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1.
Exp Parasitol ; 220: 108033, 2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33166530

RESUMO

Infection with Leishmania infantum causes the disease visceral leishmaniasis (VL), which is a serious clinical and veterinary problem. The drugs used to treat canine leishmaniasis (CanL) do not cause complete parasite clearance; they can be toxic, and emerging drug resistance in parasite populations limits their clinical utility. Therefore, in this study we have evaluated the toxicity and efficacy of joint treatment with a 1:1 mixture of sodium stibogluconate-NIV (SSG-NIV, 10 mg Sbv/day) and paromomycin-NIV (PMM-NIV, 10 mg PMM/kg/day), given intravenously daily for seven days from day 270 post-infection, to nine-month-old female beagle dogs (n = 6) experimentally infected with Leishmania infantum. Treatment significantly improved the clinical symptoms of VL infection in all the treated dogs, reduced parasite burdens in lymph nodes and bone marrow, and all symptomatic treated dogs, were asymptomatic at 90 days post-treatment. Treatment was associated with a progressive and significant decrease in specific IgG anti-Leishmania antibodies using parasite soluble antigen (p < 0.01) or rK39 (p < 0.01) as the target antigen. In addition, all dogs were classified as parasite negative based on Leishmania nested PCR and quantitative real time PCR tests and as well as an inability to culture of promastigote parasites from lymph nodes and bone marrow tissue samples taken at day 90 post-treatment. However, treatment did not cure the dogs as parasites were detected at 10 months post-treatment, indicating that a different dosing regimen is required to cause long term cure or prevent relapse.

2.
Microorganisms ; 8(7)2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32709117

RESUMO

Leishmaniasis is a vector-borne parasitic disease that has been neglected in priority for control and eradication of malaria, tuberculosis, and HIV/AIDS. Collectively, over one seventh of the world's population is at risk of being infected with 0.7-1.2 million new infections reported annually. Clinical manifestations range from self-healing cutaneous lesions to fatal visceral disease. The first anti-leishmanial drugs were introduced in the 1950's and, despite several shortcomings, remain the mainstay for treatment. Regardless of this and the steady increase in infections over the years, particularly among populations of low economic status, research on leishmaniasis remains under funded. This review looks at the drugs currently in clinical use and how they interact with the host immune response. Employing chemoimmunotherapeutic approaches may be one viable alternative to improve the efficacy of novel/existing drugs and extend their lifespan in clinical use.

3.
Microorganisms ; 8(8)2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32722326

RESUMO

Miltefosine (Milt) is the only oral treatment for visceral leishmaniasis (VL) but its use is associated with adverse effects, e.g., teratogenicity, vomiting, diarrhoea. Understanding how its chemical structure induces cytotoxicity, whilst not compromising its anti-parasitic efficacy, could identify more effective compounds. Therefore, we systemically modified the compound's head, tail and linker tested the in vitro activity of three alkylphosphocholines (APC) series against Leishmania donovani strains with different sensitivities to antimony. The analogue, APC12, with an alkyl carbon chain of 12 atoms, was also tested for anti-leishmanial in vivo activity in a murine VL model. All APCs produced had anti-leishmanial activity in the micromolar range (IC50 and IC90, 0.46- > 82.21 µM and 4.14-739.89 µM; 0.01- > 8.02 µM and 0.09-72.18 µM, respectively, against promastigotes and intracellular amastigotes). The analogue, APC12 was the most active, was 4-10 fold more effective than the parent Milt molecule (APC16), irrespective of the strain's sensitivity to antimony. Intravenous administration of 40 mg/kg APC12 to L. donovani infected BALB/c mice reduced liver and spleen parasite burdens by 60 ± 11% and 60 ± 19%, respectively, while oral administration reduced parasite load in the bone marrow by 54 ± 34%. These studies confirm that it is possible to alter the Milt structure and produce more active anti-leishmanial compounds.

4.
Front Immunol ; 10: 1957, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31475014

RESUMO

Previous studies infecting global IL-4Rα-/-, IL-4-/-, and IL-13-/-mice on a BALB/c background with the visceralizing parasite Leishmania donovani have shown that the T helper 2 cytokines, IL-4, and IL-13, play influential but not completely overlapping roles in controlling primary infection. Subsequently, using macrophage/neutrophil-specific IL-4Rα deficient BALB/c mice, we demonstrated that macrophage/neutrophil unresponsiveness to IL-4 and IL-13 did not have a detrimental effect during L. donovani infection. Here we expand on these findings and show that CD4+ T cell-(Lckcre), as well as pan T cell-(iLckcre) specific IL-4Rα deficient mice, on a BALB/c background, unlike global IL-4Rα deficient mice, are also not adversely affected in terms of resistance to primary infection with L. donovani. Our analysis suggested only a transient and tissue specific impact on disease course due to lack of IL-4Rα on T cells, limited to a reduced hepatic parasite burden at day 30 post-infection. Consequently, the protective role(s) demonstrated for IL-4 and IL-13 during L. donovani infection are mediated by IL-4Rα-responsive cell(s) other than macrophages, neutrophils and T cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucina-4/genética , Leishmania major/imunologia , Leishmaniose Visceral/imunologia , Receptores de Superfície Celular/genética , Animais , Cricetinae , Interleucina-13/imunologia , Interleucina-4/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neutrófilos/imunologia , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/imunologia
5.
J Antimicrob Chemother ; 72(12): 3334-3341, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28961913

RESUMO

Objectives: The slow development of major advances in drug discovery for the treatment of Mycobacterium tuberculosis (Mtb) infection suggests a compelling need for evaluation of more effective drug therapies against TB. New classes of drugs are constantly being evaluated for anti-mycobacterial activity with currently a very limited number of new drugs approved for TB treatment. Minor groove binders (MGBs) have previously revealed promising antimicrobial activity against various infectious agents; however, they have not yet been screened against Mtb. Methods: The mycobactericidal activity of 96 MGB compounds against Mtb was determined using an H37Rv-GFP microplate assay. MGB hits were screened for their intracellular mycobactericidal efficacy against the clinical Beijing Mtb strain HN878 in bone-marrow-derived macrophages using standard cfu counting. Cell viability was assessed by CellTiter-Blue assays. Selected MGBs were encapsulated into non-ionic surfactant vesicles (NIVs) for drug delivery system evaluation. Results: H37Rv-GFP screening yielded a hit-list of seven compounds at an MIC99 of between 0.39 and 1.56 µM. MGB-362 and MGB-364 displayed intracellular mycobactericidal activity against Mtb HN878 at an MIC50 of 4.09 and 4.19 µM, respectively, whilst being non-toxic. Subsequent encapsulation into NIVs demonstrated a 1.6- and 2.1-fold increased intracellular mycobacterial activity, similar to that of rifampicin when compared with MGB-alone formulation. Conclusions: MGB anti-mycobacterial activities together with non-toxic properties indicate that MGB compounds constitute an important new class of drug/chemical entity, which holds promise in future anti-TB therapy. Furthermore, the ability of NIVs to better deliver entrapped MGB compounds to an intracellular Mtb infection suggests further preclinical evaluation is warranted.


Assuntos
Antibacterianos/farmacologia , Produtos Biológicos/farmacologia , Sistemas de Liberação de Medicamentos , Mycobacterium/efeitos dos fármacos , Tensoativos/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Contagem de Colônia Microbiana , Proteínas de Fluorescência Verde/análise , Macrófagos/microbiologia , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Coloração e Rotulagem
6.
PLoS One ; 11(5): e0155355, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27195790

RESUMO

Extracts from twelve samples of propolis collected from different regions of Libya were tested for their activity against Trypanosoma brucei, Leishmania donovani, Plasmodium falciparum, Crithidia fasciculata and Mycobacterium marinum and the cytotoxicity of the extracts was tested against mammalian cells. All the extracts were active to some degree against all of the protozoa and the mycobacterium, exhibiting a range of EC50 values between 1.65 and 53.6 µg/ml. The toxicity against mammalian cell lines was only moderate; the most active extract against the protozoan species, P2, displayed an IC50 value of 53.2 µg/ml. The extracts were profiled by using liquid chromatography coupled to high resolution mass spectrometry. The data sets were extracted using m/z Mine and the accurate masses of the features extracted were searched against the Dictionary of Natural Products (DNP). A principal component analysis (PCA) model was constructed which, in combination with hierarchical cluster analysis (HCA), divided the samples into five groups. The outlying groups had different sets of dominant compounds in the extracts, which could be characterised by their elemental composition. Orthogonal partial least squares (OPLS) analysis was used to link the activity of each extract against the different micro-organisms to particular components in the extracts.


Assuntos
Anti-Infecciosos/química , Antiprotozoários/química , Testes de Sensibilidade Microbiana , Própole/química , Animais , Anti-Infecciosos/farmacologia , Antiprotozoários/farmacologia , Produtos Biológicos/química , Cromatografia Líquida , Análise por Conglomerados , Crithidia fasciculata/efeitos dos fármacos , Feminino , Geografia , Humanos , Concentração Inibidora 50 , Análise dos Mínimos Quadrados , Leishmania donovani/efeitos dos fármacos , Líbia , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium marinum/efeitos dos fármacos , Extratos Vegetais/química , Plasmodium falciparum/efeitos dos fármacos , Análise de Componente Principal , Própole/farmacologia , Software , Trypanosoma brucei brucei/efeitos dos fármacos , Células U937
7.
Phytother Res ; 28(12): 1756-60, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25044090

RESUMO

Propolis is increasingly being explored as a source of biologically active compounds. Until now, there has been no study of Libyan propolis. Two samples were collected in North East Libya and tested for their activity against Trypanosoma brucei. Extracts from both samples had quite high activity. One of the samples was fractionated and yielded a number of active fractions. Three of the active fractions contained single compounds, which were found to be 13-epitorulosal, acetyl-13-epi-cupressic acid and 13-epi-cupressic acid, which have been described before in Mediterranean propolis. Two of the compounds had a minimum inhibitory concentration value of 1.56 µg/mL against T. brucei. The active fractions were also tested against macrophages infected with Leishmania donovani, and again moderate to strong activity was observed with the compounds having IC50 values in the range 5.1-21.9 µg/mL.


Assuntos
Antiprotozoários/farmacologia , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Própole/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Animais , Diterpenos/química , Concentração Inibidora 50 , Leishmania donovani/efeitos dos fármacos , Líbia , Macrófagos Peritoneais/parasitologia , Masculino , Camundongos Endogâmicos BALB C
8.
J Complement Integr Med ; 9: Article 10, 2012 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-22713278

RESUMO

Preliminary investigation of the in vitro and in vivo efficacies of different extracts from the leaves of Vernonia amygdalina (VA), a plant widely used in Nigeria was evaluated in Balb/C mice infected with a laboratory strain of Leishmania major (L. major). The ability of the methanol, hexane and aqueous extracts of the plant to suppress the infection rate and its cytotoxicity on macrophages and L929 cells were determined in the in vitro study. The in vivo study evaluated time course of infection, lesion progression and the histopathology of cutaneous lesions, liver and spleen after inoculation with metacyclic promastigotes. Methanolic extract of VA containing high levels of flavanoids, was the most potent extract as it showed the highest suppression on infectivity and viability of intracellular amastigotes at a concentration lower than that which elicited cytotoxicity on macrophages. Treatment of infected mice with methanolic extract of VA showed delayed onset of disease with a significant reduction in lesion size and attenuation of the histopathological outcome characterised by intact epidermis and less tissue destruction in skin, spleen and liver. In conclusion, these results demonstrate that VA has potent antileishmanial properties which warrants further investigation into the immunological mechanism.


Assuntos
Antiprotozoários/uso terapêutico , Leishmania major , Leishmaniose Cutânea/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Vernonia , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Cromatografia em Camada Delgada , Modelos Animais de Doenças , Leishmaniose Cutânea/patologia , Fígado/efeitos dos fármacos , Fígado/parasitologia , Fígado/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Plantas Medicinais , Distribuição Aleatória , Pele/efeitos dos fármacos , Pele/parasitologia , Pele/patologia , Baço/efeitos dos fármacos , Baço/parasitologia , Baço/patologia , Resultado do Tratamento , Vernonia/química
9.
PLoS One ; 6(10): e25744, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21998690

RESUMO

BACKGROUND: 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. METHODOLOGY: 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. CONCLUSIONS: 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®.


Assuntos
Anfotericina B/administração & dosagem , Anfotericina B/farmacologia , Nanopartículas/química , Polímeros/química , Acetona/química , Administração Oral , Anfotericina B/química , Anfotericina B/uso terapêutico , Animais , Antifúngicos/administração & dosagem , Antifúngicos/química , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Química Farmacêutica , Dimetil Sulfóxido/química , Injeções Intravenosas , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Masculino , Camundongos , Ratos Sprague-Dawley , Solventes/química
10.
J Infect Dis ; 204(1): 36-43, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21628656

RESUMO

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.


Assuntos
Granuloma/patologia , Interleucina-13/imunologia , Leishmania donovani/patogenicidade , Leishmaniose Visceral/patologia , Macrófagos/imunologia , Neutrófilos/imunologia , Animais , Feminino , Granuloma/imunologia , Granuloma/parasitologia , Interleucina-13/deficiência , Leishmania donovani/imunologia , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores de Superfície Celular/imunologia
11.
Vaccine ; 27(27): 3643-9, 2009 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-19464545

RESUMO

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.


Assuntos
Vacinas contra Influenza/administração & dosagem , Veículos Farmacêuticos , Células Th1/imunologia , Células Th2/imunologia , Administração Oral , Animais , Anticorpos Antivirais/sangue , Ácidos e Sais Biliares/administração & dosagem , Feminino , Furões , Imunoglobulina G/sangue , Vacinas contra Influenza/imunologia , Interferon gama/biossíntese , Ácido Láctico , Camundongos , Camundongos Endogâmicos BALB C , Nanosferas , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Vacinação
12.
Immunology ; 125(1): 59-69, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18373668

RESUMO

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.


Assuntos
Ativação de Macrófagos/imunologia , Progesterona/imunologia , Receptores de Glucocorticoides/imunologia , Receptores de Progesterona/imunologia , Receptor 4 Toll-Like/imunologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dexametasona/farmacologia , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Células-Tronco Hematopoéticas/imunologia , Interleucina-12/biossíntese , Leishmania donovani , Leishmaniose Visceral/imunologia , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/biossíntese , Nitritos/metabolismo , Norgestrel/farmacologia , Toxoplasmose/imunologia
13.
Bioorg Med Chem Lett ; 17(3): 624-7, 2007 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-17113290

RESUMO

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.


Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Benzodiazepinas/síntese química , Benzodiazepinas/farmacologia , Leishmania/efeitos dos fármacos , Animais , Gluconato de Antimônio e Sódio/farmacologia , Antiprotozoários/toxicidade , Benzodiazepinas/toxicidade , Indicadores e Reagentes , Leishmania donovani/efeitos dos fármacos , Dose Letal Mediana , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia
14.
Biomacromolecules ; 7(12): 3452-9, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17154474

RESUMO

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.


Assuntos
Disponibilidade Biológica , Quitosana/química , Micelas , Preparações Farmacêuticas/metabolismo , Sequência de Carboidratos , Carboidratos , Portadores de Fármacos , Dados de Sequência Molecular , Tamanho da Partícula , Prednisona , Propofol , Compostos de Amônio Quaternário/química , Solubilidade
15.
Immunology ; 119(3): 348-54, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16879623

RESUMO

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.


Assuntos
Gluconato de Antimônio e Sódio/uso terapêutico , Antiprotozoários/uso terapêutico , Interleucina-18/imunologia , Leishmania donovani/isolamento & purificação , Leishmaniose Visceral/imunologia , Animais , Anticorpos Antiprotozoários/biossíntese , Células Cultivadas , Suscetibilidade a Doenças , Imunoglobulina G/sangue , Interferon gama/sangue , Interleucina-12/sangue , Interleucina-18/deficiência , Leishmania donovani/imunologia , Leishmaniose Visceral/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Baço/imunologia , Células Th1/imunologia , Resultado do Tratamento
16.
Methods ; 38(2): 90-5, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16414269

RESUMO

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.


Assuntos
Ácidos e Sais Biliares/química , Imunidade nas Mucosas/imunologia , Toxoide Tetânico/imunologia , Vacinação/métodos , Administração Oral , Animais , Formação de Anticorpos/imunologia , Portadores de Fármacos , Sistemas de Liberação de Medicamentos/métodos , Técnica de Fratura por Congelamento , Imunoglobulina A/análise , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Intestino Delgado/química , Intestino Delgado/citologia , Intestino Delgado/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica , Plasmócitos/química , Plasmócitos/citologia , Plasmócitos/imunologia , Toxoide Tetânico/administração & dosagem , Toxoide Tetânico/química
17.
Vaccine ; 22(19): 2425-9, 2004 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-15193405

RESUMO

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).


Assuntos
Sistemas de Liberação de Medicamentos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/administração & dosagem , Vacinas contra Influenza/administração & dosagem , Administração Oral , Animais , Ácidos e Sais Biliares/química , Química Farmacêutica , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/classificação , Vacinas contra Influenza/imunologia , Lipossomos/química , Camundongos , Camundongos Endogâmicos BALB C
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