LACK OF BOTH TYPE-1 AND TYPE-2 CYTOKINES, TISSUE INFLAMMATORY RESPONSES, AND IMMUNE PROTECTION DURING PULMONARY INFECTION BY MYCOBACTERIUM-BOVIS BACILLE CALMETTE-GUERIN IN IL-12-DEFICIENT MICE

Understanding of key cytokines and the nature of protective immune res ponses in pulmonary mycobacterial diseases remains a task of paramount importance. In this study, both wild-type (wt) and IL-12-deficient (I L-12(-/-)) mice were infected by airways inoculation of live Mycobacte rium bovis bacille Calmette-Guerin (BCG), The type 1 cytokines IL-12, IFN-gamma, and TNF-alpha, but not the type 2 cytokines IL-4 and granul ocyte macrophage (GM)-CSF, markedly increased in the lung and peripher al blood of wt mice postinfection, which resulted in the development o f intense granulomatous responses and the effective control of mycobac terial infection in the lung. In contrast, IL-12(-/-) mice demonstrate d a lack of both types 1 and 2 cytokines in the lung and blood and a s everely impaired tissue immune-inflammatory response lacking not only macrophages and neutrophils but CD4 and CD8 T cells and NK cells in th e lung throughout the entire course of study. Total lung mononuclear c ells isolated from these mice, in contrast to wt mice, had an impaired recall immune response to Ag challenge in vitro. These impaired respo nses resulted in an uncontrolled local growth and systemic spread of b acilli. Our findings reveal that IL-12 plays an irreplaceable role in the initiation of Th1 responses, and the loss of its function cannot b e compensated for by alternative mechanisms in the lung, This cytokine , together with IFN-gamma and TNF-alpha, and granulomatous inflammatio n are critically required for the effective control of pulmonary mycob acterial infection. Our results also indicate that the absence of type 1 cytokines does not necessarily favor a Th2 response.