Immunopathologic effects of tumor necrosis factor alpha in murine mycobacterial infection are dose dependent

In experimental mycobacterial infection, tumor necrosis factor alpha (TNF-a lpha) is required for control of bacillary growth and the protective granul omatous response, but may cause immunopathology, To directly examine the po sitive and detrimental effects of this cytokine, a murine model was used in which different amounts of TNF-alpha were delivered to the site of infecti on. Mice with a disruption in the TNF-alpha gene (TNF-KO) or wild-type mice were infected with low or high doses of recombinant Mycobacterium bovis BC G that secreted murine TNF-alpha (BCG-TNF). Infection of TNF-KO mice with B CG containing the vector (BCG-vector) at a low dose led to increased bacill ary load in all organs and an extensive granulomatous response in the lungs and spleen. The mice succumbed to the infection by similar to 40 days. How ever, when TNF-KO mice were infected with low doses of BCG-TNF, bacillary g rowth was controlled, granulomas were small and well differentiated, the sp leen was not enlarged, and the mice survived, Infection with high inocula o f BCG-TNF resulted in bacterial clearance, but was accompanied by severe in flammation in the lungs and spleen and earlier death compared to the result s from the mice infected with high inocula of BCG-vector. Wild-type mice co ntrolled infection with either recombinant strain, but showed decreased sur vival following high-dose BCG-TNF infection, The effects of TNF-alpha requi red signaling through an intact receptor, since the differential effects we re not observed when TNF-alpha receptor-deficient mice were infected. The r esults suggest that the relative amount of TNF-alpha at the site of infecti on determines whether the cytokine is protective or destructive.