In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-gamma and TNF-alpha

Gazzinelli, R.T.; Wysocka, M.; Hieny, S.; Scharton-Kersten, T.; Cheever, A.; Kühn, R.; Mueller, W.; Trinchieri, G.; Sher, A.

In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-gamma and TNF-alpha

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Item Type:	Article
Title:	In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-gamma and TNF-alpha
Creators Name:	Gazzinelli, R.T., Wysocka, M., Hieny, S., Scharton-Kersten, T., Cheever, A., Kühn, R., Mueller, W., Trinchieri, G. and Sher, A.
Abstract:	To examine the function of IL-10 synthesis during early infection with the intracellular protozoan Toxoplasma gondii, IL-10 knockout (KO) mice were inoculated with an avirulent parasite strain (ME-49). In contrast to control littermates that displayed 100% survival, the IL-10-deficient animals succumbed within the first 2 wk of the infection, with no evidence of enhanced parasite proliferation. The mortality in the IL-10 KO mice was associated with enhanced liver pathology characterized by increased cellular infiltration and intense necrosis. Levels of IL-12 and IFN-gamma in sera of infected IL-10-deficient animals were four- to sixfold higher than those in sera from control mice, as were mRNA levels for IFN-gamma, IL-1 beta, TNF-alpha, and IL-12 in lung tissue. Similarly, macrophages from IL-10 KO mice activated in vitro or in vivo with T. gondii produced higher levels of TNF-alpha and IL-12 than macrophages from control animals. Moreover, spleen cells from IL-10 KO mice infected with T. gondii secreted more IFN-gamma than splenocytes from nondeficient animals. In vitro depletion experiments indicated that CD4+ lymphocytes are the major source of the latter cytokine in the spleen cell populations, and in vivo depletion with anti-CD4 Abs protected the IL-10 KO mice from parasite-induced mortality. Together the data suggest that endogenous IL-10 synthesis plays an important role in vivo in down-regulating monokine and IFN-gamma responses to acute intracellular infection, thereby preventing host immunopathology.
Keywords:	Acute Disease, Animal Toxoplasmosis, CD4-Positive T-Lymphocytes, Cytokines, Interferon-gamma, Interleukin-10, Interleukin-12, Knockout Mice, Macrophages, Toxoplasma, Tumor Necrosis Factor-alpha, Up-Regulation, Animals, Mice
Source:	Journal of Immunology
ISSN:	0022-1767
Publisher:	American Association of Immunologists
Volume:	157
Number:	2
Page Range:	798-805
Date:	15 July 1996
Official Publication:	http://www.jimmunol.org/content/157/2/798
PubMed:	View item in PubMed

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