Model, MCMV

Figure 2 shows a model/measurement comparison from a butenedial photolysis experiment in the absence of NOx. The loss of butenedial is well predicted by MCMvS.l. However, the HO2 concentration is over-estimated by MCMv3.1 by almost an order of magnitude during the early part of the experiment. The time-dependent behaviour is also not well reproduced by the simulation as in the experiment an initial fast increase in concentration is followed by a slower linear increase until the chamber closes, while the simulation shows a fast rise followed by a fall in the HO2 concentration even while the photolysis continues. The photolysis mechanism for butenedial in the absence of NOx as implemented in MCMvS.l is shown schematically in Figure 4. This indicates fliat two HO2 radicals should be formed for each molecule of maleic anhydride and glyoxal produced, and while both these product concentrations are over-estimated this is not sufficient to account for the large over-prediction ofH02.

Comparison of modelled and measured concentrations Irom photosmog experiments on y-dicarbonyls indicated a number of shortcomings in the mechanisms. NO2 concentrationtime profiles are poorly simulated for all experiments, and the differences between experiments under different initial conditions are not well represented. It is clear that the NOxy budget is not well understood. The simulated HOx concentrations are significantly lower than the observed values and it seems that a large radical source is missing from the mechanism. However, very low HO2 radical concentrations were measured in y-dicarbonyl photolysis experiments in the absence of NOx, these measured concentrations were much lower than HO2 concentrations simulated by MCMvS.l. These important issues remain unresolved. 

The therapeutic agent should be further tested in the murine cytomegalovirus (MCMV) latent virus reactivation model if results from the influenza host resistance assay indicate a decreased functional activity for either NK, CTL, or TDAR, or a decrease in CD4+ cells as observed by immunopheno-typing. The MCMV latent virus reactivation model is discussed in detail below. The test article should be tested in the Streptococcus pneumoniae systemic model for encapsulated bacteria if immunophenotyping or histopathology, done in conjunction with the influenza host resistance model, reveals a decrease in the number of marginal zone B (MZB) cells. MZB cells are critical in host defense against bloodborne encapsulated bacteria and this host resistance assay is discussed in detail below. 

Murine Cytomegalovirus (MCMV) Latent Virus Reactivation Model... 

The critical role NK cells play in the control of infection with viruses is well-recogni2ed (French Yokoyama 2003). In the murine cytomegalovirus (MCMV) model, susceptibility to lethal infection can be overcome by a dominant allele at... 

The role of an immune-evasive gene in vivo can only be proven for MCMV and RCMV as a model for HCMV. Even though the mode of action to evade the host immune system may be different in HCMV and MCMV with respect to mechanistic details, the use of an animal model can show the relevance of the interaction between the virus functions and the host immune system. 

The cellular immune response plays a crucial role in controlling HCMV disease. Immunocompromised patients lacking a detectable HCMV-specific CD8 cytotoxic T lymphocyte (CTL) response are susceptible to HCMV infection, whereas the presence of a specific CTL response correlates with resistance to infection (Reusser et al. 1991). Adoptive transfer of in vitro expanded HCMV-specific CTL has proved effective in reconstituting a CTL response in bone marrow transplant recipients (Riddell et al. 1992 Walter et al. 1995). In the murine model, CTL are also capable of controlling both primary infection and MCMV recurrence (Biron et al. 1999 Polic et al. 1998). 

Animal models demonstrate that the IFN-stimulated JAK/STAT signal transduction pathway is critical for controlling CMV infections. STATl knockout mice and IFN-ot receptor/IFN-y receptor double knockout mice, which are deficient in IFN-stimulated signal transduction and biological responses, are exquisitely sensitive to viral infection (Durbin et al. 1996 Presti et al. 1998). In these mice, acute MCMV infection proceeds unchecked and rapidly leads to death. 

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