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Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
The intracellular pathogen Mycobacterium avium is a
major cause of opportunistic infection in AIDS patients and is
difficult to manage using conventional chemotherapeutic approaches. In
the current study, we describe a strategy for the treatment of M.
avium in T cell-deficient hosts based on the simultaneous
administration of antibiotics and the immunomodulatory cytokine IL-12.
In contrast to SCID mice, which were partially resistant, animals
lacking a functional IL-12 p40 gene were found to be highly
susceptible to M. avium infection, suggesting that the
cytokine can control bacterial growth even in immunodeficient mice.
Indeed, rIL-12 that was injected into infected SCID mice in high doses
caused small but significant reductions in splenic pathogen loads.
Moreover, a lower dose of IL-12, when combined with the
antimycobacterial drugs clarithromycin or rifabutin, induced a decrease
in bacterial numbers that was significantly greater than that resulting
from the administration of the cytokine or drug alone. A similar
synergistic effect of IL-12 and antibiotics was seen when
immunocompetent mice were treated with the same regimen. The activity
of IL-12 in these experiments was shown to be dependent upon the
induction of endogenous IFN-
. Nevertheless, IFN- itself, even
when given at a higher dose than IL-12, failed to significantly enhance
antibiotic clearance of bacteria. Together these findings suggest that
IL-12 may be a particularly potent adjunct for chemotherapy of M.
avium infection in immunocompromised individuals and may result
in more effective control of the pathogen without the need for
increased drug dosage.
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