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The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Nov 1;178(5):1541–1554. doi: 10.1084/jem.178.5.1541

Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis

PMCID: PMC2191233  PMID: 8228807

Abstract

The molecular and cellular mechanisms responsible for cytotoxic T lymphocyte (CTL)-induced immunopathology are not well defined. Using a model in which hepatitis B surface antigen (HBsAg)-specific CTL cause an acute necroinflammatory liver disease in HBsAg transgenic mice, we demonstrate that class I-restricted disease pathogenesis is an orderly, multistep process that involves direct as well as indirect consequences of CTL activation. It begins (step 1) almost immediately as a direct antigen-specific CTL-target cell interaction that triggers the HBsAg- positive hepatocyte to undergo programmed cell death (apoptosis). It progresses (step 2) within hours to a focal inflammatory response in which antigen-nonspecific lymphocytes and neutrophils amplify the local cytopathic effect of the CTL. The most destructive pathogenetic function of the CTL, however, is to secrete interferon gamma when they encounter antigen in vivo, thereby activating the intrahepatic macrophage and inducing a delayed-type hypersensitivity response (step 3) that destroys the liver and kills the mouse. We propose that the principles illustrated in this study are generally applicable to other models of class I-restricted, CTL-induced immunopathology, and we suggest that they contribute to the immunopathogenesis of viral hepatitis during hepatitis B virus infection in humans.

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Selected References

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  1. Acha-Orbea H., Mitchell D. J., Timmermann L., Wraith D. C., Tausch G. S., Waldor M. K., Zamvil S. S., McDevitt H. O., Steinman L. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell. 1988 Jul 15;54(2):263–273. doi: 10.1016/0092-8674(88)90558-2. [DOI] [PubMed] [Google Scholar]
  2. Alexander R. B., Rosenberg S. A. Long-term survival of adoptively transferred tumor-infiltrating lymphocytes in mice. J Immunol. 1990 Sep 1;145(5):1615–1620. [PubMed] [Google Scholar]
  3. Anderson J., Byrne J. A., Schreiber R., Patterson S., Oldstone M. B. Biology of cloned cytotoxic T lymphocytes specific for lymphocytic choriomeningitis virus: clearance of virus and in vitro properties. J Virol. 1985 Feb;53(2):552–560. doi: 10.1128/jvi.53.2.552-560.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barth R. J., Jr, Mulé J. J., Spiess P. J., Rosenberg S. A. Interferon gamma and tumor necrosis factor have a role in tumor regressions mediated by murine CD8+ tumor-infiltrating lymphocytes. J Exp Med. 1991 Mar 1;173(3):647–658. doi: 10.1084/jem.173.3.647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bendelac A., Carnaud C., Boitard C., Bach J. F. Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T cells. J Exp Med. 1987 Oct 1;166(4):823–832. doi: 10.1084/jem.166.4.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Buchmeier N. A., Schreiber R. D. Requirement of endogenous interferon-gamma production for resolution of Listeria monocytogenes infection. Proc Natl Acad Sci U S A. 1985 Nov;82(21):7404–7408. doi: 10.1073/pnas.82.21.7404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Celis E., Ou D., Otvos L., Jr Recognition of hepatitis B surface antigen by human T lymphocytes. Proliferative and cytotoxic responses to a major antigenic determinant defined by synthetic peptides. J Immunol. 1988 Mar 15;140(6):1808–1815. [PubMed] [Google Scholar]
  8. Chisari F. V., Filippi P., Buras J., McLachlan A., Popper H., Pinkert C. A., Palmiter R. D., Brinster R. L. Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6909–6913. doi: 10.1073/pnas.84.19.6909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chisari F. V., Filippi P., McLachlan A., Milich D. R., Riggs M., Lee S., Palmiter R. D., Pinkert C. A., Brinster R. L. Expression of hepatitis B virus large envelope polypeptide inhibits hepatitis B surface antigen secretion in transgenic mice. J Virol. 1986 Dec;60(3):880–887. doi: 10.1128/jvi.60.3.880-887.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chisari F. V., Klopchin K., Moriyama T., Pasquinelli C., Dunsford H. A., Sell S., Pinkert C. A., Brinster R. L., Palmiter R. D. Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell. 1989 Dec 22;59(6):1145–1156. doi: 10.1016/0092-8674(89)90770-8. [DOI] [PubMed] [Google Scholar]
  11. Dienes H. P., Popper H., Arnold W., Lobeck H. Histologic observations in human hepatitis non-A, non-B. Hepatology. 1982 Sep-Oct;2(5):562–571. doi: 10.1002/hep.1840020509. [DOI] [PubMed] [Google Scholar]
  12. Doherty P. C., Allan J. E., Lynch F., Ceredig R. Dissection of an inflammatory process induced by CD8+ T cells. Immunol Today. 1990 Feb;11(2):55–59. doi: 10.1016/0167-5699(90)90019-6. [DOI] [PubMed] [Google Scholar]
  13. Eichelberger M., Allan W., Zijlstra M., Jaenisch R., Doherty P. C. Clearance of influenza virus respiratory infection in mice lacking class I major histocompatibility complex-restricted CD8+ T cells. J Exp Med. 1991 Oct 1;174(4):875–880. doi: 10.1084/jem.174.4.875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gilles P. N., Fey G., Chisari F. V. Tumor necrosis factor alpha negatively regulates hepatitis B virus gene expression in transgenic mice. J Virol. 1992 Jun;66(6):3955–3960. doi: 10.1128/jvi.66.6.3955-3960.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gilles P. N., Guerrette D. L., Ulevitch R. J., Schreiber R. D., Chisari F. V. HBsAg retention sensitizes the hepatocyte to injury by physiological concentrations of interferon-gamma. Hepatology. 1992 Sep;16(3):655–663. doi: 10.1002/hep.1840160308. [DOI] [PubMed] [Google Scholar]
  16. Grisham J. W., Nopanitaya W., Compagno J., Nägel A. E. Scanning electron microscopy of normal rat liver: the surface structure of its cells and tissue components. Am J Anat. 1975 Nov;144(3):295–321. doi: 10.1002/aja.1001440304. [DOI] [PubMed] [Google Scholar]
  17. Harty J. T., Schreiber R. D., Bevan M. J. CD8 T cells can protect against an intracellular bacterium in an interferon gamma-independent fashion. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11612–11616. doi: 10.1073/pnas.89.23.11612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ishak K. G. Light microscopic morphology of viral hepatitis. Am J Clin Pathol. 1976 May;65(5 Suppl):787–827. [PubMed] [Google Scholar]
  19. Issekutz T. B., Stoltz J. M., vd Meide P. Lymphocyte recruitment in delayed-type hypersensitivity. The role of IFN-gamma. J Immunol. 1988 May 1;140(9):2989–2993. [PubMed] [Google Scholar]
  20. Jiang H., Zhang S. I., Pernis B. Role of CD8+ T cells in murine experimental allergic encephalomyelitis. Science. 1992 May 22;256(5060):1213–1215. doi: 10.1126/science.256.5060.1213. [DOI] [PubMed] [Google Scholar]
  21. Kaufman D. B., Platt J. L., Rabe F. L., Dunn D. L., Bach F. H., Sutherland D. E. Differential roles of Mac-1+ cells, and CD4+ and CD8+ T lymphocytes in primary nonfunction and classic rejection of islet allografts. J Exp Med. 1990 Jul 1;172(1):291–302. doi: 10.1084/jem.172.1.291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Koh D. R., Fung-Leung W. P., Ho A., Gray D., Acha-Orbea H., Mak T. W. Less mortality but more relapses in experimental allergic encephalomyelitis in CD8-/- mice. Science. 1992 May 22;256(5060):1210–1213. doi: 10.1126/science.256.5060.1210. [DOI] [PubMed] [Google Scholar]
  23. Lehmann-Grube F., Assmann U., Löliger C., Moskophidis D., Löhler J. Mechanism of recovery from acute virus infection. I. Role of T lymphocytes in the clearance of lymphocytic choriomeningitis virus from spleens of mice. J Immunol. 1985 Jan;134(1):608–615. [PubMed] [Google Scholar]
  24. Lemire J. M., Weigle W. O. Passive transfer of experimental allergic encephalomyelitis by myelin basic protein-specific L3T4+ T cell clones possessing several functions. J Immunol. 1986 Nov 15;137(10):3169–3174. [PubMed] [Google Scholar]
  25. Lin Y. L., Askonas B. A. Biological properties of an influenza A virus-specific killer T cell clone. Inhibition of virus replication in vivo and induction of delayed-type hypersensitivity reactions. J Exp Med. 1981 Aug 1;154(2):225–234. doi: 10.1084/jem.154.2.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Meltzer M. S. Macrophage activation for tumor cytotoxicity: characterization of priming and trigger signals during lymphokine activation. J Immunol. 1981 Jul;127(1):179–183. [PubMed] [Google Scholar]
  27. Moriyama T., Guilhot S., Klopchin K., Moss B., Pinkert C. A., Palmiter R. D., Brinster R. L., Kanagawa O., Chisari F. V. Immunobiology and pathogenesis of hepatocellular injury in hepatitis B virus transgenic mice. Science. 1990 Apr 20;248(4953):361–364. doi: 10.1126/science.1691527. [DOI] [PubMed] [Google Scholar]
  28. Mulé J. J., Rosenstein M., Shu S., Rosenberg S. A. Eradication of a disseminated syngeneic mouse lymphoma by systemic adoptive transfer of immune lymphocytes and its dependence upon a host component(s). Cancer Res. 1985 Feb;45(2):526–531. [PubMed] [Google Scholar]
  29. Pace J. L., Russell S. W., Schreiber R. D., Altman A., Katz D. H. Macrophage activation: priming activity from a T-cell hybridoma is attributable to interferon-gamma. Proc Natl Acad Sci U S A. 1983 Jun;80(12):3782–3786. doi: 10.1073/pnas.80.12.3782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pace J. L., Russell S. W., Torres B. A., Johnson H. M., Gray P. W. Recombinant mouse gamma interferon induces the priming step in macrophage activation for tumor cell killing. J Immunol. 1983 May;130(5):2011–2013. [PubMed] [Google Scholar]
  31. Penna A., Fowler P., Bertoletti A., Guilhot S., Moss B., Margolskee R. F., Cavalli A., Valli A., Fiaccadori F., Chisari F. V. Hepatitis B virus (HBV)-specific cytotoxic T-cell (CTL) response in humans: characterization of HLA class II-restricted CTLs that recognize endogenously synthesized HBV envelope antigens. J Virol. 1992 Feb;66(2):1193–1198. doi: 10.1128/jvi.66.2.1193-1198.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Rappaport A. M. The microcirculatory hepatic unit. Microvasc Res. 1973 Sep;6(2):212–228. doi: 10.1016/0026-2862(73)90021-6. [DOI] [PubMed] [Google Scholar]
  33. Romball C. G., Weigle W. O. Transfer of experimental autoimmune thyroiditis with T cell clones. J Immunol. 1987 Feb 15;138(4):1092–1098. [PubMed] [Google Scholar]
  34. Rosenberg A. S., Munitz T. I., Maniero T. G., Singer A. Cellular basis of skin allograft rejection across a class I major histocompatibility barrier in mice depleted of CD8+ T cells in vivo. J Exp Med. 1991 Jun 1;173(6):1463–1471. doi: 10.1084/jem.173.6.1463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Schofield L., Villaquiran J., Ferreira A., Schellekens H., Nussenzweig R., Nussenzweig V. Gamma interferon, CD8+ T cells and antibodies required for immunity to malaria sporozoites. Nature. 1987 Dec 17;330(6149):664–666. doi: 10.1038/330664a0. [DOI] [PubMed] [Google Scholar]
  36. Schreiber R. D., Hicks L. J., Celada A., Buchmeier N. A., Gray P. W. Monoclonal antibodies to murine gamma-interferon which differentially modulate macrophage activation and antiviral activity. J Immunol. 1985 Mar;134(3):1609–1618. [PubMed] [Google Scholar]
  37. Schultz R. M., Kleinschmidt W. J. Functional identity between murine gamma interferon and macrophage activating factor. Nature. 1983 Sep 15;305(5931):239–240. doi: 10.1038/305239a0. [DOI] [PubMed] [Google Scholar]
  38. Sheehan K. C., Ruddle N. H., Schreiber R. D. Generation and characterization of hamster monoclonal antibodies that neutralize murine tumor necrosis factors. J Immunol. 1989 Jun 1;142(11):3884–3893. [PubMed] [Google Scholar]
  39. Shu S., Fonseca L. S., Kato H., Zbar B. Mechanisms of immunological eradication of a syngeneic guinea pig tumor: participation of a component(s) of recipient origin in the expression of systemic adoptive immunity. Cancer Res. 1983 Jun;43(6):2637–2643. [PubMed] [Google Scholar]
  40. Sriram S., Carroll L., Fortin S., Cooper S., Ranges G. In vivo immunomodulation by monoclonal anti-CD4 antibody. II. Effect on T cell response to myelin basic protein and experimental allergic encephalomyelitis. J Immunol. 1988 Jul 15;141(2):464–468. [PubMed] [Google Scholar]
  41. Suzuki Y., Remington J. S. The effect of anti-IFN-gamma antibody on the protective effect of Lyt-2+ immune T cells against toxoplasmosis in mice. J Immunol. 1990 Mar 1;144(5):1954–1956. [PubMed] [Google Scholar]
  42. Thomson A. W., Fowler E. F. Carrageenan: a review of its effects on the immune system. Agents Actions. 1981 May;11(3):265–273. doi: 10.1007/BF01967625. [DOI] [PubMed] [Google Scholar]
  43. Tung K. S., Yule T. D., Mahi-Brown C. A., Listrom M. B. Distribution of histopathology and Ia positive cells in actively induced and passively transferred experimental autoimmune orchitis. J Immunol. 1987 Feb 1;138(3):752–759. [PubMed] [Google Scholar]
  44. Walker C. M., Erickson A. L., Hsueh F. C., Levy J. A. Inhibition of human immunodeficiency virus replication in acutely infected CD4+ cells by CD8+ cells involves a noncytotoxic mechanism. J Virol. 1991 Nov;65(11):5921–5927. doi: 10.1128/jvi.65.11.5921-5927.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Walker C. M., Moody D. J., Stites D. P., Levy J. A. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science. 1986 Dec 19;234(4783):1563–1566. doi: 10.1126/science.2431484. [DOI] [PubMed] [Google Scholar]
  46. Yamasaki T., Handa H., Yamashita J., Watanabe Y., Namba Y., Hanaoka M. Specific adoptive immunotherapy with tumor-specific cytotoxic T-lymphocyte clone for murine malignant gliomas. Cancer Res. 1984 May;44(5):1776–1783. [PubMed] [Google Scholar]
  47. Zinkernagel R. M., Haenseler E., Leist T., Cerny A., Hengartner H., Althage A. T cell-mediated hepatitis in mice infected with lymphocytic choriomeningitis virus. Liver cell destruction by H-2 class I-restricted virus-specific cytotoxic T cells as a physiological correlate of the 51Cr-release assay? J Exp Med. 1986 Oct 1;164(4):1075–1092. doi: 10.1084/jem.164.4.1075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. van Rooijen N., van Nieuwmegen R. Elimination of phagocytic cells in the spleen after intravenous injection of liposome-encapsulated dichloromethylene diphosphonate. An enzyme-histochemical study. Cell Tissue Res. 1984;238(2):355–358. doi: 10.1007/BF00217308. [DOI] [PubMed] [Google Scholar]

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