Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin.
TNF and lymphotoxin-alpha (LT alpha) may act at various stages of the host response to Mycobacterium tuberculosis. To dissect the effects of TNF independent of LT alpha, we have used C57BL/6 mice with a disruption of the TNF gene alone (TNF-/-). Twenty-one days following aerosol M. tuberculosis infection there was a marked increase in the number of organisms in the lungs of TNF-/- mice, and by 28-35 days all animals had succumbed, with widespread dissemination of M. tuberculosis. In comparison with the localized granulomas containing activated macrophages and T cells in lungs and livers of C57BL/6 wild-type (wt) mice, cellular infiltrates in TNF-/- mice were poorly formed, with extensive regions of necrosis and neutrophilic infiltration of the alveoli. Phenotypic analysis of lung homogenates demonstrated similar numbers of CD4+ and CD8+ T cells in TNF-/- and wt mice, but in TNF-deficient mice the lymphocytes were restricted to perivascular and peribronchial areas rather than colocated with macrophages in granulomas. T cells from TNF-/- mice retained proliferative and cytokine responses to purified protein derivative, and delayed-type hypersensitivity to purified protein derivative was demonstrable. Macrophages within the lungs of TNF-/- and wt mice showed similar levels of MHC class II and inducible nitric oxide synthase expression, and levels of serum nitrite were comparable. Thus, the enhanced susceptibility of TNF-/- is not compensated for by the presence of LT alpha, and the critical role of TNF is not in the activation of T cells and macrophages but in the local organization of granulomas.
Bean
A G
AG
Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Australia.
Roach
D R
DR
Briscoe
H
H
France
M P
MP
Korner
H
H
Sedgwick
J D
JD
Britton
W J
WJ
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D002465:Cell Movement / Q000276:immunology; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease / Q000276:immunology*; D015769:Granuloma, Respiratory Tract / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006968:Hypersensitivity, Delayed / Q000209:etiology / Q000235:genetics; D016130:Immunophenotyping; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D008233:Lymphotoxin-alpha / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009573:Nitrites / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014373:Tuberculin / Q000008:administration & dosage; D014376:Tuberculosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics* / Q000502:physiology
D000336:Aerosols; D008233:Lymphotoxin-alpha; D009573:Nitrites; D014373:Tuberculin; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma