3;8:15050
  3. Utzschneider DT, Charmoy M, Chennupati V, Pousse L, Ferreira DP, Calderon-Copete S, Danilo M, Alfei F, Hofmann M, Wieland D, Pradervand S, Thimme R, Zehn D, Held W. T Cell Factor 1-Expressing Memory-like CD8(+) T Cells Sustain the Immune Response to Chronic Viral Infections. Immunity. 2016; 45(2):415-27
  4. Hoh A, Heeg M, Ni Y, Schuch A, Binder B, Hennecke N, Blum HE, Nassal M, Protzer U, Hofmann M, Urban S, Thimme R. Hepatitis B Virus-Infected HepG2hNTCP Cells Serve as a Novel Immunological Tool To Analyze the Antiviral Efficacy of CD8+ T Cells In Vitro. J Virol. 2015; 89(14):7433-8
  5. Martin B, Hennecke N, Lohmann V, Kayser A, Neumann-Haefelin C, Kukolj G, Böcher WO, Thimme R. Restoration of HCV-specific CD8+ T cell function by interferon-free therapy. J Hepatol. 2014; 61(3):538-43
  6. Seigel B, Bengsch B, Lohmann V, Blum HE, Thimme R. Factors that determine the antiviral efficacy of HCV-specific CD8+ T cells, ex vivo. Gastroenterology 2013, 144:426-36
  7. Schmidt J, Iversen A, Tenzer, Gosticke, Priced, Lohmann V, Distler U, Bowness P, Schild, Blum HE, Klenerman P, Neumann-Haefelin C., Thimme R. Rapid antigen processing and presentation of a protective and immunodominant HLA-B*27-restricted Hepatitis C virus-specific CD8+ T-cell epitope. PLoS Pathog 2012, 8:e1003042
  8. Bengsch B, Seigel B, Flecken T, Wolanski J, Blum HE, Thimme R. Human Th17 cells express high levels of enzymatically active Dipeptidylpeptidase IV (CD26). J Immunol 2012, 188:5438-47
  9. Billerbeck E, Kang YH, Walker L, Lockstone H, Grafmueller S, Fleming V, Flint J, Willberg CB, Bengsch B, Seigel B, Ramamurthy N, Zitzmann N, Barnes EJ, Thevanayagam J, Bhagwanani A, Leslie A, Oo YH, Kollnberger S, Bowness P, Drognitz O, Adams DH, Blum HE, Thimme R*, Klenerman P*. (equal contribution) Analysis of CD161 expression on human CD8+ T cells defines a distinct functional subset with tissue-homing properties. Proc Natl Acad Sci U S A. 2010, 107:3006-11
  10. Neumann-Haefelin C, Timm J, Schmidt J, Kersting N, Fitzmaurice K, Oniangue-Ndza C, Kemper MN, Humphreys I, McKiernan S, Kelleher D, Lohmann V, Bowness P, Huzly D, Rosen HR, Kim AY, Lauer GM, Allen TM, Barnes E, Roggendorf M, Blum HE, Thimme R. Protective effect of human leukocyte antigen B27 in hepatitis C virus infection requires the presence of a genotype-specific immunodominant CD8+ T-cell epitope. Hepatology 2010, 51:54-62
  11. Jo J, Aichele U, Kersting N, Klein R, Aichele P, Bisse E, Sewell AK, Blum HE, Bartenschlager R, Lohmann V, Thimme R. Analysis of CD8+ T cell-mediated inhibition of hepatitis C virus replication using a novel immunological model. Gastroenterology2009, 136:1391-401
  12. Neumann-Haefelin C, Timm J, Spangenberg HC, Wischnowski N, Nazarova N, Kersting N, Roggendorf M, Allen TM, Blum HE, Thimme R. Virological and immunological determinants of intrahepatic virus-specific CD8+ T cell failure in chronic hepatitis C virus infection. Hepatology 2008, 47:1824-36
  13. Boettler T, Panther E, Bengsch B, Nazarova N, Spangenberg HC, Blum HE, Thimme R. Expression of the interleukin 7 receptor alpha chain on virus-specific CD8+ T cells identifies functionally and phenotypically defined memory T cells in acute resolving hepatitis B virus infection. J Virol 2006, 80:3532-40

Gastroenterologie, Hepatologie,
Endokrinologie und Infektiologie
Hugstetter Straße 55
79106 Freiburg
Info Medizin: 0761 270-34010
 

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Prof. Dr. Robert Thimme

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