Lethal granuloma disintegration in mycobacteria-infected TNFRp55-/- mice is dependent on T cells and IL-12.
Genetically susceptible, TNFRp55 gene-deficient (TNFRp55-/-) mice succumb to infection with Mycobacterium avium. Before their death, M. avium-infected TNFRp55-/- mice develop granulomatous lesions that, in contrast to granulomas in wild-type syngeneic mice, undergo acute disintegration. To determine the factors involved in these events, we depleted T cell subsets or neutralized the inflammatory cytokines IFN-gamma, IL-12, or TNF in TNFRp55-/- mice infected i.v. with M. avium. Infected TNFRp55-/- mice treated with a control mAb became moribund between days 26 and 34 postinfection, showing widespread inflammatory cell apoptosis within disintegrating granulomas. In contrast, TNFRp55-/- mice depleted of either CD4+ or CD8+ cells after granuloma initiation stayed healthy until at least day 38 postinfection and showed no signs of granuloma destruction. Neutralization of IL-12, but not of IFN-gamma or TNF, also protected M. avium-infected TNFRp55-/- mice from granuloma decomposition and from premature death. Treatment with dexamethasone or with a specific inhibitor of inducible NO synthase did not prevent granuloma dissolution or death of TNFRp55-/- mice. In conclusion, granuloma disintegration in TNFRp55-/- mice is a lethal event that is dependent on IL-12 and that is mediated by an excess of T cells.
Ehlers
S
S
Division of Molecular Infection Biology, Research Center Borstel, Germany. sehlers@fz-borstel.de
Kutsch
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Ehlers
E M
EM
Benini
J
J
Pfeffer
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K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006099:Granuloma / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology / Q000502:physiology*; D008099:Liver / Q000737:chemistry / Q000276:immunology / Q000648:ultrastructure; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009162:Mycobacterium avium / Q000472:pathogenicity; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma