Visceral Leishmaniasis in Mice Devoid of Tumor Necrosis Factor and Response to Treatment

Abstract

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...

Protective immunization against visceral leishmaniasis using Leishmania sterol 24-c-methyltransferase formulated in adjuvant

“…Also, we demonstrated that the rSMT plus MPL ® -SE vaccine induced Ag-specific T-cells which are capable of producing multiple Th1-type cytokines in response to Ag recall. All of TNF-α, IL-2 and IFN-γ are involved in protection against VL [4,5,34]. As TNF-α synergizes with IFN-γ in killing Leishmania parasites [35], induction of Ag-specific T-cells capable of producing multiple cytokines upon Ag recall might be more beneficial for control of Leishmania infection than those producing single cytokine, and such induction may be a good indicator whether a vaccine composed of Ag and adjuvant is protective against leishmaniasis.…”

“…In common with other intracellular pathogens, cellular immune responses are critical for protection against leishmaniasis. Th1 immune responses play an important role in mediating protection against Leishmania, including roles for CD4 + and CD8 + T cells, IFN-γ, IL-12, TNF-α and NO, whereas inhibitory effects have been reported for IL-10 and TGF-β [1][2][3][4][5][6][7][8][9]. Effective immunization against leishmaniasis in animal models can be effected by delivery of Agencoding DNA vectors [10][11][12] or by administration of proteins formulated with Th1-inducing adjuvants including IL-12 [13][14][15] or TLR ligands such as CpG oligonucleotides [16][17][18] and monophosphoryl lipid A [19,20].…”

Modulation of T-Cell Costimulation as Immunotherapy or Immunochemotherapy in Experimental Visceral Leishmaniasis

“…IL-12 likely drives the Th1 cell-associated mechanism and induces IFN-␥, both cytokines direct T cells and blood monocytes into granulomas at parasitized tissue foci, and IFN-␥ activates effector monocytes and macrophages to kill intracellular parasites (6,23,24,34). Endogenous IL-12 and IFN-␥, as well as other cytokines (1,29), are also required for the leishmanicidal effect of pentavalent antimony (Sb), used as conventional chemotherapy for visceral leishmaniasis (23,27,28).…”

Platelet-Activating Factor Receptor Contributes to Antileishmanial Function of Miltefosine

“…TNF-a production in response to miltefosine was completely impaired in PAF receptor-deficient macrophages. Although TNF-a was previously shown to be a strong antileishmanial cytokine (25,26), the involvement of TNF-a in miltefosine-induced PAF receptor-mediated antileishmanial function was never implicated. In this article, our observations report for the first time, to our knowledge, that PAF receptor is involved in miltefosine-induced TNF-a production and subsequent antileishmanial functions.…”