In these animals, increased PMN recruitment to the peritoneal cavity was noted as early as 60 minutes post infection, resulting in neutrophilia associated with compromise of the protect ive Th1 type immune response. In our study, in fection with an Mtb strain that is not controlled Sunitinib CAS was associated with early accumulation of higher numbers of PMN in the lungs of infected rabbits. Thus, although our results implicate PMN in the progression to active disease, it is not clear whether they drive the differential progression of infection or whether they are merely associated with differential macrophage re sponses. Recently, Berry et al. reported increased levels of interferon inducible Inhibitors,Modulators,Libraries gene transcripts, originated from myeloid cells, including PMN, in the blood of active TB patients, relative to those in latently infected Inhibitors,Modulators,Libraries individuals.

Taken together, these observations support our con clusion that during Mtb infection, increased inflamma tion with recruitment and activation of PMN is associated with progression to active disease rather than control of Inhibitors,Modulators,Libraries infection. Clearly, very early events induced by the interactions between the phagocyte and the pathogen can result in radically different outcomes, suggesting that the initial profile of macrophage differentiation will determine the nature of both innate and acquired immune responses. The range of phagocyte differentiation in duced by various Mtb strains is a manifestation of the plasticity of the cells and their ability to sense and re spond to different microbial agonists and mediators of host immunity.

Inhibitors,Modulators,Libraries However, exactly how the early inflammatory response subverts the development of a protective immune response is not fully understood. It has been shown that TNF Inhibitors,Modulators,Libraries is important for the organization and maintenance of granulomas and the as sociated host response in animal models of Mtb infec tion. In this study, we observed increased TNFA and CCL2 levels in the lungs of rabbits infected with HN878, relative to CDC1551, at 3 hours. However, pre vious studies in human and mouse monocytesmacro phages, as well as in mice, have shown that, compared to HN878, infection with CDC1551 induces higher pro duction of inflammatory molecules, including TNF and CCL 2. This discordance is most likely due to the differential kinetics of macrophage activation in vivo and invitro as well as inherent differences be tween the rabbit and mouse models.

In the present study, transcript levels in rabbit lungs were measured at 3 hours post infection, whereas protein and transcript levels of TNF and CCL 2 were determined at 7, 14, 21, 28 and 60 days definitely in infected mice or 24, 48, 72 and 96 hours in Mtb infected human PBMC, in other published reports. Importantly, increased levels of TNF have been documented in the blood and pleural fluids of active TB patients, compared to healthy contacts.