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Group of Robert Thimme

Members:

*Dial +49-761-270-33970

Research Topics

• T cell response in hepatitis B virus (HBV) infection
• T cell response in hepatitis C virus (HCV) infection
• T cell response in hepatocellular carcinoma (HCC)
• Regulatory T cells (CD4+CD25+ T cells)
• T cell differentiation and phenotype
• Influence of HLA alleles in the outcome of human viral infections

T cell responses play an important role in the outcome of HBV and HCV 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 (e.g. AFP-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 and HCV infection with a special focus on intrahepatic T cell responses as well as the mechanisms of viral persistence (e.g., viral escape, T cell dysfunction, action of regulatory T cells, role of HLA alleles). Furthermore, we study AFP-specific T cell responses in patients with HCC.

We currently co-operate with the groups of

- Prof. Dr. H. Pircher, Freiburg (Institute of Immunology)

- Dr. Paul Klenerman, Oxford (Nuffield Department of Medicine)

- Prof. Dr. F. V. Chisari, La Jolla (Scripps Research Institute)

- Dr. Volker Lohmann and Prof. Dr. Ralf Bartenschlager, Heidelberg (Institute of Molecular Virology)

- Dr. Jörg Timm, Dr. Sergei Viazov, and Prof. Dr. Michael Roggendorf, Essen (Institute of Virology)

- Dr. Susan McKiernan and Prof. Dr. Dermot Kelleher, Dublin (St. James Hospital)

- Dr. Barbara Rehermann, Bethlesda (NIH)

- Dr. Lukas Weseslindtner and Prof. Dr. Heidemarie Holzmann, Vienna (Institute of Virology)

- Prof. Dr. Thomas Baumert, Strassbourg (INSERM Strassbourg)

- PD Dr. Georg Kochs, Freiburg (Institute of Virology)

- Dr. Arash Grakoui, Atlanta (Emory University) 

- Dr. Todd M. Allen, Boston

- Dr. Astrid Iversen, Oxford

- Dr. Andrew Sewell, Cardiff University School of Medicine, UK

- Dr. David Price, Cardiff University School of Medicine, UK

Our studies are currently sponsored by

- Heisenberg-Professur der DFG

- SFB 620

- DFG Forschergruppe 1202 „Mechanisms of persistence of hepatotropic viruses“

- Graduiertenschule der DFG (Spemann Graduate School of Biology and Medicine)

- Kompetenznetz Hepatitis (HepNet)

- NIH AIDS Reagent Program

- BMBF 

- Hepato-Regio-Net

- Centre of Chronic Immunodeficiency (CCI) Freiburg

Selected Publications

1. Klenerman P, Thimme R (2011) T cell responses in hepatitis C: the good, the bad and the unconventional. Gut. Epub ahead of print

2. Witkowski M, Spangenberg HC, Neumann-Haefelin C, Büttner N, Breous E, Kersting N, Drognitz O, Hopt UT, Blum HE, Semmo N, Thimme R (2011) Lack of ex vivo peripheral and intrahepatic α-fetoprotein-specific CD4+ responses in hepatocellular carcinoma. Int J Cancer. 129(9):2171-82

3. Schmidt J, Neumann-Haefelin C, Altay T, Gostick E, Price DA, Lohmann V, Blum HE, Thimme R (2011) Immunodominance of HLA-A2-restricted hepatitis C virus-specific CD8+ T cell responses is linked to naive-precursor frequency. J Virol. 85(10):5232-6

4. Breous E, Thimme R (2011) Potential of immunotherapy for hepatocellular carcinoma. J Hepatol. 54(4):830-4

5. Bengsch B, Seigel B, Ruhl M, Timm J, Kuntz M, Blum HE, Pircher H, Thimme R (2010) Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLoS Pathog. 10;6(6):e1000947

6. Mueller M, Spangenberg HC, Kersting N, Altay T, Blum HE, Klenerman P, Thimme R, Semmo N (2010) Virus-specific CD4+ T cell responses in chronic HCV infection in blood and liver identified by antigen-specific upregulation of CD154. J Hepatol. 52(6):800-11

7. 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 (2010) 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. 107(7):3006-11

8. 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 (2010) 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. 51(1):54-62

9. Pawlotsky JM, Cocquerel L, Durantel D, Lavillette D, Lerat H, Pécheur EI, Polyak SJ, Tautz N, Thimme R (2010) HCV research 20 years after discovery: a summary of the 16th international symposium on hepatitis C virus and related viruses. Gastroenterology. 138(1):6-12.e1-2

10. Haybaeck J, Zeller N, Wolf MJ, Weber A, Wagner U, Kurrer MO, Bremer J, Iezzi G, Graf R, Clavien PA, Thimme R, Blum H, Nedospasov SA, Zatloukal K, Ramzan M, Ciesek S, Pietschmann T, Marche PN, Karin M, Kopf M, Browning JL, Aguzzi A, Heikenwalder M (2009) A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell. 6(4):295-308

11. Billerbeck E, Nakamoto N, Seigel B, Blum HE, Chang KM, Thimme R (2009) Determinants of in vitro expansion of different human virus-specific FoxP3+ regulatory CD8+ T cells in chronic hepatitis C virus infection. J Gen Virol. 90:1692-701

12. Dazert E, Neumann-Haefelin C, Bressanelli S, Fitzmaurice K, Kort J, Timm J, McKiernan S, Kelleher D, Gruener N, Tavis JE, Rosen HR, Shaw J, Bowness P, Blum HE, Klenerman P, Bartenschlager R, Thimme R (2009) Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human immune response. J Clin Invest. 119(2):376-86

13. Jo J, Aichele U, Kersting N, Klein R, Aichele P, Bisse E, Sewell AK, Blum HE, Bartenschlager R, Lohmann V, Thimme R (2009) Analysis of CD8+ T-cell-mediated inhibition of hepatitis C virus replication using a novel immunological model. Gastroenterology 136(4):1391-401

14. Thimme R, Neagu M, Boettler T, Neumann-Haefelin C, Kersting N, Geissler M, Makowiec F, Obermaier R, Hopt UT, Blum HE, Spangenberg HC (2008) Comprehensive analysis of the alpha-fetoprotein-specific CD8+ T cell responses in patients with hepatocellular carcinoma. Hepatology 48(6):1821-33

15. Neumann-Haefelin C, Timm J, Spangenberg HC, Wischniowski N, Nazarova N, Kersting N, Roggendorf M, Allen TM, Blum HE, Thimme R (2008) Virological and immunological determinants of intrahepatic virus-specific CD8+ T-cell failure in chronic hepatitis C virus infection. Hepatology 47:1824-36.

16. Neumann-Haefelin C, Frick DN, Wang JJ, Pybus OG, Salloum S, Narula GS, Eckart A, Biezynski A, Eiermann T, Klenermann P, Viazov S, Roggendorf M, Thimme R, Reiser M, Timm J (2008) Analysis of the evolutionary forces in an immunodominant CD8 epitope in the hepatitis C virus at a population level. J Virol 82:3438-51.

17. Billerbeck E, Blum HE, Thimme R (2007) Parallel expansion of human virus-specific FoxP3- effector memory and de novo generated FoxP3+ regulatory CD8+ T-cells upon antigen recognition in vitro. J Immunol 179:1039-48.

18. Neuman-Haefelin H, Killinger T, Timm J, Southwood S, McKinney D, Blum HE, Thimme R (2007) Absence of viral escape within a frequently recognized HLA-A26-restricted CD8+ T-cell epitope targeting the functionally constrained hepatitis C virus NS5A/5B cleavage site. J Gen Virol 88:1986-91.

19. Bengsch B, Spangenberg HC, Kersting N, Neumann-Haefelin C, Panther E, von Weizsacker F, Blum HE, Pircher H, Thimme R (2007) Analysis of CD127 and KLRG1 expression on HCV specific CD8+ T-cells reveals the existence of different memory T cell subsets in the peripheral blood and liver. J Virol. 81:945-53.

20. Boettler T, Panther E, Bengsch B, Nazarova N, Spangenberg HC, Blum HE, Thimme R (2006) Expression of the interleukin-7 receptor alpha chain (CD127) on virus-specific CD8+ T cells identifies functionally and phenotypically defined memory T cells during acute resolving hepatitis B virus infection. J Virol. 80:3532-3540.

21. Neumann-Haefelin C, McKiernan S, Ward S, Viazov S, Spangenberg HC, Killinger T, Baumert TF, Nazarova N, Sheridan I, Pybus O, von Weizsacker F, Roggendorf M, Kelleher D, Klenerman P, Blum HE, Thimme R (2006) Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution. Hepatology 43:563-572.

22. Thimme R, Lohmann V, Weber F (2006) A target on the move: innate and adaptive immune escape strategies of hepatitis C virus. Antiviral Res. 69:129-141.

23. Spangenberg HC, Viazov S, Kersting N, Neumann-Haefelin C, McKinney D, Roggendorf M, von Weizsacker F, Blum HE, Thimme R (2005) Intrahepatic CD8+ T-cell failure during chronic hepatitis C virus infection. Hepatology 42:828-837.

24. Thimme R, Appay V, Koschella M, Panther E, Roth E, Hislop AD, Rickinson AB, Rowland-Jones SL, Blum HE, Pircher H (2005) Increased expression of the NK cell receptor KLRG1 by virus-specific CD8 T cells during persistent antigen stimulation. J Virol. 79:12112-12116.

25. Boettler T, Spangenberg HC, Neumann-Haefelin C, Panther E, Urbani S, Ferrari C, Blum HE, von Weizsacker F, Thimme R (2005) T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection. J Virol. 79:7860-7867.

26. Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA, Purcell RH, Chisari FV (2003) CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol. 77:68-76.

27. Thimme R, Bukh J, Spangenberg HC, Wieland S, Pemberton J, Steiger C, Govindarajan S, Purcell RH, Chisari FV (2002) Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. PNAS 99:15661-15668.

28. Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV (2001) Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med. 194:1395-1406.

29. Thimme R, Chang KM, Pemberton J, Sette A, Chisari FV (2001) Degenerate immunogenicity of an HLA-A2-restricted hepatitis B virus nucleocapsid cytotoxic T-lymphocyte epitope that is also presented by HLA-B51. J Virol. 75:3984-3987.

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