Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1986 Oct 1;164(4):1075–1092. doi: 10.1084/jem.164.4.1075

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?

PMCID: PMC2188412  PMID: 3489805

Abstract

A model for immunologically T cell-mediated hepatitis was established in mice infected with lymphocytic choriomeningitis virus (LCMV). The severity of hepatitis was monitored histologically and by determination of changes in serum levels of the enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH), and alkaline phosphatase (AP). Kinetics of histological disease manifestations, increases of liver enzyme levels in the serum, and cytotoxic T cell activities in livers and spleens all correlated and were dependent upon several parameters: LCMV-isolate; LCMV-WE caused extensive hepatitis, LCMV-Armstrong virtually none. Virus dose. Route of infection; i.v. or i.p. infection caused hepatitis, whereas infection into the footpad did not. The general genetic background of the murine host; of the strains tested, Swiss mice and A-strain mice were more susceptible than C57BL or CBA mice; BALB/c and DBA/2 mice were least susceptible. The degree of immunocompetence of the murine host; T cell deficient nu/nu mice never developed hepatitis, whereas nu/+ or +/+ mice always did. B cell-depleted anti-IgM-treated mice developed immune-mediated hepatitis comparably or even more extensively than control mice. Local cytotoxic T cell activity; mononuclear cells isolated from livers during the period of overt hepatitis were two to five times more active than equal numbers of spleen cells. Adoptive transfer of nylon wool-nonadherent anti-Thy-1.2 and anti-Lyt-2 plus C- sensitive, anti-L3T4 plus C-resistant lymphocytes into irradiated mice preinfected with LCMV-WE caused a rapid time- and dose-dependent linear increase of serum enzyme levels. This increase was caused by adoptive transfer of lymphocytes if immune cell donors and recipient mice shared class I, but not when they shared class II histocompatibility antigens. The donor cell dose-dependent increase of these enzymes was first measurable 6-18 h after transfer with 2 X 10(8) cells or 3 X 10(6) cells, respectively. The time-dependent increase caused by the adoptive transfer of 1-2 X 10(8) cells was strictly linear during a period of up to 25-40 h. These results indicate single-hit kinetics of liver cell death and suggest that effector T cells destroy infected liver cells via direct contact rather than via soluble toxic mediators. The results may represent the best in vivo correlate of the in vitro 51Cr-release assay that has been analyzed so far, and strongly support the view that antiviral cytotoxic T cells are directly cytolytic in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baenziger J., Hengartner H., Zinkernagel R. M., Cole G. A. Induction or prevention of immunopathological disease by cloned cytotoxic T cell lines specific for lymphocytic choriomeningitis virus. Eur J Immunol. 1986 Apr;16(4):387–393. doi: 10.1002/eji.1830160413. [DOI] [PubMed] [Google Scholar]
  2. Bergmeyer H. U., Scheibe P., Wahlefeld A. W. Optimization of methods for aspartate aminotransferase and alanine aminotransferase. Clin Chem. 1978 Jan;24(1):58–73. [PubMed] [Google Scholar]
  3. Bianchi L. The immunopathology of acute type B hepatitis. Springer Semin Immunopathol. 1981 Apr;3(4):421–438. doi: 10.1007/BF01951491. [DOI] [PubMed] [Google Scholar]
  4. Blanden R. V. T cell response to viral and bacterial infection. Transplant Rev. 1974;19(0):56–88. doi: 10.1111/j.1600-065x.1974.tb00128.x. [DOI] [PubMed] [Google Scholar]
  5. Bowers G. N., Jr, McComb R. B. Measurement of total alkaline phosphatase activity in human serum. Clin Chem. 1975 Dec;21(13):1988–1995. [PubMed] [Google Scholar]
  6. Bro-Jørgensen K. The interplay between lymphocytic choriomeningitis virus, immune function, and hemopoiesis in mice. Adv Virus Res. 1978;22:327–369. doi: 10.1016/s0065-3527(08)60777-0. [DOI] [PubMed] [Google Scholar]
  7. Buchmeier M. J., Welsh R. M., Dutko F. J., Oldstone M. B. The virology and immunobiology of lymphocytic choriomeningitis virus infection. Adv Immunol. 1980;30:275–331. doi: 10.1016/s0065-2776(08)60197-2. [DOI] [PubMed] [Google Scholar]
  8. Byrne J. A., Oldstone M. B. Biology of cloned cytotoxic T lymphocytes specific for lymphocytic choriomeningitis virus: clearance of virus in vivo. J Virol. 1984 Sep;51(3):682–686. doi: 10.1128/jvi.51.3.682-686.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ceredig R., Dialynas D. P., Fitch F. W., MacDonald H. R. Precursors of T cell growth factor producing cells in the thymus: ontogeny, frequency, and quantitative recovery in a subpopulation of phenotypically mature thymocytes defined by monoclonal antibody GK-1.5. J Exp Med. 1983 Nov 1;158(5):1654–1671. doi: 10.1084/jem.158.5.1654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cerny A., Hügin A. W., Sutter S., Heusser C. H., Bos N., Izui S., Hengartner H., Zinkernagel R. M. Suppression of B cell development and antibody responses in mice with polyclonal rabbit and monoclonal rat anti-IgM antibodies. I. Characterization of the suppressed state. Exp Cell Biol. 1985;53(6):301–313. doi: 10.1159/000163327. [DOI] [PubMed] [Google Scholar]
  11. Cerottini J. C., Brunner K. T. Cell-mediated cytotoxicity, allograft rejection, and tumor immunity. Adv Immunol. 1974;18:67–132. doi: 10.1016/s0065-2776(08)60308-9. [DOI] [PubMed] [Google Scholar]
  12. Cole G. A., Nathanson N., Prendergast R. A. Requirement for theta-bearing cells in lymphocytic choriomeningitis virus-induced central nervous system disease. Nature. 1972 Aug 11;238(5363):335–337. doi: 10.1038/238335a0. [DOI] [PubMed] [Google Scholar]
  13. Dienstag J. L., Feinstone S. M., Purcell R. H., Hoofnagle J. H., Barker L. F., London W. T., Popper H., Peterson J. M., Kapikian A. Z. Experimental infection of chimpanzees with hepatitis A virus. J Infect Dis. 1975 Nov;132(5):532–545. doi: 10.1093/infdis/132.5.532. [DOI] [PubMed] [Google Scholar]
  14. Doherty P. C., Zinkernagel R. M. T-cell-mediated immunopathology in viral infections. Transplant Rev. 1974;19(0):89–120. doi: 10.1111/j.1600-065x.1974.tb00129.x. [DOI] [PubMed] [Google Scholar]
  15. Dudley F. J., Fox R. A., Sherlock S. Cellular immunity and hepatitis-associated, Australia antigen liver disease. Lancet. 1972 Apr 1;1(7753):723–726. doi: 10.1016/s0140-6736(72)90234-6. [DOI] [PubMed] [Google Scholar]
  16. Eddleston A. L., Williams R. HLA and liver disease. Br Med Bull. 1978 Sep;34(3):295–300. doi: 10.1093/oxfordjournals.bmb.a071515. [DOI] [PubMed] [Google Scholar]
  17. Engers H. D., Lahaye T., Sorenson G. D., Glasebrook A. L., Horvath C., Brunner K. T. Functional activity in vivo of effector T cell populations. II. Anti-tumor activity exhibited by syngeneic anti-MoMULV-specific cytolytic T cell clones. J Immunol. 1984 Sep;133(3):1664–1670. [PubMed] [Google Scholar]
  18. Frösner G. G., Schomerus H., Wiedmann K. H., Zachoval R., Bayerl B., Bäcker U., Gathof G. A., Sugg U. Diagnostic significance of quantitative determination of hepatitis B surface antigen in acute and chronic hepatitis B infection. Eur J Clin Microbiol. 1982 Feb;1(1):52–58. doi: 10.1007/BF02014141. [DOI] [PubMed] [Google Scholar]
  19. Henney C. S. Quantitation of the cell-mediated immune response. I. The number of cytolytically active mouse lymphoid cells induced by immunization with allogeneic mastocytoma cells. J Immunol. 1971 Dec;107(6):1558–1566. [PubMed] [Google Scholar]
  20. Hoffsten P. E., Oldstone M. B., Dixon F. J. Immunopathology of adoptive immunization in mice chronically infected with lymphocytic choriomeningitis virus. Clin Immunol Immunopathol. 1977 Jan;7(1):44–52. doi: 10.1016/0090-1229(77)90028-9. [DOI] [PubMed] [Google Scholar]
  21. Hoofnagle J. H., Dusheiko G. M., Schafer D. F., Jones E. A., Micetich K. C., Young R. C., Costa J. Reactivation of chronic hepatitis B virus infection by cancer chemotherapy. Ann Intern Med. 1982 Apr;96(4):447–449. doi: 10.7326/0003-4819-96-4-447. [DOI] [PubMed] [Google Scholar]
  22. Hotchin J., Kinch W., Benson L. Lytic and turbid plaque-type mutants of lymphocytic choriomeningitis virus as a cause of neurological disease or persistent infection. Infect Immun. 1971 Sep;4(3):281–286. doi: 10.1128/iai.4.3.281-286.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Joller-Jemelka H. I., Pfister H. F., Grob P. J. Die prognostische Bedeutung der quantitativen HBsAg-Bestimmung bei akuter Hepatitis B. Schweiz Med Wochenschr. 1985 Sep 14;115(37):1249–1256. [PubMed] [Google Scholar]
  24. Julius M. H., Simpson E., Herzenberg L. A. A rapid method for the isolation of functional thymus-derived murine lymphocytes. Eur J Immunol. 1973 Oct;3(10):645–649. doi: 10.1002/eji.1830031011. [DOI] [PubMed] [Google Scholar]
  25. Lee A. K., Ip H. M., Wong V. C. Mechanisms of maternal-fetal transmission of hepatitis B virus. J Infect Dis. 1978 Nov;138(5):668–671. doi: 10.1093/infdis/138.5.668. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Marshak-Rothstein A., Fink P., Gridley T., Raulet D. H., Bevan M. J., Gefter M. L. Properties and applications of monoclonal antibodies directed against determinants of the Thy-1 locus. J Immunol. 1979 Jun;122(6):2491–2497. [PubMed] [Google Scholar]
  28. Mondelli M., Eddleston A. L. Mechanisms of liver cell injury in acute and chronic hepatitis B. Semin Liver Dis. 1984 Feb;4(1):47–58. doi: 10.1055/s-2008-1040645. [DOI] [PubMed] [Google Scholar]
  29. Mondelli M., Vergani G. M., Alberti A., Vergani D., Portmann B., Eddleston A. L., Williams R. Specificity of T lymphocyte cytotoxicity to autologous hepatocytes in chronic hepatitis B virus infection: evidence that T cells are directed against HBV core antigen expressed on hepatocytes. J Immunol. 1982 Dec;129(6):2773–2778. [PubMed] [Google Scholar]
  30. Oldstone M. B., Sinha Y. N., Blount P., Tishon A., Rodriguez M., von Wedel R., Lampert P. W. Virus-induced alterations in homeostasis: alteration in differentiated functions of infected cells in vivo. Science. 1982 Dec 10;218(4577):1125–1127. doi: 10.1126/science.7146898. [DOI] [PubMed] [Google Scholar]
  31. Scullard G. H., Smith C. I., Merigan T. C., Robinson W. S., Gregory P. B. Effects of immunosuppressive therapy on viral markers in chronic active hepatitis B. Gastroenterology. 1981 Dec;81(6):987–991. [PubMed] [Google Scholar]
  32. Siddell S., Wege H., ter Meulen V. The structure and replication of coronaviruses. Curr Top Microbiol Immunol. 1982;99:131–163. doi: 10.1007/978-3-642-68528-6_4. [DOI] [PubMed] [Google Scholar]
  33. Tosolini F. A., Mims C. A. Effect of murine strain and viral strain on the pathogenesis of lymphocytic choriomeningitis infection and a study of footpad responses. J Infect Dis. 1971 Feb;123(2):134–144. doi: 10.1093/infdis/123.2.134. [DOI] [PubMed] [Google Scholar]
  34. Townsend A. R., McMichael A. J. Specificity of cytotoxic T lymphocytes stimulated with influenza virus. Studies in mice and humans. Prog Allergy. 1985;36:10–43. doi: 10.1159/000409860. [DOI] [PubMed] [Google Scholar]
  35. Vielh P., Castellazzi M. Use of a P815-derived line with an amplified adenosine deaminase gene: an improved target for cellular cytotoxicity. Eur J Immunol. 1985 Oct;15(10):981–985. doi: 10.1002/eji.1830151004. [DOI] [PubMed] [Google Scholar]
  36. WILSNACK R. E., ROWE W. P. IMMUNOFLUORESCENT STUDIES OF THE HISTOPATHOGENESIS OF LYMPHOCYTIC CHORIOMENINGITIS VIRUS INFECTION. J Exp Med. 1964 Nov 1;120:829–840. doi: 10.1084/jem.120.5.829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Zinkernagel R. M., Doherty P. C. Characteristics of the interaction in vitro between cytotoxic thymus-derived lymphocytes and target monolayers infected with lymphocytic choriomeningitis virus. Scand J Immunol. 1974;3(3):287–294. doi: 10.1111/j.1365-3083.1974.tb01259.x. [DOI] [PubMed] [Google Scholar]
  38. Zinkernagel R. M., Doherty P. C. MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness. Adv Immunol. 1979;27:51–177. doi: 10.1016/s0065-2776(08)60262-x. [DOI] [PubMed] [Google Scholar]
  39. Zinkernagel R. M., Pfau C. J., Hengartner H., Althage A. Susceptibility to murine lymphocytic choriomeningitis maps to class I MHC genes--a model for MHC/disease associations. 1985 Aug 29-Sep 4Nature. 316(6031):814–817. doi: 10.1038/316814a0. [DOI] [PubMed] [Google Scholar]
  40. Zinkernagel R. M., Sado T., Althage A., Kamisaku H. Anti-viral immune response of allogeneic irradiation bone marrow chimeras: cytotoxic T cell responsiveness depends upon H-2 combination and infectious agent. Eur J Immunol. 1984 Jan;14(1):14–23. doi: 10.1002/eji.1830140104. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES