Rapidly fatal Leishmaniasis in resistant C57BL/6 mice lacking TNF

The resolution of infections with the protozoan parasite Leishmania major i n mice requires a Th1 response that is closely associated with the expressi on of IL-12, IFN-gamma, and inducible MO synthase, Previous Ab neutralizati on studies or the use of mice deficient for both TNF receptors suggested th at TNF plays only a limited role in the control of parasite replication in vivo, In this study we demonstrate that resistant C57BL/6 (B6.WT) mice loca lly infected with L. major rapidly succumb to progressive visceral leishman iasis after deletion of the TNF gene by homologous recombination, A reducti on of the parasite inoculum to 3000 promastigotes did not prevent the fatal outcome of the disease. An influence of the altered morphology of secondar y lymphoid organs in C57B/6-TNF-/- (B6.TNF-/-) mice on the course of diseas e could be excluded by the generation of reciprocal bone marrow chimeras. A lthough infected B6.TNF-/- mice mounted an L, major-specific IFN-gamma resp onse and expressed IL-12, the onset of the immune reaction was delayed, Aft er in vitro stimulation, B6.TNF-/- inflammatory macrophages released 10-fol d less NO in response to IFN-gamma than B6,WT cells. However, in the presen ce of a costimulus, e.g., L, major infection or LPS, the production of NO b y B6.WT and B6.TNF-/- macrophages was comparable, In vivo, inducible NO syn thase protein was readily detectable in skin lesions and draining lymph nod es of B6.TNF-/- mice, but its expression was more disperse and less focal i n the absence of TNF, These are the first data to demonstrate that TNF is e ssential for the in vivo control of L, major.