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 visceralizing species of Leishmania, L. chagasi. We have evidence that a soluble factor(s) inhibits IFN-gamma production by cultured liver granuloma cells from BALB/c mice during L. chagasi infection. In contrast, liver granulomas from C3H.HeJ mice, which are genetically resistant to L. chagasi infection, produce abundant IFN-gamma. According to ELISAs and neutralization studies, there was not evidence that the Th2-type cytokines IL-10 or IL-4 contributed to IFN-gamma suppression. However, both Ab neutralization and immunohistochemistry showed that granuloma-derived TGF-beta was, at least in part, responsible for inhibiting IFN-gamma release by CD4+ cells in BALB/c liver granuloma cultures. Consistently, TGF-beta levels were high in liver granulomas from susceptible BALB/c mice but low in resistant C3H mice or in BALB/c mice that were immunized against L. chagasi disease. Administration of recombinant adenovirus expressing TGF-beta (AdV-TGFbeta) but not IL-10 (AdV-IL10) caused genetically resistant C3H mice to become significantly more susceptible to L. chagasi infection. In contrast, either AdV-TGFbeta or AdV-IL10 could abrogate the protective immune response achieved by immunization of BALB/c mice. We conclude that locally secreted TGF-beta inhibits Th1-associated cure of murine visceral leishmaniasis caused by L. chagasi, independently of Th2-type cytokines.
Wilson
M E
ME
Department of Internal Medicine, University of Iowa, Veterans Affairs Medical Center, Iowa City 52242, USA.
Young
B M
BM
Davidson
B L
BL
Mente
K A
KA
McGowan
S E
SE
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D006099:Granuloma / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D007700:Kinetics; D018314:Leishmania infantum / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008109:Liver Diseases, Parasitic / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D012995:Solubility; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D014611:Vaccination
D000953:Antigens, Protozoan; D016207:Cytokines; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D007371:Interferon-gamma