Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosisinfection, 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 indep endent 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 infe ction there was a marked increase iii the number of organisms in the lungs of TNF-/- mice, and by 28-35 days all animals had succumbed, with widesprea d dissemination of M, tuberculosis. In comparison with the localized granul omas containing activated macrophages and T cells in lungs and livers of C5 7BL/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-defi cient mice the lymphocytes were restricted to perivascular and peribronchia l areas rather than colocated with macrophages in granulomas, T cells from TNF-/- mice retained proliferative and cytokine responses to purified prote in derivative, and delayed-type hypersensitivity to purified protein deriva tive was demonstrable. Macrophages within the lungs of TNF-/- and wt mice s howed similar levels of MHC class II and inducible nitric oxide synthase ex pression, and levels of serum nitrite were comparable, Thus, the enhanced s usceptibility 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 macro phages but in the local organization of granulomas.