MURINE HEPATITIS CAUSED BY LYMPHOCYTIC CHORIOMENINGITIS VIRUS .2. CELLS INVOLVED IN PATHOGENESIS

BACKGROUND: Human virus hepatitides are often assumed to result from p athogenic immune responses rather than from direct viral cytopathic ef fects, but the details are largely unknown. Hepatitis of the mouse und ergoing infection with lymphocytic choriomeningitis (LCM) virus is an immunopathologic phenomenon, and its analysis may help us to understan d some of the events leading to the human illnesses. EXPERIMENTAL DESI GN: Mice were infected with LCM virus and were depleted of T cells or their subsets by inoculation of monoclonal antibodies; other infected mice lacked all T lymphocytes or the CD8(+) subset because of genetic defects. Also, mice were infected and transfused with unsorted or CD4( +)-enriched LCM-immune spleen cells. Subsequently, the infectious tite rs were determined, the cytolytic activities of mononuclear cells isol ated from the livers were measured, and the disease process was studie d. RESULTS: In LCM virus-infected mice devoid of all T lymphocytes, pa thologic alterations remained undetectable. In contrast, immunocompete nt animals responded with a severe hepatitis, at the height of which t he liver contained large numbers of cytolytic mononuclear leukocytes. Experiments with mice depleted of subset T lymphocytes revealed a pred ominantly CD8(+) T lymphocyte-mediated phase, which was characterized by panlobular inflammation, whereas later there was a periportal infla mmatory reaction, in which mainly CD4(+) T lymphocytes were involved. Infusion of syngeneic immune spleen cells from immunocompetent donor m ice into infected thymus-less mice resulted in virus elimination and d amage to liver cells. With a similar protocol and the use of congenic mice, CD8(+) T lymphocytes were observed to rapidly enter the recipien ts' livers, where they were present at the time liver cell injury was apparent. In mice genetically deficient in CD8(+) T lymphocytes due to disruption of the gene for beta(2)-microglobulin, a somewhat differen t type of LCM hepatitis developed that was largely dependent on CD4(+) T lymphocytes. Liver cells were also damaged in infected nude mice th at had been infused with positively selected CD4(+) spleen cells from infected +/+ mice. CONCLUSIONS: Our findings published previously (Loh ler J, Gossmann J, Kratzberg T, Lehmann-Grube F. Lab Invest 1994;70:26 3-78) and related here suggest that the hepatitis in mice undergoing i nfection with LCM virus consists of three consecutive phases, which ar e mediated predominantly by NK cells, CD8(+) T lymphocytes, and CD4(+) T lymphocytes, respectively. Presumably, other elements of the immune system, such as mononuclear phagocytes and B lymphocytes, contribute to the pathogenesis.