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)

The influence of major transplantation antigens on susceptibility to T cell-mediated disease caused by infection with the noncytopathic virus lymphocytic choriomeningitis virus (LCMV) was evaluated in B10 H-2-congenic mice. Susceptibility to early T cell-mediated liver cell destruction (day 7-9) and early mortality (before day 12) was H-2Dq linked and correlated directly with early (day 6-8) and high cytotoxic T cell activity. In contrast, susceptibility to become an LCMV carrier, inability to rapidly clear virus, or tendency to develop late hepatitis (day 14-17) was linked to Dk and correlated with absence of early cytotoxic T cell activity. Thus, H-2D-regulated T cell-immune responses controlling both virus spread and immunopathology may directly determine the type and severity of disease. The results illustrate that susceptibility to disease caused by one virus may be linked to distinct MHC alleles dependent upon the disease parameter studied.