Treatment of experimental visceral leishmaniasis in a T-cell-deficient host: response to amphotericin B and pentamidine

Murray, Henry W.; Hariprashad, June; Fichtl, Richard E.

doi:10.1128/aac.37.7.1504

Cited by 47 publications

(47 citation statements)

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“…AmB differs from Sb in not sharing a requirement for host T cells for its vivo effect (18) and, as documented here, does not require endogenous IFN-␥ or the IFN-␥-activated macrophage or its primary microbicidal mechanisms for killing of visceral L. donovani.…”

Section: Vol 68 2000 Visceral Leishmaniasis Chemotherapy 291mentioning

confidence: 99%

“…Two weeks after infection (day 0), liver parasite burdens were determined and mice then received no treatment, a single intraperitoneal injection of Sb, or three alternate-day intraperitoneal injections of AmB as in previous studies (15,18,21). Sb (sodium stibogluconate [Pentostam]; Wellcome Foundation Ltd., London, United Kingdom) was given on day 0 at either 500 or 100 mg/kg (15).…”

Section: Methodsmentioning

confidence: 99%

“…For example, AmB is fully active in nude mice (18) and limited data suggest satisfactory initial effects in AIDS-related kala-azar (13).…”

mentioning

confidence: 99%

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Roles of Endogenous Gamma Interferon and Macrophage Microbicidal Mechanisms in Host Response to Chemotherapy in Experimental Visceral Leishmaniasis

2000

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In experimental visceral leishmaniasis, in which the tissue macrophage is the target, in vivo responsiveness to conventional chemotherapy (pentavalent antimony [Sb]) requires a T-cell-dependent mechanism. To determine if this mechanism involves gamma interferon (IFN-␥)-induced activation and/or specific IFN-␥-regulated macrophage leishmanicidal mechanisms (generation of reactive nitrogen or oxygen intermediates, we treated gene-deficient mice infected with Leishmania donovani. In IFN-␥ gene knockout (GKO) mice, Sb inhibited but did not kill intracellular L. donovani (2% killing versus 76% in controls). Sb was active (>94% killing), however, in both inducible nitric oxide synthase (iNOS) knockout (KO) and respiratory burst (phagocyte oxidase)-deficient chronic granulomatous disease (X-CGD) mice. Sb's efficacy was also maintained in doubly deficient animals (X-CGD mice treated with an iNOS inhibitor). In contrast to Sb, amphotericin B (AmB) induced high-level killing in GKO mice; AmB was also fully active in iNOS KO and X-CGD animals. Although resolution of L. donovani infection requires iNOS, residual visceral infection remained largely suppressed in iNOS KO mice treated with Sb or AmB. These results indicate that endogenous IFN-␥ regulates the leishmanicidal response to Sb and achieves this effect via a pathway unrelated to the macrophage's primary microbicidal mechanisms. The role of IFN-␥ is selective, since it is not a cofactor in the response to AmB. Treatment with either Sb or AmB permits an iNOS-independent mechanism to emerge and control residual intracellular L. donovani infection.

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Section: Vol 68 2000 Visceral Leishmaniasis Chemotherapy 291mentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Roles of Endogenous Gamma Interferon and Macrophage Microbicidal Mechanisms in Host Response to Chemotherapy in Experimental Visceral Leishmaniasis

2000

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“…The basis for this lack of activity of pentavalent antimonials has been explored in immunodeficient mouse models for which the effects are probably due to deficiencies of both Th1-cell-mediated and macrophage responses (109). Experimental models have shown that the antileishmanial activity of pentamidine is also T-cell dependent whereas those of amphotericin B and miltefosine are T-cell independent (61,108). Irrespective of the findings of the experimental models, it is now known that intact immunity holds the key to the curative ability of antileishmanial drugs, including amphotericin B.…”

Section: Host Factors Host Immune Statusmentioning

confidence: 99%

Drug Resistance in Leishmaniasis

2006

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SUMMARY Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. There are significant differences in the sensitivity of these species both to the standard drugs, for example, pentavalent antimonials and miltefosine, and those on clinical trial, for example, paromomycin. Over 60% of patients with visceral leishmaniasis in Bihar State, India, do not respond to treatment with pentavalent antimonials. This is now considered to be due to acquired resistance. Although this class of drugs has been used for over 60 years for leishmaniasis treatment, it is only in the past 2 years that the mechanisms of action and resistance have been identified, related to drug metabolism, thiol metabolism, and drug efflux. With the introduction of new therapies, including miltefosine in 2002 and paromomycin in 2005-2006, it is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.

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“…In contrast to two other agents now in clinical use, amphotericin B and miltefosine (18,23,24), the in vivo leishmanicidal efficacy of pentavalent antimony (Sb), the conventional treatment for visceral leishmaniasis (25), requires an intact host T-cell (Th1 cell)-dependent response. Thus far, characterization of this mechanism indicates obligatory roles for T cells and a cytokine network involving endogenous interleukin 12 (IL-12), IFN-␥, and tumor necrosis factor (TNF) (17,23,26,27).…”

mentioning

confidence: 99%

Mononuclear Cell Recruitment, Granuloma Assembly, and Response to Treatment in Experimental Visceral Leishmaniasis: Intracellular Adhesion Molecule 1-Dependent and -Independent Regulation

Murray

2000

Infect Immun

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In experimental visceral leishmaniasis, acquired resistance to intracellular Leishmania donovani is Th1 cell cytokine dependent and largely mediated by gamma interferon (IFN-␥); the same response also permits conventional antimony (Sb) chemotherapy to express its leishmanicidal effect. Since the influxing blood monocyte (which utilizes endothelial cell ICAM-1 for adhesion and tissue entry) is a primary effector target cell for this cytokine mechanism, we tested the monocyte's role in host responsiveness to chemotherapy in mice with ICAM-1 gene disruptions. Mutant animals failed to develop any early granulomatous tissue response in the liver, initially supported high-level visceral parasite replication, and showed no killing after Sb treatment; the leishmanicidal response to a directly acting, alternative chemotherapeutic probe, amphotericin B, was intact. However, mutant mice proceeded to express a compensatory, ICAM-1-independent response leading to mononuclear cell influx and granuloma assembly, control over visceral infection, and the capacity to respond to Sb. Together, these results point to the recruitment of emigrant monocytes and mononuclear cell granuloma formation, mediated by ICAM-1-dependent and -independent pathways, as critical determinants of host responsiveness to conventional antileishmanial chemotherapy.

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Treatment of experimental visceral leishmaniasis in a T-cell-deficient host: response to amphotericin B and pentamidine

Cited by 47 publications

References 13 publications

Roles of Endogenous Gamma Interferon and Macrophage Microbicidal Mechanisms in Host Response to Chemotherapy in Experimental Visceral Leishmaniasis

Roles of Endogenous Gamma Interferon and Macrophage Microbicidal Mechanisms in Host Response to Chemotherapy in Experimental Visceral Leishmaniasis

Drug Resistance in Leishmaniasis

Mononuclear Cell Recruitment, Granuloma Assembly, and Response to Treatment in Experimental Visceral Leishmaniasis: Intracellular Adhesion Molecule 1-Dependent and -Independent Regulation

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