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-γ, 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-γ 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.

The immunopathogenesis of mycobacterial infections frequently involves the formation of caseating granulomas which cause tissue destruction and, in the case of tuberculosis (TB), may lead to cavity formation. Both intravenous and aerosol models of Mycobacterium tuberculosis infection in mice do not reflect the pulmonary lesions characteristic of TB patients. Using both low‐dose (102 colony‐forming units, cfu) and high‐dose (105 cfu) aerosol infection with a highly virulent strain of Mycobacterium avium (TMC724) in C57BL/6 mice, it is now shown that these mice are capable of developing centrally caseating necrosis in lung granulomas after approximately 4 months of infection. In contrast, mice infected intravenously with the high dose never developed this type of lesion, although bacterial counts in their lungs reached levels comparable to those attained by aerosol‐infected mice (1010 cfu). To study the relevance of events signalled by tumour necrosis factor (TNF) in this model, TNFRp55 gene‐deficient and syngeneic C57BL/6 immunocompetent mice were infected with 105 cfu M. avium via aerosol. In gene‐deficient mice, newly formed pulmonary granulomas acutely disintegrated, showing signs of apoptotic cell death and neutrophil influx, and TNFRp55 knock‐out mice all succumbed to infection just beyond the stage of granuloma initiation. Aerogenic infection with M. avium in mice is a suitable model to study the immunopathogenesis of granuloma necrosis because it closely mimicks the histopathology of mycobacterial infections in humans, including TB. Furthermore, the use of TNFRp55 gene‐deficient mice in this model establishes a role for TNF in maintaining the integrity of a developing pulmonary granuloma. Copyright © 1999 John Wiley & Sons, Ltd.