The production of immunosuppressive cytokines, such as IL-10 and TGF-β, has been documented in individuals diagnosed with active tuberculosis. In addition, IL-10 production is increased within the lungs of mice that have chronic mycobacterial infection. Therefore, we hypothesized that the down-regulatory properties of IL-10 might contribute to the reactivation of chronic Mycobacterium tuberculosis infection in mice. To determine the influence of IL-10 on the course of infection, transgenic mice producing increased amounts of IL-10 under the control of the IL-2 promotor were infected with M. tuberculosis via the respiratory route. Mice that overexpressed IL-10 showed no increase in susceptibility during the early stages of infection, but during the chronic phase of the infection showed evidence of reactivation tuberculosis with a highly significant increase in bacterial numbers within the lungs. Reactivation was associated with the formation of macrophage-dominated lesions, decreased mRNA production for TNF and IL-12p40, and a decrease in Ag-specific IFN-γ secretion. These data support the hypothesis that IL-10 plays a pivotal role during the chronic/latent stage of pulmonary tuberculosis, with increased production playing a potentially central role in promoting reactivation tuberculosis.

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In this study different inbred strains of mice appeared to control and contain a low dose aerosol infection with Mycobacterium tuberculosis in a similar manner, giving rise to a chronic state of disease. Thereafter, however, certain strains gradually began to show evidence of regrowth of the infection, whereas others consistently did not. Using C57BL/6 mice as an example of a resistant strain and CBA/J mice as an example of a strain susceptible to bacterial growth, we found that these animals revealed distinct differences in the cellular makeup of lung granulomas. The CBA/J mice exhibited a generally poor lymphocyte response within the lungs and vastly increased degenerative pathology at a time associated with regrowth of the infection. As a possible explanation for these events, it was then observed that the CBA/J mouse strain was also less able to upregulate adhesion molecules, including CD11a and CD54, on circulating lymphocytes. These results therefore suggest that a failure to control a chronic infection with M. tuberculosis may reflect an inability to localize antigen-specific lymphocytes within the lung.Disease caused by Mycobacterium tuberculosis is often not due to primary infection but instead is caused by reactivation of a latent or dormant infection that the patient may have carried for many years (20). It is unclear however, how the host initially expresses resistance in the lung and why this resistance is eventually lost, thus allowing bacterial regrowth. In this regard, the mouse is a useful model of specific resistance to M. tuberculosis infection. After low or moderate doses of bacilli are delivered by either intravenous or aerogenic routes, an apparently stable chronic disease state is established after a few weeks in the infected organs of the animal (3, 24). This chronic infection continues for a prolonged period in the C57BL/6 mouse strain until influenced by immunosenescence (23). It is currently speculated that during the chronic phase of infection, the bacteria remain in some form of latent state.That this assumption may be wrong, however, is suggested by recent evidence indicating that chronic M. tuberculosis infection in the lung is in fact a dynamic event (27), at least in terms of granuloma pathology, which changes dramatically over the life span of the animal. In addition, studies directed toward understanding the role of the Bcg gene (Nramp1) have shown that certain inbred strains of mice clearly differ in their ability to survive a chronic M. tuberculosis infection (16, 18), in confirmation of much earlier reports of this phenomenon (15,26).The results of the current study confirm and extend these findings by showing that certain strains of mice, although able to initially control a low-dose aerosol infection with M. tuberculosis, eventually succumb during the chronic phase of disease. The current study shows that this early mortality was associated with an increased bacterial burden within the lung and occurred prior to events that could be attributed to immunosenesence (23). Comp...