Although various antimicrobial drugs show appreciable bactericidal activity in the early phase (2 to 4 weeks after
infection) of Mycobacterium avium complex (MAC)
infections in mice, no
drug, as far as we know, can continue to exert the growth inhibiting activity against the bacteria at the site of
infection in the progressed stage. Here, we studied the mechanisms of the bacterial regrowth which usually starts around 2-4 weeks after
infection. First, the changes in the level of
TNF-alpha, IFN-gamma,
IL-6 and
IL-10 in the lungs and spleen during the course of MAC
infections was examined. Tissue levels of
TNF-alpha and
IL-10 increased around weeks 2 to 4, then rapidly decreased thereafter, and returned to the normal levels by week 8, while levels of IFN-gamma and
IL-6 remained very low throughout the observation period. In this experiment, the bacterial CFUs rapidly decreased during the first 2 weeks of the treatment with a
rifamycin derivative,
KRM-1648, and thereafter the regrowth of the organisms was observed even in mice treated continuously with
KRM-1648, although the rate of bacterial growth in the treated mice was much lower than in untreated control mice. Second, effect of either anti-
TGF-beta or anti-IL-10 antibody on intracellular growth of MAC in human monocytes cultured in vitro in the medium with or without addition of
TNF-alpha or IFN-gamma were examined. Anti-
TGF-beta and anti-IL-10
antibodies potently reduced the bacterial growth in monocytes. Effects of
TNF-alpha and IFN-gamma in reducing the bacterial growth was potentiated by the addition of either anti-
TGF-beta or anti-IL-10 antibody. Third, anti-IL-10 antibody augmented to some extent the chemotherapeutic efficacy of
KRM-1648 against MAC
infection, when the
drug was given to mice at weeks 2 and 4 after
infection. From these results, it is suggested that
IL-10 derived from MAC-infected macrophages in response to stimulation with some bacterial components, such as
lipoarabinomannan, might downregulate the antimicrobial function of host macrophages against MAC.