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1.
J Environ Pathol Toxicol Oncol ; 39(3): 213-224, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865913

RESUMO

Asthma is a chronic, serious allergic inflammatory disease in the airway. The inflammation in the airway is induced by the allergic T-helper 2 cells (Th2 cells), which leads to unfettered production of inflammatory cytokines. The accretion of inflammatory cells in the airway also speeds up the secretion of reactive oxygen species (ROS) and suppresses antioxidative processes. Hence, the present work aimed to study the antiasthmatic efficacy of betulin and its effect in suppressing the inflammatory markers of ovalbumin (OVA) challenged asthmatic mice. The observed results revealed that the levels of inflammatory cells including neutrophils, eosinophils, lymphocytes, and macrophages were effectively decreased by betulin treatment; furthermore, the inflammatory markers IL-4, IL-5, IL-13, and TNF-α levels were notably suppressed by betulin administration in OVA-challenged asthmatic mice. Similarly, the oral administration of betulin showed a reduction in IgE level and elevation in the IFN-γ level in bronchoalveolar lavage fluid (BALF). The elevated levels of antioxidant enzymes like catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD) were observed in betulin treated mice. Furthermore, reduced levels of reactive oxygen species like NO2, NO3, and MDA were noted in the betulin treated group. Consistently, airway hyperreactivity (AHR) was depleted in the betulin administered group compared with the OVA-challenged asthmatic group. Betulin treatment was revealed to have noteworthy antiasthmatic effects mediated by the suppression of production of inflammatory cells and the expression of other inflammatory markers. Furthermore, the elevation in the level of antioxidant markers helped to disclose the original regulatory mode of betulin on asthma treatment.


Assuntos
Antiasmáticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Triterpenos/uso terapêutico , Animais , Antiasmáticos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Asma/imunologia , Asma/metabolismo , Biomarcadores/análise , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Eosinófilos/citologia , Feminino , Imunoglobulina E/sangue , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Estresse Oxidativo/imunologia , Espécies Reativas de Oxigênio/metabolismo , Testes de Função Respiratória , Triterpenos/administração & dosagem
2.
J Environ Pathol Toxicol Oncol ; 39(3): 225-234, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865914

RESUMO

Asthma is marked by chronic irritation in the airway lumen of the lungs due to the accretion of inflammatory cells that influence the regular inhalation process. An extended buildup of inflammation leads to oxidative pressure and the repression of antioxidant functions. In the current study, a potential compound, boldine, was tested for the containment of provocative markers along the path of antiasthmatic activity in an ovalbumin (OVA)-induced asthmatic mice model. As an effect, the boldine (10 and 20 mg/kg) treatment suppressed inflammatory cells such as eosinophil, macrophage, neutrophil, lymphocyte, and other inflammatory markers in the bronchoalveolar lavage fluid (BALF) of OVA-induced mice. Likewise, immunoglobulin E (IgE) levels were drastically condensed in the serum of boldine-treated animals. Levels of enzymatic and nonenzymatic antioxidants, such as superoxide dismutase (SOD) and glutathione (GSH), were upregulated in the boldine treatment group compared to the asthmatic control group, which displays the antioxidant effects of boldine on asthmatic animals. Interestingly, the reactive oxygen species (ROS) and malonaldehyde (MDA) levels were repressed in the BALF of boldine-treated mice groups. Therefore, the effects of boldine are significant for the management of asthma, reducing the accrual of inflammatory cells, along with other inflammatory markers, while improving antioxidant markers and containing ROS. Hence, boldine may be an option for clinical trials of chronic asthma management.


Assuntos
Antiasmáticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/metabolismo , Aporfinas/uso terapêutico , Asma/tratamento farmacológico , Animais , Antiasmáticos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Aporfinas/administração & dosagem , Asma/imunologia , Biomarcadores/análise , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/análise , Modelos Animais de Doenças , Eosinófilos/citologia , Imunoglobulina E/sangue , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Espécies Reativas de Oxigênio/metabolismo , Testes de Função Respiratória
3.
Nat Commun ; 11(1): 3858, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737343

RESUMO

Checkpoint blockade therapy has provided noteworthy benefits in multiple cancers in recent years; however, its clinical benefits remain confined to 10-40% of patients with extremely high costs. Here, we design an ultrafast, low-temperature, and universal self-assembly route to integrate immunology-associated large molecules into metal-organic-framework (MOF)-gated mesoporous silica (MS) as cancer vaccines. Core MS nanoparticles, acting as an intrinsic immunopotentiator, provide the niche, void, and space to accommodate antigens, soluble immunopotentiators, and so on, whereas the MOF gatekeeper protects the interiors from robust and off-target release. A combination of MOF-gated MS cancer vaccines with systemic programmed cell death 1 (PD-1) blockade therapy generates synergistic effects that potentiate antitumour immunity and reduce the effective dose of an anti-PD-1 antibody to as low as 1/10 of that for PD-1 blockade monotherapy in E.G7-OVA tumour-bearing mice, with eliciting the robust adaptive OVA-specific CD8+ T-cell responses, reversing the immunosuppressive pathway and inducing durable tumour suppression.


Assuntos
Anticorpos Neutralizantes/farmacologia , Vacinas Anticâncer/farmacologia , Linfoma/terapia , Estruturas Metalorgânicas/farmacologia , Nanopartículas/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/química , Citotoxicidade Imunológica , Composição de Medicamentos , Feminino , Humanos , Imunidade Inata/efeitos dos fármacos , Imunoterapia/métodos , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfoma/imunologia , Linfoma/mortalidade , Linfoma/patologia , Estruturas Metalorgânicas/síntese química , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Receptor de Morte Celular Programada 1/imunologia , Dióxido de Silício/química , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Cancer Immunol Immunother ; 69(10): 1959-1972, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32388678

RESUMO

Cancer vaccine development has proven challenging with the exception of some virally induced cancers for which prophylactic vaccines exist. Currently, there is only one FDA approved vaccine for the treatment of prostate cancer and as such prostate cancer continues to present a significant unmet medical need. In this study, we examine the effectiveness of a therapeutic cancer vaccine that combines the ISCOMATRIX™ adjuvant (ISCOMATRIX) with the Toll-like receptor 3 agonist, polyinosinic-polycytidylic acid (Poly I:C), and Flt3L, FMS-like tyrosine kinase 3 ligand. We employed the TRAMP-C1 (transgenic adenocarcinoma of the mouse prostate) model of prostate cancer and the self-protein mPAP (prostatic acid phosphatase) as the tumor antigen. ISCOMATRIX™-mPAP-Poly I:C-Flt3L was delivered in a therapeutic prime-boost regime that was consistently able to achieve complete tumor regression in 60% of animals treated and these tumor-free animals were protected upon rechallenge. Investigations into the underlying immunological mechanisms contributing to the effectiveness of this vaccine identified that both innate and adaptive responses are elicited and required. NK cells, CD4+ T cells and interferon-γ were all found to be critical for tumor control while tumor infiltrating CD8+ T cells became disabled by an immunosuppressive microenvironment. There is potential for broader application of this cancer vaccine, as we have been able to demonstrate effectiveness in two additional cancer models; melanoma (B16-OVA) and a model of B cell lymphoma (Eµ-myc-GFP-OVA).


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Colesterol/administração & dosagem , Melanoma Experimental/imunologia , Fosfolipídeos/administração & dosagem , Neoplasias da Próstata/imunologia , Saponinas/administração & dosagem , Animais , Apoptose , Linfócitos T CD8-Positivos/efeitos dos fármacos , Proliferação de Células , Modelos Animais de Doenças , Combinação de Medicamentos , Humanos , Interferon gama/metabolismo , Masculino , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Poli I-C/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Pharmacol Sci ; 143(3): 182-187, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32386904

RESUMO

Memory CD8+ cytotoxic T-lymphocytes (CTLs) play a key role in protective immunity against infection and cancer. However, the induction of memory CTLs with currently available vaccines remains difficult. The chemokine receptor XCR1 is predominantly expressed on CD103+ cross-presenting dendritic cells (DCs). Recently, we have demonstrated that a high activity form of murine lymphotactin/XCL1 (mXCL1-V21C/A59C), a ligand of XCR1, can induce antigen-specific memory CTLs by increasing the accumulation of CD103+ DCs in the vaccination site and the regional lymph nodes. Here, we combined a hydrophilic gel patch as a transcutaneous delivery device and mXCL1-V21C/A59C as an adjuvant to further enhance memory CTL responses. The transcutaneous delivery of ovalbumin (OVA) and mXCL1-V21C/A59C by the hydrophilic gel patch increased CD103+ DCs in the vaccination site and the regional lymph nodes for a prolonged period of time compared with the intradermal injection of OVA and mXCL1-V21C/A59C. Furthermore, the hydrophilic gel patch containing OVA and mXCL1-V21C/A59C strongly induced OVA-specific memory CTLs and efficiently inhibited the growth of OVA-expressing tumors more than the intradermal injection of OVA and mXCL1-V21C/A59C. Collectively, this type of hydrophilic gel patch and a high activity form of XCL1 may provide a useful tool for the induction of memory CTL responses.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Quimiocinas C/administração & dosagem , Quimiocinas C/imunologia , Imunização/métodos , Adesivo Transdérmico , Animais , Antígenos CD , Linhagem Celular , Células Dendríticas/imunologia , Géis , Interações Hidrofóbicas e Hidrofílicas , Cadeias alfa de Integrinas , Camundongos Endogâmicos C57BL , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Fatores de Tempo
6.
Nanotoxicology ; 14(5): 711-724, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32374645

RESUMO

Prenatal particle exposure has been shown to increase allergic responses in offspring. Carbon nanotubes (CNTs) possess immunomodulatory properties, but it is unknown whether maternal exposure to CNTs interferes with offspring immune development. Here, C57Bl/6J female mice were intratracheally instilled with 67 of µg multiwalled CNTs on the day prior to mating. After weaning, tolerance and allergy responses were assessed in the offspring. Offspring of CNT-exposed (CNT offspring) and of sham-exposed dams (CTRL offspring) were intranasally exposed to ovalbumin (OVA) once weekly for 5 weeks to induce airway mucosal tolerance. Subsequent OVA sensitization and aerosol inhalation caused low or no OVA-specific IgE production and no inflammation. However, the CNT offspring presented with significantly lower OVA-specific IgG1 levels than CTRL offspring. In other groups of 5-week-old offspring, low-dose sensitization with OVA and subsequent OVA aerosol inhalation led to significantly lower OVA-specific IgG1 production in CNT compared to CTRL offspring. OVA-specific IgE and airway inflammation were non-significantly reduced in CNT offspring. The immunomodulatory effects of pre-gestational exposure to multiwalled CNTs were unexpected, but very consistent. The observations of suppressed antigen-specific IgG1 production may be of importance for infection or vaccination responses and warrant further investigation.


Assuntos
Formação de Anticorpos/efeitos dos fármacos , Antígenos/toxicidade , Hipersensibilidade/etiologia , Nanotubos de Carbono/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Antígenos/química , Feminino , Humanos , Hipersensibilidade/imunologia , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Inflamação , Exposição Materna/efeitos adversos , Camundongos , Camundongos Endogâmicos BALB C , Nanotubos de Carbono/química , Ovalbumina/imunologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia
7.
Food Chem ; 327: 127037, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32446030

RESUMO

In this work, the mechanism of the effect of lipid oxidation on the IgG/IgE binding ability of ovalbumin (OVA) was investigated via the peroxyl radicals produced by 2, 2'-azobis (2-amidinopropane) dihydrochloride to simulate lipid oxidation. Results showed that the structure of OVA unfolded partially with an increase in oxidation degree, leading to the exposure of the allergenic epitopes and increasing the IgG/IgE binding ability of OVA. Nine oxidation sites were found on the α-helix, and these sites may unwind the α-helix and expose the allergenic epitopes on the OVA surface, leading to antibody recognition and combination. Consequently, the IgG/IgE binding ability of OVA was increased. In conclusion, the allergenic capacity of OVA can be promoted by modifying peroxyl radical oxidation in processing egg products.


Assuntos
Amidinas/metabolismo , Biomimética , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Metabolismo dos Lipídeos , Ovalbumina/imunologia , Ovalbumina/metabolismo , Animais , Oxirredução
8.
Proc Natl Acad Sci U S A ; 117(23): 12980-12990, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32461368

RESUMO

The aryl hydrocarbon receptor (AhR) represents an environmental sensor regulating immune responses. In the skin, AhR is expressed in several cell types, including keratinocytes, epidermal Langerhans cells (LC), and dermal dendritic cells (DC). The mechanisms how AhR activates or inhibits cutaneous immune responses remain controversial, owing to differences in the cell-specific functions of AhR and the different activating ligands. Therefore, we sought to investigate the role of AhR in LC and langerin+ and negative DC in the skin. To this aim, we generated Langerin-specific and CD11c-specific knockout (-/-) mice lacking AhR, respectively, in LC and Langerin+ dermal DC and in all CD11c+ cells. These were then tested in an epicutaneous protein (ovalbumin, Ova) sensitization model. Immunofluorescence microscopy and flow cytometry revealed that Langerin-AhR-/- but not CD11c-AhR-/- mice harbored a decreased number of LC with fewer and stunted dendrites in the epidermis as well as a decreased number of LC in skin-draining lymph nodes (LN). Moreover, in the absence of AhR, we detected an enhanced T helper type-2 (Th2) [increased interleukin 5 (IL-5) and interleukin 13 (IL-13)] and T regulatory type-1 (Tr1) (IL-10) response when LN cells were challenged with Ova in vitro, though the number of regulatory T cells (Treg) in the LN remained comparable. Langerin-AhR-/- mice also exhibited increased blood levels of Ova-specific immunoglobulin E (IgE). In conclusion, deletion of AhR in langerin-expressing cells diminishes the number and activation of LC, while enhancing Th2 and Tr1 responses upon epicutaneous protein sensitization.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células de Langerhans/imunologia , Receptores de Hidrocarboneto Arílico/metabolismo , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Administração Cutânea , Animais , Antígenos de Superfície/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Epiderme/imunologia , Epiderme/metabolismo , Técnicas de Inativação de Genes , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Células de Langerhans/metabolismo , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismo , Camundongos , Camundongos Transgênicos , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Receptores de Hidrocarboneto Arílico/genética , Linfócitos T Reguladores/metabolismo , Células Th2/metabolismo
9.
Ecotoxicol Environ Saf ; 199: 110740, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32446102

RESUMO

Dibutyl phthalate (DBP) is one of the most ubiquitous phthalate esters found in everyday products, and is receiving increased attention as an immunologic adjuvant. However, information regarding DBP-aggravated allergic asthma is still limited. This study used a mouse model sensitized with ovalbumin (OVA) to determine any adverse effects of DBP on allergic asthma. Our results reveal that allergic asthmatic mice exposed to DBP for an extended period had a significant increase in inflammatory cell infiltration; a significant increase in levels of serum immunoglobulin and T helper 2 cell (Th2) and T helper 17 cell (Th17) cytokines in lung tissue; and significant changes in lung histology and AHR, all of which are typical asthmatic symptoms. The levels of oxidative stress and levels of the neuropeptide, calcitonin gene related peptide (CGRP), were also elevated after DBP exposure. Interestingly, blocking oxidative stress by administering melatonin (MT) not only reduced oxidative stress and CGRP levels, but also ameliorated the asthmatic symptoms. Collectively, these results show that DBP exacerbates asthma-like pathologies by increasing the expression of CGRP mediated by oxidative stress.


Assuntos
Asma/induzido quimicamente , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Dibutilftalato/toxicidade , Poluentes Ambientais/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Asma/imunologia , Asma/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia
10.
PLoS One ; 15(5): e0226233, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379832

RESUMO

Allergic asthma is the most common phenotype of the pathology, having an early-onset in childhood and producing a Th2-driven airways remodeling process that leads to symptoms and pathophysiological changes. The avoidance of aeroallergen exposure in early life has been shown to prevent asthma, but without repeated success and with the underlying preventive mechanisms at the beginning of asthma far to be fully recognized. In the present study, we aimed to evaluate if neonatal LPS-induced boost in epithelial host defenses contribute to prevent OVA-induced asthma in adult mice. To this, we focused on the response of bronchiolar club cells (CC), which are highly specialized in maintaining the epithelial homeostasis in the lung. In these cells, neonatal LPS administration increased the expression of TLR4 and TNFα, as well as the immunodulatory/antiallergic proteins: club cell secretory protein (CCSP) and surfactant protein D (SP-D). LPS also prevented mucous metaplasia of club cells and reduced the epidermal growth factor receptor (EGFR)-dependent mucin overproduction, with mice displaying normal breathing patterns after OVA challenge. Furthermore, the overexpression of the epithelial Th2-related molecule TSLP was blunted, and normal TSLP and IL-4 levels were found in the bronchoalveolar lavage. A lower eosinophilia was detected in LPS-pretreated mice, along with an increase in phagocytes and regulatory cells (CD4+CD25+FOXP3+ and CD4+IL-10+), together with higher levels of IL-12 and TNFα. In conclusion, our study demonstrates stable asthma-preventive epithelial effects promoted by neonatal LPS stimulation, leading to the presence of regulatory cells in the lung. These anti-allergic dynamic mechanisms would be overlaid in the epithelium, favored by an adequate epidemiological environment, during the development of asthma.


Assuntos
Asma/imunologia , Bronquíolos/efeitos dos fármacos , Bronquíolos/imunologia , Citocinas/metabolismo , Epitélio/imunologia , Imunidade Inata , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Alérgenos/imunologia , Animais , Animais Recém-Nascidos , Asma/prevenção & controle , Modelos Animais de Doenças , Epitélio/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Ovalbumina/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
11.
Int J Nanomedicine ; 15: 2685-2697, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368049

RESUMO

Background: Nanocarriers could deliver significantly higher amounts of antigen to antigen-presenting cells (APCs), which have great potential to stimulate humoral and cellular response in cancer immunotherapy. Thereafter, silica solid nanosphere (SiO2) was prepared, and a model antigen (ovalbumin, OVA) was covalently conjugated on the surface of SiO2 to form nanovaccine (OVA@SiO2). And the application of OVA@SiO2 for cancer immunotherapy was evaluated. Materials and Methods: SiO2 solid nanosphere was prepared by the Stöber method, then successively aminated by aminopropyltriethoxysilane and activated with glutaraldehyde. OVA was covalently conjugated on the surface of activated SiO2 to obtain nanovaccine (OVA@SiO2). Dynamic light scattering, scanning electron microscope, and transmission electron microscope were conducted to identify the size distribution, zeta potential and morphology of OVA@SiO2. The OVA loading capacity was investigated by varying glutaraldehyde concentration. The biocompatibility of OVA@SiO2 to DC2.4 and RAW246.7 cells was evaluated by a Cell Counting Kit-8 assay. The uptake of OVA@SiO2 by DC2.4 and its internalization pathway were evaluated in the absence or presence of different inhibitors. The activation and maturation of bone marrow-derived DC cells by OVA@SiO2 were also investigated. Finally, the in vivo transport of OVA@SiO2 and its toxicity to organs were appraised. Results: All results indicated the successful covalent conjugation of OVA on the surface of SiO2. The as-prepared OVA@SiO2 possessed high antigen loading capacity, which had good biocompatibility to APCs and major organs. Besides, OVA@SiO2 facilitated antigen uptake by DC2.4 cells and its cytosolic release. Noteworthily, OVA@SiO2 significantly promoted the maturation of dendritic cells and up-regulation of cytokine secretion by co-administration of adjuvant CpG-ODN. Conclusion: The as-prepared SiO2 shows promising potential for use as an antigen delivery carrier.


Assuntos
Antígenos/metabolismo , Vacinas Anticâncer/farmacologia , Imunoterapia/métodos , Nanosferas/química , Ovalbumina/química , Adjuvantes Imunológicos/administração & dosagem , Animais , Apresentação do Antígeno , Antígenos/administração & dosagem , Antígenos/química , Antígenos/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/química , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Nanosferas/administração & dosagem , Oligodesoxirribonucleotídeos/administração & dosagem , Ovalbumina/imunologia , Ovalbumina/farmacocinética , Células RAW 264.7 , Dióxido de Silício/química
12.
PLoS One ; 15(5): e0233047, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32392269

RESUMO

Fruits have been widely considered as the default "health foods" because they contain numerous vitamins and minerals needed to sustain human health. Fermentation strategies have been utilized to enhance the nutritive and flavor features of healthy and readily consumable fruit products while extending their shelf lives. A traditional fermented multi-fruit beverage was made from five fruits including kiwi, guava, papaya, pineapple, and grape fermented by Saccharomyces cerevisiae along with lactic acid bacteria and acetic acid bacteria. The immunomodulatory properties of the fermented multi-fruit beverage, in vivo nonspecific and ovalbumin (OVA)-specific immune response experiments using female BALB/c mice were performed. Administration of the fermented multi-fruit beverage reduced the calorie intake, thus resulting in a less weight gain in mice compared to the water (placebo)-fed mice. In the nonspecific immune study model, the fermented multi-fruit beverage enhanced phagocytosis and T cell proliferation but did not affect B cell proliferation and immunoglobulin G (IgG) production. Analysis of cytokine secretion profile also revealed that the fermented multi-fruit beverage enhanced proinflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, and T helper (Th)1-related cytokine interferon (IFN)-γ production, thus creating an immunostimulatory effect. Nonetheless, in the specific immune study model, the results showed that the fermented multi-fruit beverage decreased the production of proinflammatory cytokines IL-6 and TNF-α production in OVA-immunized mice. Moreover, it also caused a decrease in the production of anti-OVA IgG1, which was accompanied by a decrease in Th2-related cytokines IL-4 and IL-5 production and an increase in Th1-related cytokine IFN-γ production, indicating that it may have the potential to shift the immune system from the allergen-specific Th2 responses toward Th1-type responses. The results indicate that fermented multi-fruit beverage has the potential to modulate immune responses both in a nonspecific and specific manners.


Assuntos
Citocinas/metabolismo , Alimentos e Bebidas Fermentados/microbiologia , Frutas/imunologia , Ovalbumina/administração & dosagem , Linfócitos T/metabolismo , Acetobacteraceae/fisiologia , Administração Oral , Animais , Peso Corporal , Feminino , Imunoglobulina G/metabolismo , Lactobacillales/fisiologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Fagocitose , Saccharomyces cerevisiae/fisiologia , Células Th1/imunologia , Células Th2/imunologia , Vacinação
13.
Med Sci Monit ; 26: e920583, 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32249275

RESUMO

BACKGROUND Bifidobacteria are among the probiotics used in treating intestinal diseases and are rarely used for allergic asthma treatment. The present study investigated the mechanism of B. infantis in treating allergic asthma in mice. MATERIAL AND METHODS A total of 40 male Balb/c mice were randomized into control, ovalbumin (OVA), montelukast (Mon), and B. infantis (B10) groups, and allergic asthma was induced in the OVA, Mon, and B10 groups. Airway reactivity was measured on day 29 by methacholine at various doses. The numbers of total cells and inflammatory cells in bronchoalveolar lavage fluid (BALF) were counted by blood cell counter and Diff-Quik staining. Hematoxylin-eosin (HE) staining was performed to observe inflammatory cell infiltration in lung tissues. Total IgE and OVA-specific IgE in serum were measured by ELISA. Mucin 5AC expression was detected by Western blot to evaluate airway obstruction. The levels of Th1 (IFN-γ, IL-2) and Th2 (IL-4, IL-5, IL-13) cytokines in BALF and tissues were detected by ELISA and qRT-PCR, respectively. RESULTS The mice in the OVA group had airway hyperreactivity, while the symptoms in the B10 group and Mon group were effectively relieved. B10 reduced the number of inflammatory cells in BALF as well as inflammatory cell infiltration in tissues. Moreover, the levels of total serum IgE, OVA-specific IgE, and Mucin 5AC were increased in the OVA group, but were reduced in the Mon group and B10 group. B. infantis increased the levels of Th1 cytokines and decreased those of Th2 cytokines. CONCLUSIONS B. infantis can reduce the infiltration of inflammatory cells induced by OVA-specific antibodies in mice. B. infantis has therapeutic effects on allergic asthma by promoting Th1 and inhibiting Th2 immune responses.


Assuntos
Asma/terapia , Bifidobacterium longum subspecies infantis , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Imunoglobulina E/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Distribuição Aleatória , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia
14.
Mol Immunol ; 121: 167-185, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32229377

RESUMO

Some studies have shown that maturation of dendritic cells (DCs) is modulated directly by pathogen components via pattern recognition receptors such as Toll-like receptors, but also by signal like CD40 ligand (CD40 L or CD154) mediated by activated T cells. Several reports indicate that invariant natural killer T (iNKT) cells up-regulate CD40 L upon stimulation and thereby induce activation and maturation of DCs through crosslink with CD40. Our previous findings indicated that iNKT cells promote Th2 cell responses through the induction of immunogenic maturation of lung DCs (LDCs) in the asthmatic murine, but its mechanism remains unclear. Therefore, we investigated the immunomodulatory effects of blockade of CD40 L using anti-CD40 L treatment on Th2 cell responses and immunogenic maturation of LDCs, and further analyzed whether these influences of blockade of CD40 L were related to lung iNKT cells using iNKT cell-deficient mice and the combination treatment of specific iNKT cell activation with anti-CD40 L treatment in murine models of asthma. Our findings showed that blockade of CD40 L using anti-CD40 L treatment attenuated Th2 cell responses in wild-type (WT) mice, but not in CD1d-deficient mice sensitized and challenged with ovalbumin (OVA) or house dust mite (HDM). Meanwhile, blockade of CD40 L down-regulated immunogenic maturation of LDCs in WT mice, but not in CD1d-deficient mice sensitized and challenged with OVA. Additionally, agonistic anti-CD40 treatment reversed the inhibitory effects of anti-CD40 L treatment on Th2 cell responses and LDC activation in an OVA-induced mouse model of asthma. Furthermore, LDCs from asthmatic mice treated with anti-CD40 L could significantly reduce the influence on Th2 cell responses in vivo and in vitro. Finally, α-Galactosylceramide plus anti-CD40 L treatment stimulated lung iNKT cells, but suppressed Th2 cell responses in the asthmatic mice. Taken together, our data raise an evidence that blockade of CD40 L attenuates Th2 cell responses through the inhibition of immunogenic maturation of LDCs, which may be at least partially related to lung iNKT cells in murine models of asthma.


Assuntos
Asma/tratamento farmacológico , Ligante de CD40/antagonistas & inibidores , Células Dendríticas/imunologia , Células T Matadoras Naturais/efeitos dos fármacos , Células Th2/imunologia , Animais , Antígenos CD1d/genética , Asma/imunologia , Asma/patologia , Ligante de CD40/imunologia , Ligante de CD40/metabolismo , Comunicação Celular/imunologia , Modelos Animais de Doenças , Feminino , Galactosilceramidas/administração & dosagem , Humanos , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Ovalbumina/imunologia , Pyroglyphidae/imunologia
15.
Toxicol Appl Pharmacol ; 395: 114981, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32240662

RESUMO

What factors and underlying mechanisms influence the occurrence of the atopic march remain unclear. Recent studies suggest that exposure to diisononyl phthalate (DINP) might be associated with the occurrence of atopic dermatitis (AD) and asthma. However, little is known about the role of DINP exposure in the atopic march. In this study, we investigated the effect of DINP exposure on the progression from AD to asthma, and explored the potential mechanisms. We built an atopic march mouse model from AD to asthma, by exposure to DINP and sensitization with OVA. Pyrrolidine dithiocarbamate and SB203580 were used to block NF-κB and p38 MAPK respectively, to explore the possible molecular mechanisms. The data showed that DINP aggravated airway remodeling and airway hyperresponsiveness (AhR) in the progression from AD to asthma, induced a sharp increase in IL-33, IgE, Th2 and Th17 cytokines, and resulted in an increase in the expression of thymic stromal lymphopoietin (TSLP) and in the number of inflammatory cells. Blocking NF-κB inhibited AD-like lesions, and the production of IL-33 and TSLP in the progression of AD, while alleviating airway remodeling, AhR, and the expression of Th2 and Th17 cytokines in both the progression of AD and the asthmatic phenotype. Blocking p38 MAPK in the progression of asthma, inhibited airway remodeling, AhR, and the expression of Th2 and Th17 cytokines. The results demonstrated that exposure to DINP enhanced the immune response to memory CD4+ T helper cells through the NF-κB and p38 MAPK signaling pathways, leading to an aggravation of the atopic march.


Assuntos
Hipersensibilidade Imediata/induzido quimicamente , NF-kappa B/fisiologia , Ácidos Ftálicos/toxicidade , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia , Remodelação das Vias Aéreas/efeitos dos fármacos , Animais , Asma/induzido quimicamente , Citocinas/biossíntese , Dermatite Atópica/induzido quimicamente , Modelos Animais de Doenças , Progressão da Doença , Ativação Enzimática/efeitos dos fármacos , Hipersensibilidade Imediata/imunologia , Hipersensibilidade Imediata/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/antagonistas & inibidores , Ovalbumina/imunologia , Hipersensibilidade Respiratória/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Organismos Livres de Patógenos Específicos , Células Th17/imunologia , Células Th2/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
16.
Nat Commun ; 11(1): 1817, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286311

RESUMO

Dendritic cells (DCs) constitute a specialized population of immune cells that present exogenous antigen (Ag) on major histocompatibility complex (MHC) class I molecules to initiate CD8 + T cell responses against pathogens and tumours. Although cross-presentation depends critically on the trafficking of Ag-containing intracellular vesicular compartments, the molecular machinery that regulates vesicular transport is incompletely understood. Here, we demonstrate that mice lacking Kif5b (the heavy chain of kinesin-1) in their DCs exhibit a major impairment in cross-presentation and thus a poor in vivo anti-tumour response. We find that kinesin-1 critically regulates antigen cross-presentation in DCs, by controlling Ag degradation, the endosomal pH, and MHC-I recycling. Mechanistically, kinesin-1 appears to regulate early endosome maturation by allowing the scission of endosomal tubulations. Our results highlight kinesin-1's role as a molecular checkpoint that modulates the balance between antigen degradation and cross-presentation.


Assuntos
Apresentação do Antígeno/imunologia , Células Dendríticas/metabolismo , Endossomos/metabolismo , Cinesina/metabolismo , Ácidos/metabolismo , Animais , Antígenos/metabolismo , Antígenos CD/metabolismo , Células da Medula Óssea/citologia , Proliferação de Células , Endocitose , Antígenos de Histocompatibilidade Classe I/metabolismo , Cinesina/deficiência , Camundongos Knockout , Camundongos Transgênicos , Microtúbulos/metabolismo , Neoplasias/patologia , Ovalbumina/imunologia , Solubilidade
17.
Curr Pharm Biotechnol ; 21(10): 927-938, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32065101

RESUMO

BACKGROUND: The essential oil of methyl eugenol rich Cymbopogon khasianus Hack. was evaluated and its bioactivities were compared with pure methyl eugenol. So far, methyl eugenol rich essential oil of lemongrass was not studied for any biological activities; hence, the present study was conducted. OBJECTIVE: This study examined the chemical composition of essential oil of methyl eugenol rich Cymbopogon khasianus Hack., and evaluated its antioxidant, anti-inflammatory, antimicrobial, and herbicidal properties and genotoxicity, which were compared with pure compound, methyl eugenol. MATERIAL AND METHODS: Methyl eugenol rich variety of Cymbopogon khasianus Hack., with registration no. INGR18037 (c.v. Jor Lab L-9) was collected from experimental farm CSIR-NEIST, Jorhat, Assam (26.7378°N, 94.1570°E). The essential oil wasobtained by hydro-distillation using a Clevenger apparatus. The chemical composition of the essential oil was evaluated using GC/MS analysis and its antioxidant (DPPH assay, reducing power assay), anti-inflammatory (Egg albumin denaturation assay), and antimicrobial (Disc diffusion assay, MIC) properties, seed germination effect and genotoxicity (Allium cepa assay) were studied and compared with pure Methyl Eugenol compound (ME). RESULTS: Major components detected in the Essential Oil (EO) through Gas chromatography/mass spectroscopy analysis were methyl eugenol (73.17%) and ß-myrcene (8.58%). A total of 35components were detected with a total identified area percentage of 98.34%. DPPH assay revealed considerable antioxidant activity of methyl eugenol rich lemongrass essential oil (IC50= 2.263 µg/mL), which is lower than standard ascorbic acid (IC50 2.58 µg/mL), and higher than standard Methyl Eugenol (ME) (IC50 2.253 µg/mL). Methyl eugenol rich lemongrass EO showed IC50 38.00 µg/mL, ME 36.44 µg/mL, and sodium diclofenac 22.76 µg/mL, in in-vitro anti-inflammatory test. Moderate antimicrobial activity towards the 8 tested microbes was shown by methyl eugenol rich lemongrass essential oil whose effectiveness against the microbes was less as compared to pure ME standard. Seed germination assay further revealed the herbicidal properties of methyl eugenol rich essential oil. Moreover, Allium cepa assay revealed moderate genotoxicity of the essential oil. CONCLUSION: This paper compared the antioxidant, anti-inflammatory, antimicrobial, genotoxicity and herbicidal activities of methyl eugenol rich lemongrass with pure methyl eugenol. This methyl eugenol rich lemongrass variety can be used as an alternative of methyl eugenol pure compound. Hence, the essential oil of this variety has the potential of developing cost-effective, easily available antioxidative/ antimicrobial drugs but its use should be under the safety range of methyl eugenol and needs further clinical trials.


Assuntos
Cymbopogon/química , Eugenol/análogos & derivados , Óleos Voláteis/farmacologia , Folhas de Planta/química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Compostos de Bifenilo/química , Aberrações Cromossômicas/efeitos dos fármacos , Cymbopogon/genética , Eugenol/isolamento & purificação , Eugenol/farmacologia , Eugenol/toxicidade , Fungos/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Óleos Voláteis/isolamento & purificação , Óleos Voláteis/toxicidade , Ovalbumina/imunologia , Picratos/química , Extratos Vegetais/química
18.
Mol Immunol ; 120: 43-51, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32050111

RESUMO

Food protein-induced allergies are primarily aggravated due to imbalance immune responses. Earlier studies by different research groups have reported that the intervention of Lactobacillus pentosus (L. pentosus) S-PT84 can modulate T-helper (Th)1/Th2 balance through regulatory T cells and can effectively promote type 1 immunity by activating dendritic cells and natural killer cells, such biological activity makes L. pentosus S-PT84 a potential mediation in controlling food allergy. Thus, this study aimed to evaluate the effects of L. pentosus S-PT84 against egg ovalbumin (OVA)-induced allergic response in mice. BALB/c mice (n = 12/group) were sensitized with OVA (50 µg/mice) via intraperitoneal injection (IP) for four weeks and subsequently administered with three different doses of L. pentosus S-PT84 via pelleted diet. The allergenic status was assessed by clinical signs, serum histamine, mouse mast cell protease (MMCP) level, and antibody activity, cytokines level in splenocytes, and expression of T regulatory cells (T-regs) in blood. The intervention of L. pentosus S-PT84, precisely at the high dose (0.6 % L. pentosus S-PT84 in pelleted diet) group, significantly reduced the clinical allergenic symptoms and reduced the histamine and MMCP levels in serum. However, the intervention of L. pentosus S-PT84 did not affect the OVA-specific IgE, IgG concentration, but led to lower the total IgE and IgG titers, suggesting that the therapeutic effect of L. pentosus S-PT84 may be due to development of immune tolerance. Moreover, differences in the immune response were observed after L. pentosus S-PT84 intervention, as it significantly reduced the production of IL-4, IL-17, and increased the population of CD25+Foxp3+ cells. Thus, it can be concluded that the intervention of L. pentosus S-PT84 provides a potential therapeutic strategy to reduce the chicken egg OVA-induced allergic symptoms.


Assuntos
Hipersensibilidade a Ovo/imunologia , Hipersensibilidade a Ovo/terapia , Imunoterapia/métodos , Lactobacillus pentosus/imunologia , Alérgenos/imunologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta Imunológica , Feminino , Tolerância Imunológica , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Imunomodulação , Imunossupressão/métodos , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia
19.
J Med Chem ; 63(6): 3290-3297, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32101001

RESUMO

We have prepared a number of saponin-based vaccine adjuvant candidates. These unnatural saponins have a different terminal-functionalized side chain incorporated into the glucuronic acid unit that is attached to a triterpenoid core at its C3 position. The semisynthetic saponin adjuvants have shown significantly different immunostimulatory activities, suggesting that the structure of the side chain, triterpenoid core, and oligosaccharide domain together orchestrate saponin adjuvant's potentiation of immune responses. Among these new adjuvant candidates, VSA-2 (5b), a derivative of Momordica saponin (MS) II, showed consistent enhancement of immunoglobulin G2a (IgG2a) production when it was in formulation with either ovalbumin or recombinant hemagglutinin B (rHagB) antigen. With rHagB antigen, it induced a significantly higher IgG2a response than the positive control GPI-0100, a well-studied semisynthetic saponin adjuvant mixture derived from Quillaja saponaria Molina saponins, known for its ability to induce a balanced Th1/Th2 immunity. These results confirm that Momordica saponins are a viable natural source to provide potent saponin adjuvants after simple chemical derivatization and identify VSA-2 (5b) as another MS-based promising immunostimulant lead owing to its distinctive ability in potentiating the IgG2a response.


Assuntos
Adjuvantes Imunológicos/farmacologia , Saponinas/farmacologia , Adesinas Bacterianas/imunologia , Adjuvantes Imunológicos/síntese química , Animais , Formação de Anticorpos/efeitos dos fármacos , Galinhas , Feminino , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Lectinas/imunologia , Camundongos Endogâmicos BALB C , Estrutura Molecular , Ovalbumina/imunologia , Saponinas/síntese química , Saponinas/imunologia , Células Th1/efeitos dos fármacos
20.
Cell Immunol ; 349: 104049, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32057353

RESUMO

Pathogenic microorganisms utilize multiple approaches to break down host immunity in favor of their invasion, of which, cystatin C is one of the soluble factors secreted by parasites reported to affect host immunity in vivo. The cellular targets and mechanisms of action in vivo of cystatin C, however, are far from clear. As professional antigen-presenting cells, dendritic cells (DCs) are first immune cells that contact foreign pathogenic agents or their products to initiate immune responses. We previously reported that cystatin C can regulate the functions of DCs in terms of suppressed CD4+ T cell activation but enhanced Th1/Th17 differentiation via different mechanisms. Here, we further verified these regulatory effects of cystatin C on DCs in vivo. We found that the suppressive role of DC-mediated CD4+ T cell proliferation by cystatin C was partly cell-contact independent and extended to CD8+ T cells in vivo. Although cystatin C-overexpressing DCs trafficked equally as their mock-transduced counterparts, their adoptive transfer suppressed CD8+ T cell immunity and resulted in compromised tumor rejection in both vaccination and treatment regimes. Compared with their role in promoting Th17 differentiation in vivo, cystatin C-transduced DCs had far greater ability to induce T regulatory cells (Tregs), leading to collectively a higher Treg/Th17 ratio in an adoptively transferred disease model, and thus relieved Th17-dependent autoimmunity. Collectively, these data demonstrated strong in vivo evidences for immune regulatory roles of cystatin C in DCs and provided theoretical basis for the application of cystatin C-transduced cell therapy in the treatment or remission of certain autoimmune diseases. (246).


Assuntos
Transferência Adotiva , Artrite Experimental/terapia , Doenças Autoimunes/terapia , Cistatina C/fisiologia , Células Dendríticas/imunologia , Evasão Tumoral/imunologia , Transferência Adotiva/efeitos adversos , Animais , Comunicação Celular , Células Cultivadas , Cistatina C/genética , Células Dendríticas/transplante , Regulação para Baixo , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/genética , Granzimas/biossíntese , Granzimas/genética , Imunoterapia Adotiva , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Ativação Linfocitária , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Ovalbumina/imunologia , Proteínas Citotóxicas Formadoras de Poros/biossíntese , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Recombinantes/metabolismo , Organismos Livres de Patógenos Específicos , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Transdução Genética
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