IL-12 Promotes Drug-Induced Clearance of Mycobacterium avium Infection in Mice

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-gamma. Nevertheless, IFN-gamma 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.