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.
Doherty
T M
TM
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Health, Bethesda, MD 20892, USA.
Sher
A
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D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D017291:Clarithromycin / Q000008:administration & dosage; D003433:Crosses, Genetic; D004359:Drug Therapy, Combination; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000502:physiology / Q000627:therapeutic use; D018664:Interleukin-12 / Q000172:deficiency / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009162:Mycobacterium avium / Q000276:immunology*; D017828:Rifabutin / Q000008:administration & dosage; D014376:Tuberculosis / Q000188:drug therapy* / Q000276:immunology* / Q000382:microbiology
D000276:Adjuvants, Immunologic; D018664:Interleukin-12; D017828:Rifabutin; D007371:Interferon-gamma; D017291:Clarithromycin