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Transgene1
Department of Pathology and Molecular Medicine, and Division of Infectious Diseases, Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada
Humans with immune-compromised conditions such as SCID are unable
to control infection caused by normally nonpathogenic intracellular
pathogens such as Mycobacterium bovis bacillus
Calmette-Guérin. We found that SCID beige mice lacking both
lymphocytes and NK cells had functionally normal lung macrophages and
yet a selectively impaired response of type 1 cytokines IFN-
and
IL-12, but not TNF-
, during M. bovis bacillus
Calmette-Guérin infection. These mice succumbed to such
infection. A repeated lung gene transfer strategy was designed to
reconstitute IFN- in the lung, which allowed investigation of
whether adequate activation of innate macrophages could enhance host
defense in the complete absence of lymphocytes. IFN- transgene-based
treatment was initiated 10 days after the establishment of
mycobacterial infection and led to increased levels of both IFN- and
IL-12, but not TNF-, in the lung. Lung macrophages were activated to
express increased MHC molecules, type 1 cytokines and NO, and increased
phagocytic and mycobactericidal activities. Activation of innate
immunity markedly inhibited otherwise uncontrollable growth of
mycobacteria and prolonged the survival of infected SCID hosts. Thus,
our study proposes a cytokine transgene-based therapeutic modality to
enhance host defense in immune-compromised hosts against intracellular
bacterial infection, and suggests a central effector activity played by
IFN--activated macrophages in antimycobacterial cell-mediated
immunity.
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