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ABSTRACT: Previous studies comparing interleukin 4 receptor α (IL-4Rα)(-/-) and interleukin 4 (IL-4)(-/-) BALB/c mice have indicated that interleukin 13 (IL-13), whose receptor shares the IL-4Rα subunit with IL-4, plays a protective role during visceral leishmaniasis. We demonstrate that IL-13(-/-) BALB/c mice were less able to control hepatic growth of Leishmania donovani compared with wild-type mice. This correlated with significantly retarded granuloma maturation in IL-13(-/-) mice, defective interferon γ (IFN-γ) production, and elevated IL-4 and interleukin 10 (IL-10) levels. L. donovani-infected IL-13(-/-) mice also responded poorly to sodium stibogluconate-mediated chemotherapy compared with wild-type BALB/c mice. Because murine lymphocytes do not have IL-13 receptors, we examined the ability of macrophage/neutrophil-specific IL-4Rα(-/-) mice to control primary infection with L. donovani and to respond to chemotherapy. Macrophage/neutrophil-specific IL-4Rα(-/-) mice were as resistant to leishmaniasis as wild-type mice, and chemotherapy retained its efficacy. Consequently, in L. donovani infected BALB/c mice, IL-13 promotes hepatic granuloma formation and controls parasite burdens independently of direct effects on macrophages/neutrophils.
The Journal of Infectious Diseases 07/2011; 204(1):36-43. · 6.41 Impact Factor
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ABSTRACT: Despite advances in the treatment, the morbidity and mortality rate associated with invasive aspergillosis remains unacceptably high (70-90%) in immunocompromised patients. Amphotericin B (AMB), a polyene antibiotic with broad spectrum antifungal activity appears to be a choice of treatment but is available only as an intravenous formulation; development of an oral formulation would be beneficial as well as economical.
Poly(lactide-co-glycolode) (PLGA) nanoparticles encapsulating AMB (AMB-NPs) were developed for oral administration. The AMB-NPs were 113 ± 20 nm in size with ~70% entrapment efficiency at 30% AMB w/w of polymer. The in vivo therapeutic efficacy of oral AMB-NPs was evaluated in neutropenic murine models of disseminated and invasive pulmonary aspergillosis. AMB-NPs exhibited comparable or superior efficacy to that of Ambisome® or Fungizone™ administered parenterally indicating potential of NPs as carrier for oral delivery.
The present investigation describes an efficient way of producing AMB-NPs with higher AMB pay-load and entrapment efficiency employing DMSO as solvent and ethanol as non-solvent. The developed oral formulation was highly efficacious in murine models of disseminated aspergillosis as well as an invasive pulmonary aspergillosis, which is refractory to treatment with IP Fungizone™ and responds only modestly to AmBisome®.
PLoS ONE 01/2011; 6(10):e25744. · 4.09 Impact Factor
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ABSTRACT: Previous studies, using parenteral administration of antigen in lipid vesicles, have indicated a possible role for vesicle size in determining the Th1/Th2 bias of the resulting immune response. We have also demonstrated that the incorporation of bile salts into lipid vesicles (bilosomes) allows successful induction of mucosal and systemic immunity via the oral route. The following study was therefore carried out to determine whether size could also influence the Th1/Th2 bias in the immune response to bilosome entrapped influenza A antigen containing haemagglutinin administered by the oral route in the mouse and whether this could influence the disease process in the classical ferret model of disease. Consequently we produced two formulations of influenza A antigen entrapped in bilosomes: BV3 which contained a single population (range 10-100 nm, Z-average diameter 250 nm) and BV which had two populations (60-350 and 400-2,500 nm, Z-average 980 nm). Following oral vaccination of BALB/c mice, BV was found to generate an immune response that had a significantly greater Th1 bias than BV3 as measured by serum IgG2a production and antigen-induced spleen cell IFN-gamma production. In the traditional infection challenge model (ferrets) vaccination with BV (large) vesicles resulted in greater protection in terms of symptom-score and a higher responder number. However, both oral vaccine formulations were an improvement on intramuscular administration in terms of higher antibody production, lower temperatures, and reduced symptoms over time, post-infection. The results presented here demonstrate that oral vaccine formulations can be physically modified to manipulate resultant immune responses following vaccination and consequently can be designed to enhance the effectiveness of candidate vaccine antigens.
Vaccine 07/2009; 27(27):3643-9. · 3.77 Impact Factor
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ABSTRACT: Macrophage function has been demonstrated to be subject to modulation by progesterone. However, as this steroid hormone can act through the glucocorticoid receptor as well as the progesterone receptor, the mechanism of action has not been precisely characterized. To determine the mode of action, we compared the ability of progesterone, norgestrel (a synthetic progesterone-receptor-specific agonist) and dexamethasone (a synthetic glucocorticoid receptor agonist) to modulate macrophage function following stimulation of the Toll-like receptor-4 (TLR-4) ligand lipopolysaccharide (LPS). The results demonstrate that following stimulation of TLR-4 with LPS and cotreatment with either progesterone or dexamethasone, but not norgestrel, there is a significant reduction in nitric oxide (NO) production, indicating that this progesterone-mediated effect is through ligation of the glucocorticoid receptor. In contrast, LPS-induced interleukin-12 (IL-12) production could be downregulated by all three steroids, indicating that ligation by progesterone of either the glucocorticoid or the progesterone receptors or both could mediate this effect. While progesterone downmodulated NO-mediated killing of Leishmania donovani by activated macrophages in vitro, most probably via the glucocorticoid receptor, it had little effect on Toxoplasma gondii growth in these cells. This would suggest that progesterone-mediated increased susceptibility to T. gondii during pregnancy is more likely to be related to the ability of the hormone to downregulate IL-12 production and a type-1 response utilizing the progesterone as well as the glucocorticoid receptors.
Immunology 04/2008; 125(1):59-69. · 3.32 Impact Factor
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ABSTRACT: The continual increase in drug resistance; the lack of new chemotherapeutic agents; the toxicity of existing agents and the increasing morbidity with HIV co-infection mean the search for new antileishmanial agents has never been more urgent. We have identified the benzodiazepines as a structural class for antileishmanial hit optimisation, and demonstrated that their in vitro activity is comparable with the clinically used drug, sodium stibogluconate, and that the compounds are not toxic to macrophages.
Bioorganic & Medicinal Chemistry Letters 03/2007; 17(3):624-7. · 2.55 Impact Factor
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ABSTRACT: Immunity to Leishmania donovani is associated with an interleukin (IL)-12 driven T helper 1 (Th1) response. In addition, the ability to respond to chemotherapy with sodium stibogluconate (SSG) requires a fully competent immune response and both Th1 and Th2 responses have been shown to positively influence the outcome of drug treatment. In the present study, the influence of IL-18, which can modulate both interferon (IFN)-gamma and IL-4 production, on the outcome of primary L. donovani infection and SSG therapy following infection was assessed using BALB/c IL-18-deficient and wild type mice. IL-18 deficiency was associated with an increased susceptibility to L. donovani infection, evident by day 40 post infection, resulting in higher parasite burdens in the spleen, liver, and bone marrow compared with wild type control animals. Infected IL-18-deficient mice had significantly lower splenocyte concanavalin A (ConA) induced IFN-gamma production as well as lower serum IL-12 and IFN-gamma levels, indicating a reduced Th1 response. However, drug treatment was equally effective in both mouse strains and restored serum IL-12 and IFN-gamma levels, and IFN-gamma production by ConA stimulated splenocytes of IL-18-deficient mice, to levels equivalent to similarly treated wild type mice.
Immunology 12/2006; 119(3):348-54. · 3.32 Impact Factor
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Xioazhong Qu,
Vitaliy V Khutoryanskiy,
Ailsa Stewart,
Samina Rahman,
Brigitte Papahadjopoulos-Sternberg,
Christine Dufes,
Dave McCarthy,
Clive G Wilson,
Robert Lyons, Katharine C Carter,
Andreas Schätzlein,
Ijeoma F Uchegbu
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ABSTRACT: Amphiphilic chitosan-based polymers (Mw < 20 kDa) self-assemble in aqueous media at low micromolar concentrations to give previously unknown micellar clusters of 100-300 nm in size. Micellar clusters comprise smaller 10-30 nm aggregates, and the nanopolarity/drug incorporation efficiency of their hydrophobic domains can be tailored by varying the degree of lipidic derivatization and molecular weight of the carbohydrate. The extent of drug incorporation by these novel micellar clusters is 1 order of magnitude higher than is seen with triblock copolymers, with molar polymer/drug ratios of 1:48 to 1:67. On intravenous injection, the pharmacodynamic activity of a carbohydrate propofol formulation is increased by 1 order of magnitude when compared to a commercial emulsion formulation, and on topical ocular application of a carbohydrate prednisolone formulation, initial drug aqueous humor levels are similar to those found with a 10-fold dose of prednisolone suspension.
Biomacromolecules 12/2006; 7(12):3452-9. · 5.48 Impact Factor
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ABSTRACT: Protein antigens administered via the oral route are exposed to a hostile environment in the gastrointestinal tract, consisting of digestive enzymes and a range of pH (1-7.5). Using a delivery system can afford protection to entrapped components against degradation and permit delivery of antigen to the cells responsible for generating local and systemic immune responses. In this comparative study, mice were immunised orally with tetanus toxoid (40 or 200 microg dose/mouse, four doses in total) entrapped in non-ionic surfactant vesicles formulated with bile salts (bilosomes). The higher entrapped dose (BV-TT, 200 microg) induced IgG1 by study week 3 to similar levels to those observed with subcutaneous un-entrapped TT at the lower (<50 microg) dose. However, both bilosome formulations (BV-TT, low, and high doses), though not un-entrapped TT, caused a rise in the numbers of IgA positive plasma cells observed in the small intestine, primarily in the first 15 cm of the small intestine.
Methods 03/2006; 38(2):90-5. · 4.01 Impact Factor
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ABSTRACT: Vaccine antigens administered by the oral route are often degraded by gastric secretions during gastrointestinal transit. This necessitates larger and more frequent doses of antigen for vaccination. A delivery system, which overcomes this, is a lipid vesicle containing bile salts (bilosome), which prevents antigen degradation and enhances mucosal penetration. The effect of bilosome formulation modification on vaccine transit efficacy across the mucosa was determined. Specific antibody levels were assessed by end-point titre ELISA and the subclasses determined. Significant IgG1 titres were induced when the protein loading was doubled from 15 to 30 microg (P=0.009) and was equivalent to antigen administration by the subcutaneous route. No IgG2a was induced, indicating the generation of a TH2 response. Significant mucosal IgA levels were also observed with this treatment group (P=0.05).
Vaccine 07/2004; 22(19):2425-9. · 3.77 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Previous studies, using parenteral administration of antigen in lipid vesicles, have indicated a possible role for vesicle size in determining the Th1/Th2 bias of the resulting immune response. We have also demonstrated that the incorporation of bile salts into lipid vesicles (bilosomes) allows successful induction of mucosal and systemic immunity via the oral route. The following study was therefore carried out to determine whether size could also influence the Th1/Th2 bias in the immune response to bilosome entrapped influenza A antigen containing haemagglutinin administered by the oral route in the mouse and whether this could influence the disease process in the classical ferret model of disease. Consequently we produced two formulations of influenza A antigen entrapped in bilosomes: BV3 which contained a single population (range 10–100 nm, Z-average diameter 250 nm) and BV which had two populations (60–350 and 400–2500 nm, Z-average 980 nm). Following oral vaccination of BALB/c mice, BV was found to generate an immune response that had a significantly greater Th1 bias than BV3 as measured by serum IgG2a production and antigen-induced spleen cell IFN-γ production. In the traditional infection challenge model (ferrets) vaccination with BV (large) vesicles resulted in greater protection in terms of symptom-score and a higher responder number. However, both oral vaccine formulations were an improvement on intramuscular administration in terms of higher antibody production, lower temperatures, and reduced symptoms over time, post-infection. The results presented here demonstrate that oral vaccine formulations can be physically modified to manipulate resultant immune responses following vaccination and consequently can be designed to enhance the effectiveness of candidate vaccine antigens.
Vaccine.
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[show abstract]
[hide abstract]
ABSTRACT: Vaccine antigens administered by the oral route are often degraded by gastric secretions during gastrointestinal transit. This necessitates larger and more frequent doses of antigen for vaccination. A delivery system, which overcomes this, is a lipid vesicle containing bile salts (bilosome), which prevents antigen degradation and enhances mucosal penetration. The effect of bilosome formulation modification on vaccine transit efficacy across the mucosa was determined. Specific antibody levels were assessed by end-point titre ELISA and the subclasses determined. Significant IgG1 titres were induced when the protein loading was doubled from 15 to 30 μg (P=0.009) and was equivalent to antigen administration by the subcutaneous route. No IgG2a was induced, indicating the generation of a TH2 response. Significant mucosal IgA levels were also observed with this treatment group (P=0.05).
Vaccine.
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[show abstract]
[hide abstract]
ABSTRACT: Protein antigens administered via the oral route are exposed to a hostile environment in the gastrointestinal tract, consisting of digestive enzymes and a range of pH (1–7.5). Using a delivery system can afford protection to entrapped components against degradation and permit delivery of antigen to the cells responsible for generating local and systemic immune responses. In this comparative study, mice were immunised orally with tetanus toxoid (40 or 200 μg dose/mouse, four doses in total) entrapped in non-ionic surfactant vesicles formulated with bile salts (bilosomes). The higher entrapped dose (BV-TT, 200 μg) induced IgG1 by study week 3 to similar levels to those observed with subcutaneous un-entrapped TT at the lower (<50 μg) dose. However, both bilosome formulations (BV-TT, low, and high doses), though not un-entrapped TT, caused a rise in the numbers of IgA positive plasma cells observed in the small intestine, primarily in the first 15 cm of the small intestine.
Methods.
