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Z Gastroenterol 2004; 42(1): 39-46
DOI: 10.1055/s-2004-812688
Übersicht
© Karl Demeter Verlag im Georg Thieme Verlag Stuttgart · New York

Die Rolle der virusspezifischen T-Zellantwort bei der akuten und chronischen Hepatitis-B- und -C-Virusinfektion

The Role of the Virus Specific T-Cell Response in Acute and Chronic HBV and HCV InfectionE. Panther1 , H. C. Spangenberg1 , C. Neumann-Haefelin1 , K. Rösler1 , H. E. Blum1 , F. von Weizsäcker1 , R. Thimme1
  • 1Abteilung Innere Medizin II (Gastroenterologie, Hepatologie, Endokrinologie, Infektiologie) Medizinische Universitätsklinik Freiburg
Further Information

Publication History

Manuskript-Eingang: 4. November 2003

Annahme nach Revision: 17. November 2003

Publication Date:
02 February 2004 (online)

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Zusammenfassung

Infektionen mit dem Hepatitis-B- (HBV) und Hepatitis-C-Virus (HCV) gehören weltweit zu den häufigsten Ursachen der chronischen Hepatitis mit dem Risiko der Entwicklung einer Leberzirrhose und des hepatozellulären Karzinoms. Die grundlegenden Mechanismen, die für die Viruselimination oder -persistenz verantwortlich sind, sind noch weit gehend ungeklärt. Die Immunpathogenese der HBV- und HCV-Infektion wird wesentlich durch die virusspezifische T-Zell-Antwort bestimmt. Während der akuten Phase findet man eine starke und multispezifische, d. h. gegen verschiedene Epitope des Virus gerichtete T-Zellantwort, die zur Elimination des Virus führen kann. Gelingt es dem Organismus nicht, das Virus zu eliminieren, können die T-Zellen in der chronischen Phase der Erkrankung wesentlich zur Entstehung der entzündlichen Lebererkrankung beitragen. In dieser Übersichtsarbeit werden die aktuellen Konzepte über die Rolle der virusspezifischen T-Zellantwort bei der akuten und chronischen Hepatitis-B- und -C-Virusinfektion zusammenfassend dargestellt.

Abstract

Infections with hepatitis B (HBV) and hepatitis C virus (HCV) are worldwide one of the most frequent causes for chronic liver disease, liver cirrhosis and hepatocellular carcinoma. The mechanisms responsible for the elimination or the persistence of the virus are not well understood. The immunopathogenesis of HBV and HCV infection is primarily mediated by virus specific CD4+- and CD8+-T-cells. During acute infection a strong and multispecific T-cell response against different viral epitopes can be detected and is associated with the clearance of the virus. In case of viral persistence virus specific T-cells contribute to liver inflammation. In this article we summarize the current concepts about the role of the virus specific T-cell response in acute and chronic HBV and HCV infection.

Schlüsselwörter

Hepatitis B - Hepatitis C - Immunologie - T-Zellen

Key words

Hepatitis B - Hepatitis C - immunology - T cells

Literatur

  • 1 Bertoni R, Sidney J, Fowler P. et al . Human histocompatibility leukocyte antigen-binding supermotifs predict broadly cross-reactive cytotoxic T lymphocyte responses in patients with acute hepatitis.  J Clin Invest. 1997;  100 503-513
    PubMedGoogle Scholar
  • 2 Maini M K, Boni C, Ogg G S. et al . Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection.  Gastroenterology. 1999;  117 1386-1396
    PubMedGoogle Scholar
  • 3 Thimme R, Chang K M, Pemberton J. et al . Degenerate immunogenicity of an HLA-A2-restricted hepatitis B virus nucleocapsid cytotoxic T-lymphocyte epitope that is also presented by HLA-B51.  J Virol. 2001;  75 3984-3987
    CrossrefPubMedGoogle Scholar
  • 4 Urbani S, Boni C, Missale G. et al . Virus-specific CD8+ lymphocytes share the same effector-memory phenotype but exhibit functional differences in acute hepatitis B and C.  J Virol. 2002;  76 1242-1234
    PubMedGoogle Scholar
  • 5 Thimme R, Wieland S, Steiger C. et al . CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection.  J Virol. 2003;  77 68-76
    CrossrefPubMedGoogle Scholar
  • 6 Chisari F V. Rous-Whipple Award Lecture. Viruses, immunity, and cancer: lessons from hepatitis B.  Am J Pathol. 2000;  156 1117-1132
    PubMedGoogle Scholar
  • 7 Guidotti L G, Ishikawa T, Hobbs M V. et al . Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes.  Immunity. 1996;  4 25-36
    CrossrefPubMedGoogle Scholar
  • 8 Guidotti L G, Rochford R, Chung J. et al . Viral clearance without destruction of infected cells during acute HBV infection.  Science. 1999;  284 825-829
    CrossrefPubMedGoogle Scholar
  • 9 Baron J, Gardiner L, Nishimura S. et al . Activation of a nonclassical NKT cell subset in a transgenic mouse model of hepatitis B virus infection.  Immunity. 2002;  16 583-594
    CrossrefPubMedGoogle Scholar
  • 10 Guidotti L G, Chisari F V. Noncytolytic control of viral infections by the innate and adaptive immune response.  Annu Rev Immunol. 2001;  19 65-91
    CrossrefPubMedGoogle Scholar
  • 11 Kakimi K, Guidotti L G, Koezuka Y. et al . Natural killer T cell activation inhibits hepatitis B virus replication in vivo.  J Exp Med. 2000;  192 921-930
    CrossrefPubMedGoogle Scholar
  • 12 Pasquetto V, Guidotti L, Kakimi K. et al . C. Host-virus interactions during malaria infection in hepatitis B virus transgenic mice.  J Exp Med. 2000;  192 529-536
    CrossrefPubMedGoogle Scholar
  • 13 Webster G, Reignat S, Maini M. et al . Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms.  Hepatology. 2001;  32 1117-1124
    PubMedGoogle Scholar
  • 14 Rehermann B, Ferrari C, Pasquinelli C. et al . The hepatitis B virus persists for decades after patients’ recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response.  Nat Med. 1996;  2 1104-1108
    CrossrefPubMedGoogle Scholar
  • 15 Chisari F V. Cytotoxic T cells and viral hepatitis.  J Clin Invest. 1997;  99 1472-1477
    CrossrefPubMedGoogle Scholar
  • 16 Boni C, Bertoletti A, Penna A. et al . Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B.  J Clin Invest. 1998;  102 968-975
    PubMedGoogle Scholar
  • 17 Boni C, Penna A, Ogg G. et al . Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy.  Hepatology. 2001;  33 963-971
    CrossrefPubMedGoogle Scholar
  • 18 Rehermann B, Chang K M, McHutchinson J. et al . Differential cytotoxic T-lymphocyte responsiveness to the hepatitis B and C viruses in chronically infected patients.  J Virol. 1996;  70 7092-7102
    PubMedGoogle Scholar
  • 19 Maini M K, Boni C, Lee C K. et al . The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection.  J Exp Med. 2000;  191 1269-1280
    CrossrefPubMedGoogle Scholar
  • 20 Kakimi K, Lane T E, Wieland S. et al . Blocking chemokine responsive to gamma-2/interferon (IFN)-gamma inducible protein and monokine induced by IFN-gamma activity in vivo reduces the pathogenetic but not the antiviral potential of hepatitis B virus-specific cytotoxic T lymphocytes.  J Exp Med. 2001;  194 1755-1766
    CrossrefPubMedGoogle Scholar
  • 21 Orland J R, Wright T L, Cooper S. Acute hepatitis C.  Hepatology. 2001;  33 321-327
    CrossrefPubMedGoogle Scholar
  • 22 Gerlach J, Diepolder H, Zachoval R. et al . Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance.  Gastroenterology. 2003;  125 80-88
    CrossrefPubMedGoogle Scholar
  • 23 Diepolder H M, Zachoval R, Hoffmann R M. et al . Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection.  Lancet. 1995;  346 1006-1007
    CrossrefPubMedGoogle Scholar
  • 24 Gerlach J T, Diepolder H M, Jung M C. et al . Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T- cell response in acute hepatitis C.  Gastroenterology. 1999;  117 933-941
    CrossrefPubMedGoogle Scholar
  • 25 Gruner N H, Gerlach T J, Jung M C. et al . Association of hepatitis C virus-specific CD8+ T cells with viral clearance in acute hepatitis C.  J Infect Dis. 2000;  181 1528-1536
    CrossrefPubMedGoogle Scholar
  • 26 Lechner F, Gruener N H, Urbani S. et al . CD8+ T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained.  Eur J Immunol. 2000;  30 2479-2487
    CrossrefPubMedGoogle Scholar
  • 27 Lechner F, Wong D K, Dunbar P R. et al . Analysis of successful immune responses in persons infected with hepatitis C virus.  J Exp Med. 2000;  191 1499-1512
    CrossrefPubMedGoogle Scholar
  • 28 Thimme R, Oldach D, Chang K M. et al . Determinants of Viral Clearance and Persistence during Acute Hepatitis C Virus Infection.  J Exp Med. 2001;  194 1395-1406
    CrossrefPubMedGoogle Scholar
  • 29 Cooper S, Erickson A L, Adams E J. et al . Analysis of a successful immune response against hepatitis C virus.  Immunity. 1999;  10 439-449
    CrossrefPubMedGoogle Scholar
  • 30 Thimme R, Bukh J, Spangenberg H. et al . Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease.  Proc Natl Acad Sci USA. 2002;  99 15 661-15 668
    PubMedGoogle Scholar
  • 31 Su A, Pezacki J, Wodicka L. et al . Genomic analysis of the host response to hepatitis C virus infection.  Proc Natl Acad Sci USA. 2002;  99 16 669-16 674
    PubMedGoogle Scholar
  • 32 Frese M, Schwarzle V, Barth K. et al . Interferon-gamma inhibits replication of subgenomic and genomic hepatitis C virus RNAs.  Hepatology. 2002;  35 694-703
    CrossrefPubMedGoogle Scholar
  • 33 Foy E, Li K, Wang C. et al . Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease.  Science. 2003;  300 1445-1448
    PubMedGoogle Scholar
  • 34 Gale M J, Korth M and Katze M. Repression of the PKR protein kinase by the hepatitis C virus NS5A protein: a potential mechanism of interferon resistance.  Clin Diagn Virol. 1998;  10 157-162
    CrossrefPubMedGoogle Scholar
  • 35 Tan S L, Katze M G. How hepatitis C virus counteracts the interferon response: the jury is still out on NS5A.  Virology. 2001;  284 1-12
    CrossrefPubMedGoogle Scholar
  • 36 Taylor D, Shi S, Romano P. et al . Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein.  Science. 1999;  285 107-110
    CrossrefPubMedGoogle Scholar
  • 37 Crotta S, Stilla A, Wack A. et al . Inhibition of Natural Killer Cells through Engagement of CD81 by the Major Hepatitis C Virus Envelope Protein.  J Exp Med. 2002;  195 35-42
    PubMedGoogle Scholar
  • 38 Tseng C T, Klimpel G R. Binding of the hepatitis C virus envelope protein e2 to CD81 inhibits natural killer cell functions.  J Exp Med. 2002;  195 43-50
    CrossrefPubMedGoogle Scholar
  • 39 Missale G, Bertoni R, Lamonaca V. et al . Different clinical behaviors of acute hepatitis C virus infection are associated with different vigor of the anti-viral cell-mediated immune response.  J Clin Invest. 1996;  98 706-714
    PubMedGoogle Scholar
  • 40 Bain C, Fatmi A, Zoulim F. et al . Impaired Allostimulatory Function of Dendritic Cells in Chronic Hepatitis C Infection.  Gastroenterology. 2001;  120 512-524
    PubMedGoogle Scholar
  • 41 Erickson A L, Kimura Y, Igarashi S. et al . The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes.  Immunity. 2001;  15 885-895
    PubMedGoogle Scholar
  • 42 Gruener N H, Lechner F, Jung M C. et al . Sustained dysfunction of antiviral cd8(+) t lymphocytes after infection with hepatitis c virus.  J Virol. 2001;  75 5550-5558
    CrossrefPubMedGoogle Scholar
  • 43 Battegay M, Fikes J, Di Bisceglie A M. et al . Patients with chronic hepatitis C have circulating cytotoxic T cells which recognize hepatitis C virus-encoded peptides binding to HLA-A2.1 molecules.  J Virol. 1995;  69 2462-2470
    PubMedGoogle Scholar
  • 44 Cerny A, McHutchison J G, Pasquinelli C. et al . Cytotoxic T lymphocyte response to hepatitis C virus-derived peptides containing the HLA A2.1 binding motif.  J Clin Invest. 1995;  95 521-530
    PubMedGoogle Scholar
  • 45 Chang K, Thimme R, Melpolder J. et al . Differential CD4(+) and CD8(+) T-cell responsiveness in hepatitis C virus infection.  Hepatology. 2001;  33 267-276
    CrossrefPubMedGoogle Scholar
  • 46 Ferrari C, Valli A, Galati L. et al . T-cell response to structural and nonstructural hepatitis C virus antigens in persistent and self-limited hepatitis C virus infections.  Hepatology. 1994;  19 286-295
    CrossrefPubMedGoogle Scholar
  • 47 Koziel M J, Dudley D, Afdhal N. et al . Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes recognize epitopes in the core and envelope proteins of HCV.  J Virol. 1993;  67 7522-7532
    PubMedGoogle Scholar
  • 48 Koziel M J, Dudley D, Afdhal N. et al . HLA class I-restricted cytotoxic T lymphocytes specific for hepatitis C virus. Identification of multiple epitopes and characterization of patterns of cytokine release.  J Clin Invest. 1995;  96 2311-2321
    PubMedGoogle Scholar
  • 49 Wong D K, Dudley D D, Dohrenwend P B. et al . Detection of Diverse Hepatitis C Virus (HCV)-Specific Cytotoxic T Lymphocytes in Peripheral Blood of Infected Persons by Screening for Responses to All Translated Proteins of HCV.  J Virol. 2001;  75 1229-1235
    CrossrefPubMedGoogle Scholar
  • 50 Grabowska A M, Lechner F, Klenerman P. et al . Direct ex vivo comparison of the breadth and specificity of the T cells in the liver and peripheral blood of patients with chronic HCV infection.  Eur J Immunol. 2001;  31 2388-2394
    CrossrefPubMedGoogle Scholar
  • 51 He X S, Rehermann B, Lopez-Labrador F X. et al . Quantitative analysis of hepatitis C virus-specific CD8(+) T cells in peripheral blood and liver using peptide-MHC tetramers.  Proc Natl Acad Sci USA. 1999;  96 5692-5697
    CrossrefPubMedGoogle Scholar
  • 52 Ulsenheimer A, Gerlach J, Gruener N. et al . Detection of functionally altered hepatitis C virus-specific CD4 T cells in acute and chronic hepatitis C.  J Virol. 2003;  37 1189-1198
    PubMedGoogle Scholar
  • 53 Wedemeyer H, He X S, Nascimbeni M. et al . Impaired Effector Function of Hepatitis C Virus-Specific CD8(+) T Cells in Chronic Hepatitis C Virus Infection.  J Immunol. 2002;  169 3447-3458
    PubMedGoogle Scholar
  • 54 Appay V, Dunbar P, Callan M. et al . Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections.  Nat Med. 2002;  84 379-385
    PubMedGoogle Scholar
  • 55 Farci P, Alter H J, Govindarajan S. et al . Lack of protective immunity against reinfection with hepatitis C virus.  Science. 1992;  258 135-140
    CrossrefPubMedGoogle Scholar
  • 56 Kao J H, Chen P J, Wang J T. et al . Superinfection by homotypic virus in hepatitis C virus carriers: studies on patients with post-transfusion hepatitis.  J Med Virol. 1996;  50 303-308
    CrossrefPubMedGoogle Scholar
  • 57 Lai M E, Mazzoleni A P, Argiolu F. et al . Hepatitis C virus in multiple episodes of acute hepatitis in polytransfused thalassaemic children.  Lancet. 1994;  343 388-390
    CrossrefPubMedGoogle Scholar
  • 58 Prince A M, Brotman B, Huima T. et al . Immunity in hepatitis C infection.  J Infect Dis. 1992;  165 438-443
    CrossrefPubMedGoogle Scholar
  • 59 Proust B, Dubois F, Bacq Y. et al . Two successive hepatitis C virus infections in an intravenous drug user.  J Clin Microbiol. 2000;  38 3125-3127
    PubMedGoogle Scholar
  • 60 Thimme R, Spangenberg H, Blum H E. Bridge over troubled water: Protection against hepatitis C virus persistence?.  Hepatology. 2002;  36 1537-1539
    PubMedGoogle Scholar
  • 61 Mehta S H, Cox A, Hoover D R. et al . Protection against persistence of hepatitis C.  Lancet. 2002;  359 1478-1483
    CrossrefPubMedGoogle Scholar
  • 62 Bassett S E, Guerra B, Brasky K. et al . Protective immune response to hepatitis C virus in chimpanzees rechallenged following clearance of primary infection.  Hepatology. 2001;  33 1479-1487
    CrossrefPubMedGoogle Scholar
  • 63 Major M E, Mihalik K, Puig M. et al . Previously infected and recovered chimpanzees exhibit rapid responses that control hepatitis C virus replication upon rechallenge.  J Virol. 2002;  76 6586-6595
    CrossrefPubMedGoogle Scholar
  • 64 Weiner A J, Paliard X, Selby M J. et al . Intrahepatic genetic inoculation of hepatitis C virus RNA confers cross-protective immunity.  J Virol. 2001;  75 7142-7148
    CrossrefPubMedGoogle Scholar
  • 65 Shoukry N, Grakoui A, Houghton M. et al . Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection.  J Exp Med. 2003;  197 1645-1655
    CrossrefPubMedGoogle Scholar

Dr. R. Thimme

Abteilung Innere Medizin II

Hugstetter Str. 55

79106 Freiburg

Email: thimme@med1.ukl.uni-freiburg.de