To control tuberculosis worldwide, the burden of adult pulmonary disease must be reduced. Although widely used, Mycobacterium bovis BCG vaccination given at birth does not protect against adult pulmonary disease. Therefore, postexposure vaccination of adults with mycobacterial antigens is being considered. We examined the effect of various mycobacterial antigens on mice with prior M. tuberculosis infection. Subcutaneous administration of live or heat-treated BCG with or without lipid adjuvants to infected mice induced increased antigen-specific T-cell proliferation but did not reduce the bacterial load in the lungs and caused larger lung granulomas. Similarly, additional mycobacterial antigen delivered directly to the lungs by aerosol infection with viable M. tuberculosis mixed with heat-killed Mycobacterium tuberculosis (1:1) also did not reduce the bacillary load but caused increased expression of tumor necrosis factor alpha (TNF-␣) and interleukin 6 (IL-6), which was associated with larger granulomas in the lungs. When M. tuberculosis-infected mice were treated with recombinant BCG that secreted cytokines shown to reduce disease in a preinfection vaccine model, the BCG secreting TNF-␣, and to a lesser extent, IL-2 and gamma interferon (IFN-␥), caused a significant increase in granuloma size in the lungs. Moreover, treatment of M. tuberculosis-infected mice with recombinant murine TNF-␣ resulted in increased inflammation in the lungs and accelerated mortality without affecting the bacillary load. Taken together, these studies suggest that administration of mycobacterial antigens to mice with prior M. tuberculosis infection leads to immune activation that may exacerbate lung pathology via TNF-␣-induced inflammation without reducing the bacillary load.

Tuberculous meningitis (TBM), the most severe form of Mycobacterium tuberculosis infection in humans, is associated with significant morbidity and mortality despite successful treatment with antituberculous drugs. This is due to the irreversible brain damage subsequent to the local inflammatory response of the host to M. tuberculosis. Corticosteroids have been used in conjunction with antituberculous therapy in an attempt to modulate the inflammatory response, but this strategy has been of limited success. Therefore, we examined whether combining antituberculous drugs with the immunomodulatory drug thalidomide or with a new thalidomide analog, immunomodulatory drug 3 (IMiD3), would be effective in reducing morbidity and mortality in an experimental rabbit model of TBM. Intracisternal inoculation of 5 ؋ 10 4 CFU of Mycobacterium bovis Ravenel in rabbits induced progressive subacute meningitis characterized by high cerebrospinal fluid (CSF) leukocytosis, protein influx, release of tumor necrosis factor (TNF), substantial meningeal inflammation, and mortality by day 28. Treatment with antituberculous drugs or with antituberculous drugs plus thalidomide improved the clinical course of disease somewhat and increased survival to about 50%. In contrast, treatment with antituberculous drugs in combination with IMiD3 limited pathological neurologic changes and resulted in marked improvement (73%) in survival. IMiD3 treatment was also associated with reduced leukocytosis in the CSF and significantly lower levels of TNF in CSF and plasma. Histologically, the meningeal inflammation in animals treated with antituberculous drugs plus IMiD3 was considerably attenuated compared to that of the other treatment groups. These results suggest a potential role for IMiD3 in the management of TBM in patients.

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