Effects of immunosuppression with cyclophosphamide on acute murine cytomegalovirus infection and virus-augmented natural killer cell activity

Abstract

The effects of cyclophosphamide (CY) treatment on acute murine cytomegalovirus (MCMV) infection were studied to explore the potential usefulness of MCMV as a means of detecting immune dysfunction and to identify host defense mechanisms important for protection against MCMV. Conditions found optimal for enhancing MCMV infection with CY included infecting adult mice with 2 x 105 PFU or more of virus and administering 80 mg or more of CY per kg 1 to 3 days later. In addition to enhanced mortality, virus titers in lung, liver, and spleen were elevated in CY-treated mice, and wet weights of liver, spleen, and thymus were depressed when compared with those of infected but untreated mice. Treatment with CY before MCMV challenge was not as efficient a means of enhancing mortality as treatment after virus challenge. The effect that the time of CY administration relative to infection had on mortality correlated with the effect of such timing on natural killer cell activity. Animals treated before infection exhibited depressed natural killer cell activity initially. However, they rapidly recovered this response, and by 5 days postinfection they had the same level of virus-augmented activity seen in untreated mice. In contrast, animals treated after infection did not recover natural killer cell activity and were more likely to die. A similar correlation was not obtained when the effects of CY on lymphocyte responses to B and T cell mitogens were examined, nor were there striking differences in pathology between the treatment groups. The data suggest an important role for natural killer cells in host defense against MCMV. Also, increased susceptibility to MCMV may provide a useful indicator of deficits in the natural killer cell response.

Trigger‐dependent differences determine therapeutic outcome in murine primary hemophagocytic lymphohistiocytosis

“…The lack of disease signs in lymphocyte‐deficient NK cell depleted RAG‐deficient mice at a time point when PKO mice died with full‐blown HLH clearly indicates that this early death (day 7) is largely immune‐mediated. Nevertheless, the later death (days 15–20) observed in these and several other immunodeficient mice with impaired MCMV control illustrates an eventually severe additional direct virus‐induced effect [38,46–50]. Leukocytosis and increased TNF‐α and IL‐6 production in anti‐IFN‐γ treated MCMV‐PKO mice as well as increased liver NK cells in MCMV infected versus LCMV infected souris mice also implicate additional layers of disease immunopathogenesis that are uncovered by neutralization of IFN‐γ.…”

“…Infection of NK cell depleted RAG −/− mice showed that this lymphocyte‐independent damage is not responsible for the early severe immunopathological disease observed in PKO mice. Nevertheless, it likely causes the later lethality observed in various immunodeficient mouse strains with impaired MCMV control [38,46–50]. Moreover, this viral cytopathogenicity is also expected to increase and shift the overall inflammatory response.…”