The course of infections and pathology in immunomodulated NOD/LtSz-SCID mice inoculated with Plasmodium falciparum laboratory lines and clinical isolates

Moreno, Angel J.; Ferrer, Elizabeth; Arahuetes, Susana; Eguiluz, César; Rooijen, Nico van; Benito, Agustín

doi:10.1016/j.ijpara.2005.10.012

Cited by 25 publications

(37 citation statements)

References 28 publications

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“…These modifications include: 1) variations in the dose and schedule of administration of the different components ( i.e . infected and uninfected HuRBC, clo-lip and NIMP-R14, including modifications proposed by others [12]); 2) use of various agents to reduce innate immunity, such as cyclophosphamide, cisplatinium, irradiation, dexamethasone, TGF-β, splenectomy, TMβ-1 antibody targeting NK cells 3) Addition of metabolic precursors such as pABA, folinic acid to supply nutritive factors for the parasite 4) Addition of antioxidants such as vitamin E, N-acetyl cysteine (NAC), trolox, 8-aminoguanidine. These empirical approaches never brought a significant or reproducible improvement of parasite survival in NOD/SCID mice.…”

Section: Resultsmentioning

confidence: 99%

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Analysis of innate defences against Plasmodium falciparum in immunodeficient mice

Arnold

Tyagi

Mejia

et al. 2010

Malar J

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BackgroundMice with genetic deficiencies in adaptive immunity are used for the grafting of human cells or pathogens, to study human diseases, however, the innate immune responses to xenografts in these mice has received little attention. Using the NOD/SCID Plasmodium falciparum mouse model an analysis of innate defences responsible for the substantial control of P. falciparum which remains in such mice, was performed.MethodsNOD/SCID mice undergoing an immunomodulatory protocol that includes, clodronate-loaded liposomes to deplete macrophages and an anti-polymorphonuclear leukocytes antibody, were grafted with human red blood cells and P. falciparum. The systematic and kinetic analysis of the remaining innate immune responses included the number and phenotype of peripheral blood leukocytes as well as inflammatory cytokines/chemokines released in periphery. The innate responses towards the murine parasite Plasmodium yoelii were used as a control.ResultsResults show that 1) P. falciparum induces a strong inflammation characterized by an increase in circulating leukocytes and the release of inflammatory cytokines; 2) in contrast, the rodent parasite P. yoelii, induces a far more moderate inflammation; 3) human red blood cells and the anti-inflammatory agents employed induce low-grade inflammation; and 4) macrophages seem to bear the most critical function in controlling P. falciparum survival in those mice, whereas polymorphonuclear and NK cells have only a minor role.ConclusionsDespite the use of an immunomodulatory treatment, immunodeficient NOD/SCID mice are still able to mount substantial innate responses that seem to be correlated with parasite clearance. Those results bring new insights on the ability of innate immunity from immunodeficient mice to control xenografts of cells of human origin and human pathogens.

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Section: Resultsmentioning

confidence: 99%

“…In the current study, a previously described immunomodulation protocol was employed [11], modified as described in [12]. On day -13, each mouse received a dose of 10 mg/kg of mAb NIMP-R14 by i.p.…”

Section: Methodsmentioning

confidence: 99%

Analysis of innate defences against Plasmodium falciparum in immunodeficient mice

Arnold

Tyagi

Mejia

et al. 2010

Malar J

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“…falciparum infection in humanized mice was obtained as described (29). Mice bearing parasitemias Ͼ0.1% were selected to evaluate the activity of PA1103/SAR116242, chloroquine, and artesunate in this model.…”

Section: Methodsmentioning

confidence: 99%

Selection of a trioxaquine as an antimalarial drug candidate

Coslédan

Fraisse

Pellet

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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135

126

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Trioxaquines are antimalarial agents based on hybrid structures with a dual mode of action. One of these molecules, PA1103/ SAR116242, is highly active in vitro on several sensitive and resistant strains of Plasmodium falciparum at nanomolar concentrations (e.g., IC 50 value ‫؍‬ 10 nM with FcM29, a chloroquineresistant strain) and also on multidrug-resistant strains obtained from fresh patient isolates in Gabon. This molecule is very efficient by oral route with a complete cure of mice infected with chloroquine-sensitive or chloroquine-resistant strains of Plasmodia at 26 -32 mg/kg. This compound is also highly effective in humanized mice infected with P. falciparum. Combined with a good drug profile (preliminary absorption, metabolism, and safety parameters), these data were favorable for the selection of this particular trioxaquine for development as drug candidate among 120 other active hybrid molecules.curative drug ͉ malaria ͉ Plasmodium ͉ heme ͉ alkglation

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“…The first one requires chemical in vivo depletion of phagocytic cells from immunodeficient mice engrafted with hE in order to allow the growth of P. falciparum after intraperitoneal (i.p.) infection (2,8). However, its variable kinetics of parasitemia and, particularly, the use of toxic reagents, which might affect the efficacy of antimalarials or effector cells, have limited its use in drug discovery (5).…”

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confidence: 99%

Improved Murine Model of Malaria UsingPlasmodium falciparumCompetent Strains and Non-Myelodepleted NOD-scid IL2Rγ^nullMice Engrafted with Human Erythrocytes

Jiménez-Dı́az

Mulet

Viera

et al. 2009

Antimicrob Agents Chemother

177

153

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Murine models of Plasmodium falciparum malaria may become crucial tools in drug discovery. Here we show that non-myelodepleted NOD-scid IL2R␥ null mice engrafted with human erythrocytes support an infectious burden up to tenfold higher than that supported by engrafted NOD-scid ␤2microglobulin null mice. The new model was validated for drug discovery and was used to assess the therapeutic efficacy of 4-pyridones, selective inhibitors of P. falciparum cytochrome bc 1 .Malaria is caused by the erythrocytic stages of protozoan parasites of the genus Plasmodium. Among the species pathogenic for humans, Plasmodium falciparum is responsible for 300 to 500 million cases of malaria and over a million deaths annually, particularly in developing countries. The development of new antimalarial medicines and vaccines is a key part of the global strategy for malaria eradication (6).P. falciparum almost exclusively infects human erythrocytes (hE). As a result, candidate drugs and vaccines in early stages of preclinical development are usually tested in vivo by measuring their therapeutic efficacy against rodent-adapted plasmodial species and by assessing the antiparasitic response of non-human immune systems, respectively (11). To overcome the host specificity issue, two conceptually different murine models of erythrocytic stages of P. falciparum malaria have been developed. The first one requires chemical in vivo depletion of phagocytic cells from immunodeficient mice engrafted with hE in order to allow the growth of P. falciparum after intraperitoneal (i.p.) infection (2, 8). However, its variable kinetics of parasitemia and, particularly, the use of toxic reagents, which might affect the efficacy of antimalarials or effector cells, have limited its use in drug discovery (5). Recently, a new P. falciparum murine model that does not require in vivo myeloablative treatment of mice and is suitable for drug discovery was described (1). In this new model, NOD-scid mice genetically deficient in beta-2 microglobulin (␤2 m tm1Unc , abbreviated as ␤2 m null ) engrafted with hE (HM-␤2 m null ) are infected intravenously with P. falciparum strains selected in vivo for their competence to grow reproducibly in hE-engrafted immunodeficient mice (1).The NOD-scid ␤2 m null mouse strain retains residual NK cell activity as well as other innate immune functions and shows a high incidence of early thymic lymphomas, which dramatically diminish their life span (4). These characteristics may be a serious problem for addressing long-term pharmacokinetic/ pharmacodynamic (PK/PD) studies because of the relatively low total parasite burden per mouse achievable (1) and the short life span of NOD-scid ␤2 m null mice (4). Interestingly, NOD-scid strains carrying a null mutation of the interleukin 2 (IL-2) receptor ␥ chain (IL2R␥ tm1Wjll , abbreviated as IL2R␥ null ) have been developed (10). These murine strains lack fully mature NK cells and show additional defects in their innate immune system that explain their greater ability to support the engraftme...

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The course of infections and pathology in immunomodulated NOD/LtSz-SCID mice inoculated with Plasmodium falciparum laboratory lines and clinical isolates

Cited by 25 publications

References 28 publications

Analysis of innate defences against Plasmodium falciparum in immunodeficient mice

Analysis of innate defences against Plasmodium falciparum in immunodeficient mice

Selection of a trioxaquine as an antimalarial drug candidate

Improved Murine Model of Malaria UsingPlasmodium falciparumCompetent Strains and Non-Myelodepleted NOD-scid IL2Rγ^nullMice Engrafted with Human Erythrocytes

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The course of infections and pathology in immunomodulated NOD/LtSz-SCID mice inoculated with Plasmodium falciparum laboratory lines and clinical isolates

Cited by 25 publications

References 28 publications

Analysis of innate defences against Plasmodium falciparum in immunodeficient mice

Analysis of innate defences against Plasmodium falciparum in immunodeficient mice

Selection of a trioxaquine as an antimalarial drug candidate

Improved Murine Model of Malaria UsingPlasmodium falciparumCompetent Strains and Non-Myelodepleted NOD-scid IL2RγnullMice Engrafted with Human Erythrocytes

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Product

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Improved Murine Model of Malaria UsingPlasmodium falciparumCompetent Strains and Non-Myelodepleted NOD-scid IL2Rγ^nullMice Engrafted with Human Erythrocytes