Although tumor necrosis factor (TNF) initially came to prominence because of its anti-tumor activity, most attention is now focused on its proinflammatory actions. TNF appears to play a critical role in both early and late events involved in inflammation, from localizing the noxious agent and amplifying the cellular and mediator responses at the local site and systemically, to editing (e.g., apoptosis) injured cells or effete immune cells and repairing inflammatory damage. We have generated mice deficient in TNF (TNF ؊/؊ mice) and have begun to examine the multiple functions attributed to TNF. TNF

Tumor necrosis factor (TNF)-deficient mice were challenged with Leishmania donovani to characterize TNF in the response of visceral intracellular infection to antileishmanial chemotherapy. In wild-type controls (i) liver infection peaked at week 2 and resolved, (ii) discrete liver granulomas developed at weeks 2 to 4 and involuted, and (iii) leishmanicidal responses to antimony (Sb), amphotericin B (AmB), and miltefosine were intact. In TNF knockout (KO) mice (i) initial liver infection was unrestrained, plateaued, and then declined somewhat by week 6, (ii) an absent early granulomatous reaction abruptly accelerated with striking tissue inflammation, widespread hepatic necrosis, and 100% mortality by week 10, and (iii) while the initial response to AmB and miltefosine was intact, killing induced by Sb therapy was reduced by >50%. Although initial AmB treatment during weeks 2 to 3 killed 98% of liver parasites, 75% of AmB-treated KO mice subsequently relapsed and died by week 12; however, additional maintenance AmB preserved long-term survival. These results for a model of visceral infection indicate that endogenous TNF is required early on to control intracellular L. donovani, support granuloma development, and mediate optimal initial effects of Sb and prevent relapse after ordinarily curative AmB treatment. A compensatory, TNF-independent antileishmanial mechanism developed in TNF KO mice; however, its effect was uncontrolled fatal inflammation. Chemotherapeutic elimination of the parasite stimulus reversed the hyperinflammatory response and preserved survival.The pleiotropic cytokine tumor necrosis factor (TNF) appears to be a prominent component of a diverse spectrum of both beneficial and deleterious inflammatory responses (2, 34). Among the beneficial effects of endogenous TNF is its complex role in inducing macrophage activation and enhancing host antimicrobial defense, particularly against intracellular pathogens (2, 34). Such a role, initially demonstrated by the capacity of treatment with anti-TNF antibodies to exacerbate infection, has recently been confirmed in a number of models using TNFand TNF receptor-deficient (knockout [KO]) mice (1,4,6,7,12,21,23,26,35,36).In a previous report, we illustrated the critical role of endogenous TNF in the multicytokine-mediated host defense response which controls experimental visceral leishmaniasis, a disseminated protozoal infection in which macrophages of the liver, spleen, and bone marrow are targeted (31, 33; reviewed in reference 13). Challenging normal BALB/c mice with Leishmania donovani induced TNF in infected liver and spleen, and increasing tissue TNF levels reflected both initial control over parasite replication and subsequent near resolution of visceral infection by week 8 (31, 33). Repeated injections of anti-TNF antiserum abolished acquired resistance, permitting intracellular amastigotes to replicate freely within visceral macrophages. At the same time, 8 weeks of anti-TNF treatment did not appear to interfere with the orderly assembly of inflammat...