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...

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Published in:	The Journal of immunology (1950) Vol. 161; no. 11; pp. 6148 - 6155
Main Authors:	Wilson, M E, Young, B M, Davidson, B L, Mente, K A, McGowan, S E
Format:	Journal Article
Language:	English
Published:	United States 01-12-1998
Subjects:	Adenoviridae - genetics Animals Antigens, Protozoan - immunology Antigens, Protozoan - pharmacology Cells, Cultured Cytokines - biosynthesis Cytokines - secretion Disease Models, Animal Genetic Vectors - administration & dosage Genetic Vectors - immunology Granuloma - immunology Granuloma - metabolism Interferon-gamma - antagonists & inhibitors Interferon-gamma - biosynthesis Interleukin-10 - biosynthesis Kinetics Leishmania chagasi Leishmania infantum - immunology Leishmaniasis, Visceral - immunology Leishmaniasis, Visceral - metabolism Leishmaniasis, Visceral - pathology Liver Diseases, Parasitic - immunology Liver Diseases, Parasitic - metabolism Mice Mice, Inbred BALB C Mice, Inbred C3H Solubility Transforming Growth Factor beta - biosynthesis Transforming Growth Factor beta - immunology Transforming Growth Factor beta - physiology Vaccination
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0022-1767 1550-6606
DOI:	10.4049/jimmunol.161.11.6148