IL-12 PROMOTES DRUG-INDUCED CLEARANCE OF MYCOBACTERIUM-AVIUM INFECTION IN MICE

The intracellular pathogen Mycobacterium avium is a major cause of opp ortunistic infection in AIDS patients and is difficult to manage using conventional chemotherapeutic approaches. In the current study, we de scribe a strategy for the treatment of M., avium in T cell-deficient h osts based on the simultaneous administration of antibiotics and the i mmunomodulatory cytokine IL-12, In contrast to SCID mice, which were p artially resistant, animals lacking a functional IL-12 p40 gene were f ound 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 dos es caused small but significant reductions in splenic pathogen loads. Moreover, a lower dose of IL-12, when combined with the antimycobacter ial drags clarithromycin or rifabutin, induced a decrease in bacterial numbers that was significantly greater than that resulting from Me ad ministration of the cytokine or drop alone. A similar synergistic effe ct of IL-12 and antibiotics was seen when immunocompetent mice were tr eated with the same regimen. The activity of IL-12 in these experiment s was shown to be dependent upon the induction of endogenous IFN-gamma . Nevertheless, IFN-gamma itself, even when given at a higher dose tha n IL-12, failed to significantly enhance antibiotic clearance of bacte ria, Together these findings suggest that IL-12 may be a particularly potent adjunct for chemotherapy of M., avium infection in immunocompro mised individuals and may result in more effective control of the path ogen without the need for increased drug dosage.