Enhancement of Leishmanicidal Activity of Human Macrophages Against Leishmania major and Leishmania donovani Infection Using Recombinant Human Granulo

Al-Zamel, Faten; Al-Shammary, Fahad J.; El-Shewemi, S.; Soliman, Rafik

doi:10.1016/s0934-8840(96)80027-2

Cited by 11 publications

(9 citation statements)

References 35 publications

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“…Interestingly, Leishmania antigens presented by GM-CSF-derived macrophages could protect susceptible mice against challenge with L. major by activating TH1 cells (15). While GM-CSF demonstrates a clear-cut leishmanicidal activity in vitro and in vivo in the L. donovani model (29,54), the results obtained in the literature with L. major were more conflicting, suggesting that GM-CSF may play a positive (2,15,19,21), neutral (12), or negative (18,47) role in host defense. Our results indicated that recombinant GM-CSF parasites were eliminated much more rapidly inside macrophages compared to control cells and that this occurred independently of the macrophage type used for infection ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…However, IFN-␥ had no effect on disease Here we have chosen to express the GM-CSF gene by the parasite, since this cytokine has often been associated with both macrophage activation and subsequent parasite killing. Indeed, it has been reported that pretreatment of macrophages with GM-CSF enhances the intracellular killing of L. tropica (19), L. donovani (54), L. major (2), and L. mexicana amazonensis (21) in vitro. Moreover, GM-CSF showed clear-cut antileishmanial activity in vivo, associated with both mobilization of neutrophils and monocytes (29), and its combination with pentavalent antimony has been used successfully for the treatment of visceral leishmaniasis (5).…”

Section: Discussionmentioning

confidence: 99%

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RecombinantLeishmania majorSecreting Biologically Active Granulocyte-Macrophage Colony-Stimulating Factor Survives Poorly in Macrophages In Vitro and Delays Disease Development in Mice

et al. 2003

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Leishmania is an intracellular pathogen that replicates inside macrophages. Activated macrophages produce a specific subset of cytokines that play an important role in the control of Leishmania infections. As part of our interest in developing suicide parasites that produce abortive infections for the purposes of vaccination, we engineered recombinant Leishmania major strains producing biologically active granulocyte-macrophage colony-stimulating factor (GM-CSF). We showed that GM-CSF is being produced in the phagosomes of infected macrophages and that it can be detected in the culture supernatants of both infected macrophages and extracellular parasites. Our data support the notion that GM-CSF secreted by both developmental forms of recombinant L. major can activate macrophages to produce high levels of proinflammatory cytokines such as interleukin-1␤ (IL-1␤), IL-6, and IL-18 and various chemokines including RANTES/CCL5, MIP-1␣/CCL3, MIP-1␤/CCL4, MIP-2/CXCL2, and MCP-1/CCL2, which enhance parasite killing. Indeed, GM-CSF-expressing parasites survive poorly in macrophages in vitro and produce delayed lesion development in susceptible BALB/c mice in vivo. Selective killing of intracellular Leishmania expressing cytokine genes capable of activating cellular responses may constitute a promising strategy to control and/or prevent parasitic infections.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

RecombinantLeishmania majorSecreting Biologically Active Granulocyte-Macrophage Colony-Stimulating Factor Survives Poorly in Macrophages In Vitro and Delays Disease Development in Mice

et al. 2003

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“…A number of previous studies have reported increased levels of CIC containing parasite Ags in human Leishmania infection (16 -23). The cytokine GM-CSF induced by Leishmania Ags (15) might be either beneficial by activating macrophages to become leishmanicidal (11,12) or detrimental by stimulating inflammation through a T cell-driven delayed-type hypersensitivity response, thereby facilitating Leishmania-associated kidney involvement (31,32).…”

Section: Discussionmentioning

confidence: 99%

“…Addition of GM-CSF to human monocytes in vitro increases their leishmanicidal effects (11), and, when mice infected with L. donovani were treated with murine GM-CSF, they showed increased leishmanicidal activity, as well as leukocytosis and myelomonocytic accumulation in infected viscera (12). In a small placebocontrolled study, GM-CSF-treated Leishmania chagasi-infected patients had a significantly reduced number of secondary infections, along with increased neutrophil counts (13).…”

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confidence: 99%

Circulating Immune Complexes (IC) and IC-Induced Levels of GM-CSF Are Increased in Sudanese Patients with Acute Visceral Leishmania donovani Infection Undergoing Sodium Stibogluconate Treatment: Implications for Disease Pathogenesis

Elshafie

Åhlin

Mathsson

et al. 2007

The Journal of Immunology

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Infection with Leishmania donovani is associated with IL-10 as well as with GM-CSF. Immune complexes (IC) exert important functions by stimulation of monocytes/macrophage-mediated production of pro- and anti-inflammatory cytokines in rheumatic diseases. In this investigation, we have explored IC-induced cytokine production during Leishmania infection. Sera from 43 patients with visceral leishmaniasis (VL), 17 patients with post-kala-azar dermal leishmaniasis, and 20 healthy Sudanese controls were precipitated with polyethylene glycol (PEG). The PEG precipitates were added to serum-free PBMC for 20 h,whereupon supernatant levels of IL-1β, IL-6, IL-10, IL-1 receptor antagonist protein, TNF-α, TNF receptor p75, and GM-CSF were investigated using ELISA. Circulating levels of C1q-binding IC were also measured in the serum samples. PEG precipitates from Leishmania-infected patients induced significantly higher levels of GM-CSF (p = 0.0037) and IL-10 (p < 0.0001), as well as of IL-6 (p < 0.0001) and IL-1 receptor antagonist (p = 0.0238) as compared with PEG precipitates from controls. Patients with acute VL as well as VL patients receiving sodium stibogluconate treatment displayed significantly increased levels of PEG precipitate-induced GM-CSF. The induction of GM-CSF by circulating IC was especially prominent in acute VL patients receiving sodium stibogluconate treatment; ANOVA revealed significant interaction between disease activity and treatment for PEG precipitate-induced levels of GM-CSF (disease activity, p = 0.0006; treatment, p = 0.0005; interaction, p = 0.0046). Parallel associations were determined for C1q-binding immune complexes, but not for any cytokine other than GM-CSF. The importance of IC-induced GM-CSF in leishmaniasis warrants further study.

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“…9 In vitro, GM-CSF has been shown to activate macrophages to kill leishmania. 10,11 Besides its microbicidal activity, GM-CSF is known also to stimulate fibrosis and tissue wound healing. 12,13 It has been shown that GM-CSF used in low doses has an effect in platelet function in the bone marrow.…”

Section: Introductionmentioning

confidence: 99%

Successful Treatment of Refractory Cutaneous Leishmaniasis With Gm-CSF and Antimonials

Almeida¹,

Brito²,

Machado³

et al. 2005

Am J Trop Med Hyg

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Therapeutic failure in the treatment of cutaneous leishmaniasis (CL) occurs in 5% of patients infected by Leishmania braziliensis. This study evaluates the use of topically applied granulocyte macrophage colony-stimulating factor (GM-CSF) combined with the standard dose of antimony to treat refractory cases of CL. Five patients who had received three courses or more of antimony were enrolled in an open-label clinical trial. One to 2 mL of the GM-CSF solution (10 mug/mL in 0.9% saline) was reapplied topically, and dressings were changed three times per week for 3 weeks, associated with standard parenteral antimony (20 mg kg(-1) day(-1) for 20 days). All the patients healed their CL ulcers; 3 healed within 50 days (21, 27, and 44 days) and 2 in 118 and 120 days after beginning therapy. There were no side effects. This study shows that combined topically applied GM-CSF and antimony can be effective and well tolerated in the treatment of relapsed CL.

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Enhancement of Leishmanicidal Activity of Human Macrophages Against Leishmania major and Leishmania donovani Infection Using Recombinant Human Granulo

Cited by 11 publications

References 35 publications

RecombinantLeishmania majorSecreting Biologically Active Granulocyte-Macrophage Colony-Stimulating Factor Survives Poorly in Macrophages In Vitro and Delays Disease Development in Mice

RecombinantLeishmania majorSecreting Biologically Active Granulocyte-Macrophage Colony-Stimulating Factor Survives Poorly in Macrophages In Vitro and Delays Disease Development in Mice

Circulating Immune Complexes (IC) and IC-Induced Levels of GM-CSF Are Increased in Sudanese Patients with Acute Visceral Leishmania donovani Infection Undergoing Sodium Stibogluconate Treatment: Implications for Disease Pathogenesis

Successful Treatment of Refractory Cutaneous Leishmaniasis With Gm-CSF and Antimonials

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