T-cell response to hepatitis B and C

• Applicant: Professor Dr. Robert Thimme
• Subject Area: Gastroenterology
• Term: from 2002 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5361025

• Final Report Year: 2010

Final Report Abstract

Im Rahmen der Förderung durch das Emmy Noether Programm ist es gelungen, eine immunologisch-virologisch tätige Arbeitsgruppe an der Abteilung Innere Medizin II in Freiburg zu etablieren, die sich mit den Mechanismen der Viruselimination und Persistenz bei der HBV und HCV Infektion beschäftigt. Die Ergebnisse dieser translationalen Studien zeigen, dass verschiedene Mechanismen zum Versagen der CD8+ T-Zell Antwort beitragen, wie z.B. die Ausbildung von viralen Escapemutationen und das Vorliegen einer CD8+ T-Zell Dysfunktion. Letztere ist u.a. bedingt durch eine fehlende CD4+ T-Zell Hilfe, die Wirkung von regulatorischen T-Zellen, eine fehlerhafte T-Zell Differenzierung und die Wirkung inhibitorischer Moleküle, wie z.B. PD-1. Die Ergebnisse sind Grundlage für weiterführende Arbeiten gewesen.

Publications

• Increased expression of the natural killer cell receptor KLRG1 by virus-specific CD8+ T cells during persistent antigen stimulation. J Virol 2005, 79(18): 12112-6
  Thimme R, Appay V, Koschella M, Panther E, Roth E, Hislop AD, Rickinson AB, Rowland-Jones S, Blum HE, Pircher HP
  
• Intrahepatic CD8+T cell failure during chronic hepatitis C virus infection. Hepatology 2005, 42 (4): 828-37
  Spangenberg HC, Viazow S, Kersting N, Neumann-Haefelin C, Roggendorf M, von Weizsaeckcer F, Blum HE, Thimme R
  
• T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of HCV-specific CD8+T cells. J Virol 2005, 79 (12): 7860-7
  Boettler T, Spangenberg HC, Neumann-Haefelin C, Panther E, Urbani S, Ferrari C, Blum HE, von Weizsaecker F, Thimme R
  
• Binding of hepatitis C virus envelope to target cells induces a cascade of cell signals important for antiviral immune responses and lipid metabolism. Hepatology 2006, 43 (6): 1326-36
  Fang X, Wilpert J, Barth H, Gissler B, Kreutz C,Timmer J, Donauer J, Thimme R, von Weizsäcker F, Blum HE, Baumert TF
  
• Dominant influence of an HLA-B27 restricted virus-specific CD8+T cell response in viral clearance and viral adaptation in hepatitis C virus infection. Hepatology 2006, 43(3): 563-72
  Neumann-Haefelin C, McKiernan S, Ward S, Viazow S, Spangenberg HC, Killinger T, Baumert TF, Nazarowa N, von Weizsäcker F, Roggendorf M, Kelleher D, Klenerman P, 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 (7): 3532-40
  Boettler T, Panther E, Bengsch B, Nazarova N, Spangenberg HC, Blum HE, Thimme R
  
• Absence of viral escape within an immunodominant HLA-A26 restricted CD8+ T cell epitope due to functional constraints. J Gen Virol 2007, 88 (Pt 7): 1986-91
  Neumann-Haefelin C, Killinger T, Timm J, Kersting N, Spangenberg HC, Blum HE, Thimme R
  
• Emergence of CD 127+and KLRG1- proliferative competent hepatitis C virus specific memory phenotype CD8+ T cells despite viral persistence. J Virol 2007, 81 (2): 945-53
  Bengsch B, Spangenberg HC, Kersting N, Neumann-Haefelin C, Panther E, von Weizsäcker F, Blum HE, Pircher HP and Thimme R
  
• Immune responses against HCV-NS3 after accidental infection with HCV-NS3 recombinant vaccina virus. J Viral Hepat 2007, 14 (11):817-9
  Eisenbach C, Neumann-Haefelin C, Freyse A, Korsukéwitz T, Hoyler B, Stremmel W, Thimme R, Encke J
  
• Parallel expansion of virus-specific FoxP3- effector and FoxP3- regulatory CD8+ T cells on recognition of the same antigen. J Immunol 2007, 179(2): 1039-48
  Billerbeck E, Blum HE, Thimme R
  
• Tracking virus-specific CD4+ T cells during and after acute hepatitis C virus infection. PLoS ONE 2007, 2: e649
  Lucas M, Ulsenheimer A, Pfafferot K, Heeg MH, Gaudieri S, Gruner N, Rauch A, Gerlach JT, Jung MC, Zachoval R, Pape GR, Schraut W, Santantonio T, Nitschko H, Obermeier M, Phillips R, Scriba TJ, Semmo N, Day C, Weber JN, Fidler S, Thimme R, Haberstroh A, Baumert TF, Klenerman P, Diepolder HM
  
• CD161 expresion on hepatitis C virus-specific CD8+ T cells suggests a distinct pathway of T cell differentiation. Hepatology 2008, 47 (2): 396-406
  Northfield JW, Kasprowicz V, Lucas M, Kersting N, Bengsh B, Kim A, Phillips RE, Walker BD, Thimme R, Lauer G, Klenerman P
  
• Escape from HLA-B*08 restricted CD8 T cells by hepatitis C virus is associated with fitness costs. J Virol. 2008; 82(23): 11803-12
  Salloum S, Oniangue-Ndza C, Neumann-Haefelin C, Hudson L, Giugliano S, Aus dem Siepen M, Nattermann J, Spengler U, Lauer G, Wiese M, Klenerman P, Bright H, Scherbaum N, Thimme R, Roggendorf M, Viazov S, Timm J
  
• Identification of CD4 T-Cell Epitopes in Soluble Liver Antigen/Liver Pancreas Autoantigen in Autoimmune Hepatitis. Gastroenterology 2008; 135(6):2107-18
  Mix H, Weiler-Normann C, Thimme R, Ahlenstiel G, Shin EC, Herkel J, David CS, Lohse AW, Rehermann B
  
• Previously infected chimpanzees are not consistently protected against reinfection or persistent infection after reexposure to the identical hepatitis C virus strain. J Virol. 2008;82 (16):8183-95
  Bukh J, Thimme R, Meunier JC, Faulk K, Spangenberg HC, Chang KM, Satterfield W, Chisari FV, Purcell RH
  
• Scavenger reseptor class B is required for hepatitis C virus uptake and cross-presentation by human dendritic cells. J Virol 2008, 82 (7): 3466-79
  Earth H, Schnober EK, Neumann-Haefelin HC, Thumann C, Zeisel MB, Diepolder HM, Hu Z, Liang TJ, Blum HE, Thimme R, Lambotin M, Baumert TF
  
• Virological and immunological determinants of intrahepatic virus-specific CD8+ T cell failure in chronic hepatitis C virus infection. Hepatology 2008, 47 (6): 1824-36
  Neumann-Haefelin C, Timm J, Spangenberg HC, Wischnowski N, Nazarova N, Kersting N, Roggendorf M, Allen TM, Blum HE, Thimme R