Visceral leishmaniasis in mice devoid of tumor necrosis factor and response to treatment

Tumor necrosis factor (TNF)-deficient mice were challenged with Leishmania donovani to characterize TNF in the response of visceral intracellular infe ction to antileishmanial chemotherapy. In wild-type controls (i) liver infe ction peaked at week 2 and resolved, (ii) discrete liver granulomas develop ed at weeks 2 to 4 and involuted, and (iii) leishmanicidal responses to ant imony (Sb), amphotericin B (AmB), and miltefosine were intact. In TNF knock out (KO) mice (i) initial liver infection was unrestrained, plateaued, and then declined somewhat by week 6, (ii) an absent early granulomatous reacti on abruptly accelerated with striking tissue inflammation, widespread hepat ic necrosis, and 100% mortality by week 10, and (iii) while the initial res ponse 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 an d died by week 12; however, additional maintenance AmB preserved long-term survival. These results for a model of visceral infection indicate that end ogenous TNF is required early on to control intracellular L. donovani, supp ort granuloma development, and mediate optimal initial effects of Sb and pr event relapse after ordinarily curative AmB treatment. A compensatory, TNF- independent antileishmanial mechanism developed in TNF KO mice; however, it s effect was uncontrolled fatal inflammation. Chemotherapeutic elimination of the parasite stimulus reversed the hyperinflammatory response and preser ved survival.