THE IMPORTANCE OF TGF-BETA IN MURINE VISCERAL LEISHMANIASIS

IFN-gamma is critical for the cure of leishmaniasis in humans and mice . BALB/c mice are genetically susceptible to infection with the viscer alizing species of Leshmania, L. chagasi, We have evidence that a solu ble factor(s) inhibits IFN-gamma production by cultured liver granulom a cells from BALB/c mice during L, chagasi infection, In contrast, liv er granulomas from C3H.HeJ mice, which are genetically resistant to L. chagasi infection, produce abundant IFN-gamma. According to ELISAs an d neutralization studies, there was not evidence that the Th2-type cyt okines IL-10 or IL-4 contributed to IFN-gamma suppression. However, bo th Ab neutralization and immunohistochemistry showed that granuloma-de rived TGF-beta was, at least in part, responsible for inhibiting IFN-g amma release by CD4(+) cells in BALB/c liver granuloma cultures, Consi stently, TGF-beta levels were high in liver granulomas from susceptibl e BALB/c mice but low in resistant C3H mice or in BALB/c mice that wer e immunized against L, chagasi disease. Administration of recombinant adenovirus expressing TGF-beta (AdV-TGF beta) but nut IL-10 (AdV-IL10) caused genetically resistant C3H mice to become significantly more su sceptible to L, chagasi infection. In contrast, either AdV-TGF beta or AdV-IL10 could abrogate the protective immune response achieved by im munization of BALB/c mice. We conclude that locally secreted TGF-beta inhibits Th1-associated cure of murine visceral leishmaniasis caused b y L. chagasi, independently of Th2-type cytokines.