S.D. Olver

Cytomegalovirus hepatitis: characterization of the inflammatory infiltrate in resistant and susceptible mice.

Mice susceptible and resistant to murine cytomegalovirus (MCMV) were infected with this virus and livers were harvested after 2–231 days. Cryostat sections were stained to visualize cells bearing CD4, CDS8 or Mac‐1 antigens. Mac‐1+ cells were prevalent in inflammatory foci after 2 days. These cells persisted in susceptible BALB/c and A/J mice, but disappeared from livers of resistant C57BI/6 and CBA/CaH mice by day 28. T cell inflammation peaked on days 7–11. This declined by day 56 in C57BI/6 and CBA/CaH mice, but persisted in BALB/c and A/J mice for at least 231 days. Persistent CD8+ cells were dispersed throughout the parenchyma. More CD8+ cells were observed 7–14 days after infection in the livers of bg/bg (natural killer (NK) cell‐deficient) C57B1/6 and CBA mice, and in C57BI/6 mice depleted of NK 1.1 cells by MoAb. Thus, mice of strains susceptible to MCMV exhibit hepatitis characterized by persistence of dispersed CD8+ cells. This phenomenon may be limited by NK ceils in resistant strains.

Characterization of thymic involution induced by murine cytomegalovirus infection

Infection of BALB/c mice with murine cytomegalovirus (MCMV) decreased the numbers of cells recovered from the thymus by 80–90% after 4–7 days, although less than 10 thymocytes per million were productively infected with the virus. A loss of cortical thymocytes was evident in histologic sections and correlated with depletion of CD4+CD8+ cells.

The roles of tumour necrosis factor-alpha, interleukin-1 and interleukin-12 in murine cytomegalovirus infection.

The roles of the inflammatory cytokines tumour necrosis factor‐α (TNF‐α), interleukin‐1 (IL‐1) and IL‐12, in murine cytomegalovirus (MCMV) disease were investigated in susceptible BALB/c and resistant C57BL/6 mice. MCMV infection induced IL‐1 and TNF‐α production by peritoneal cells from BALB/c mice, as demonstrated previously in C57BL/6 mice. Overt ill‐health and viral replication in the spleens of BALB/c mice were increased by in vivo treatment with soluble TNF‐α receptors to inhibit the activity of this cytokine, whilst antibodies to IL‐12 had a similar but more restricted effect. C57BL/6 mice were not affected by either treatment, suggesting TNF‐α and IL‐12 are not critical for natural killer cell‐mediated restriction of viral replication in the spleen. Soluble TNF‐α receptors and antibodies to IL‐12 also enhanced MCMV titres and numbers of viral antigen‐positive cells in the livers of BALB/c mice and TNF‐α receptors have similar effects in C57BL/6 livers. In contrast, IL‐1 receptors improved the health of MCMV‐infected BALB/c mice and reduced viral replication and hepatitis at some time‐points. Mechanisms which may underlie these changes are discussed.

The association between murine cytomegalovirus induced hepatitis and the accummulation of oval cells

The accumulation of oval cells is an early event in the development of hepatocellular carcinoma induced by certain experimental regimes involving hepatocarcinogens. Oval cells have also been observed during chronic hepatitis induced by alcohol and iron overload. In this study, livers of murine cytomegalovirus (MCMV) infected mice were examined to determine whether hepatitis induced by this virus could initiate oval cell proliferation. BALB/c and C57BL/6 mice were infected with MCMV and studied 4, 8, 10 and 12 months later, alongside control (uninfected) mice. The livers were examined histochemically, immunocytochemically and by in situ hybridization to identify oval cells, inflammatory cells and proliferating cells. Oval cells were seen in the periportal regions of livers from MCMV infected BALB/c mice. These increased in number from 4 to 12 months after infection in parallel with increases in the numbers of inflammatory cells, even though cells expressing MCMV antigens were no longer evident in these samples. Proliferating oval cells and hepatocytes were identified by PCNA staining, indicating an increased level of liver regeneration in the infected livers. C57BL/6 mice are less susceptible to persistent MCMV hepatitis and had fewer oval cells than BALB/c mice. Thus the study demonstrates an association between MCMV induced hepatitis, inflammation, and presence of oval cells.