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*
Immunology and Infection Program, Department of Pathology, McMaster University, Hamilton, Ontario, Canada;
Pasteur Mérieux Connaught, North York, Ontario, Canada; and
Hoffmann-La Roche, Inc., Nutley, NJ 07110
Understanding of key cytokines and the nature of protective immune
responses in pulmonary mycobacterial diseases remains a task of
paramount importance. In this study, both wild-type (wt) and
IL-12-deficient (IL-12-/-) mice were infected by
airways inoculation of live Mycobacterium bovis bacille
Calmette-Guérin (BCG). The type 1 cytokines IL-12, IFN-
, and
TNF-
, but not the type 2 cytokines IL-4 and granulocyte macrophage
(GM)-CSF, markedly increased in the lung and peripheral blood of wt
mice postinfection, which resulted in the development of intense
granulomatous responses and the effective control of mycobacterial
infection in the lung. In contrast, IL-12-/- mice
demonstrated a lack of both types 1 and 2 cytokines in the lung and
blood and a severely impaired tissue immune-inflammatory response
lacking not only macrophages and neutrophils but CD4 and CD8 T cells
and NK cells in the lung throughout the entire course of study. Total
lung mononuclear cells isolated from these mice, in contrast to wt
mice, had an impaired recall immune response to Ag challenge in vitro.
These impaired responses resulted in an uncontrolled local growth and
systemic spread of bacilli. Our findings reveal that IL-12 plays an
irreplaceable role in the initiation of Th1 responses, and the loss of
its function cannot be compensated for by alternative mechanisms in the
lung. This cytokine, together with IFN- and TNF-, and
granulomatous inflammation are critically required for the effective
control of pulmonary mycobacterial infection. Our results also indicate
that the absence of type 1 cytokines does not necessarily favor a Th2
response.
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