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1.
Clin Rev Allergy Immunol ; 59(2): 160-174, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31359247

RESUMO

Asthma has been increasingly recognized as being a heterogeneous disease with multiple distinct mechanisms and pathophysiologies. Evidence continues to build regarding the existence of different cell types, environmental exposures, pathogens, and other factors that produce a similar set of symptoms known collectively as asthma. This has led to a movement from a "one size fits all" symptom-based methodology to a more patient-centered, individualized approach to asthma treatment targeting the underlying disease process. A significant contributor to this shift to more personalized asthma therapy has been the increasing availability of numerous biologic therapies in recent years, providing the opportunity for more targeted treatments. When targeted biologics began to be developed for treatment of asthma, the hope was that distinct biomarkers would become available, allowing the clinician to determine which biologic therapy was best suited for which patients. Presence of certain biomarkers, like eosinophilia or antigen-specific IgE, is important features of specific asthma phenotypes. Currently available biomarkers can help with decision making about biologics, but are generally too broad and non-specific to clearly identify an asthma phenotype or the single biologic best suited to an asthmatic. Identification of further biomarkers is the subject of intense research. Yet, identifying a patient's asthma phenotype can help in predicting disease course, response to treatment, and biologic therapies to consider. In this review, major asthma phenotypes are reviewed, and the evidence for the utility of various biologics, both those currently on the market and those in the development process, in each of these phenotypes is explored.


Assuntos
Asma/diagnóstico , Asma/terapia , Terapia Biológica , Fenótipo , Aspergilose Broncopulmonar Alérgica/complicações , Aspergilose Broncopulmonar Alérgica/imunologia , Aspergilose Broncopulmonar Alérgica/microbiologia , Asma/etiologia , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Terapia Biológica/métodos , Biomarcadores , Gerenciamento Clínico , Suscetibilidade a Doenças , Eosinofilia/imunologia , Eosinofilia/metabolismo , Eosinofilia/patologia , Exercício Físico , Humanos , Imunoglobulina E/imunologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Obesidade/complicações , Obesidade/metabolismo , Guias de Prática Clínica como Assunto , Células Th2/imunologia , Células Th2/metabolismo , Resultado do Tratamento
2.
Am J Respir Cell Mol Biol ; 51(5): 615-25, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24810144

RESUMO

Growth arrest-specific gene (Gas)6 is a secreted vitamin K-dependent protein with pleiotropic effects via activation of receptor tyrosine kinase Tyro3, Axl, and Mertk receptors, but little is known about its role in allergic airway disease. We investigated the role of Gas6 in the development of fungal allergic airway disease in mice. The immune response was evaluated in Gas6-deficient (Gas6-/-) and wild-type (WT) mice and in recombinant Gas6-treated WT mice during Aspergillus fumigatus-induced allergic airway disease. Gas6 plasma levels were significantly elevated in adult clinical asthma of all severities compared with subjects without asthma. In a murine model of fungal allergic airway disease, increased protein expression of Axl and Mertk were observed in the lung. Airway hyperresponsiveness (AHR), whole lung Th2 cytokine levels, goblet cell metaplasia, and peribronchial fibrosis were ameliorated in Gas6-/- mice compared with WT mice with fungal allergic airway disease. Intranasal Gas6 administration into WT mice had a divergent effect on airway inflammation and AHR. Specifically, a total dose of 2 µg of exogenous Gas6 (i.e., low dose) significantly increased whole lung Th2 cytokine levels and subsequent AHR, whereas a total dose of 7 µg of exogenous Gas6 (i.e., high dose) significantly suppressed Th1 and Th2 cytokines and AHR compared with appropriate control groups. Mechanistically, Gas6 promoted Th2 activation via its highest affinity receptor Axl expressed by myeloid DCs. Intranasal administration of Gas6 consistently exacerbated airway remodeling compared with control WT groups. These results demonstrate that Gas6 enhances several features of fungal allergic airway disease.


Assuntos
Aspergilose Broncopulmonar Alérgica/imunologia , Aspergilose Broncopulmonar Alérgica/metabolismo , Aspergillus fumigatus/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Remodelação das Vias Aéreas/imunologia , Animais , Asma/imunologia , Asma/metabolismo , Líquido da Lavagem Broncoalveolar/imunologia , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologia , Células Th1/citologia , Células Th1/imunologia , Células Th2/citologia , Células Th2/imunologia
3.
J Antimicrob Chemother ; 60(5): 1080-4, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17855727

RESUMO

OBJECTIVES: Invasive pulmonary aspergillosis is associated with high mortality. To assess new antifungal therapy options, animal models have to be developed to assess, in an appropriate setting, the activity of new drugs. METHODS: Male albino CD rats (125-150 g) were fed with a protein-free diet and received dexamethasone thrice weekly subcutaneously during the whole experiment. After 2 weeks, an inoculum of 10(6) conidia of Aspergillus fumigatus (H11-20) was injected intratracheally. Antifungal treatment was initiated and continued for a total of 7 days. Animals were grouped in numbers of 10. One group of animals served as untreated control, whereas the others were treated with amphotericin B intraperitoneally (2 and 4 mg/kg) and posaconazole via gavage (2, 4, 10 and 20 mg/kg). Survival and log(10) cfu/g of the lungs were the endpoints. The strain H11-20 was tested for susceptibility in vitro to amphotericin B and posaconazole, respectively. Fungal burden of the lungs was expressed as log(10) cfu/g. Survival analysis was performed by the Kaplan-Meier method. Differences in fungal burden were assessed by the Mann-Whitney test. RESULTS: All untreated animals died within a week. Amphotericin B and posaconazole at 2 mg/kg demonstrated survival benefits over control (P = 0.01 and P = 0.04). Dosages of 4 mg/kg were superior to 2 mg/kg for amphotericin B (P = 0.02) and posaconazole (P < 0.05), respectively. No further survival benefits were demonstrated beyond dosages of 10 mg/kg. Rats treated with 20 mg/kg posaconazole, however, had a lower fungal burden than all the other treatment groups (P = 0.0002). CONCLUSIONS: Posaconazole and amphotericin B are effective in a dosage-dependent manner in this pulmonary aspergillosis model in immunocompromised rats.


Assuntos
Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Aspergilose Broncopulmonar Alérgica/tratamento farmacológico , Dexametasona/farmacologia , Triazóis/uso terapêutico , Anfotericina B/administração & dosagem , Animais , Antifúngicos/administração & dosagem , Aspergilose Broncopulmonar Alérgica/imunologia , Aspergillus fumigatus/efeitos dos fármacos , Relação Dose-Resposta a Droga , Farmacorresistência Fúngica , Quimioterapia Combinada , Hospedeiro Imunocomprometido , Masculino , Testes de Sensibilidade Microbiana , Ratos , Ratos Sprague-Dawley , Triazóis/administração & dosagem
4.
J Immunol ; 167(11): 6583-92, 2001 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-11714828

RESUMO

IL-13 has emerged as a major contributor to allergic and asthmatic responses, and as such it represents an attractive target in these diseases. In this study, IL-13-responsive cells in the lung were targeted via the intranasal administration of IL-13-PE38QQR (IL-13-PE), comprised of human IL-13 and a derivative of Pseudomonas exotoxin, to Aspergillus fumigatus-sensitized mice challenged with A. fumigatus spores, or conidia. Mice received 50, 100, or 200 ng of IL-13-PE or diluent alone (i.e., control group) on alternate days from day 14 to day 28 after the conidia challenge. The control group of mice exhibited significant airway hyperreactivity, goblet cell hyperplasia, and peribronchial fibrosis at day 28 after conidia. Although the two lower doses of IL-13-PE had limited therapeutic effects in mice with fungal-induced allergic airway disease, the highest dose of IL-13-PE tested significantly reduced all features of airway disease compared with the control group. Whole lung mRNA expression of IL-4Ralpha and IL-13Ralpha1 was markedly reduced, whereas bronchoalveolar lavage and whole lung levels of IFN-gamma were significantly elevated in mice treated with 200 ng of IL-13-PE compared with the control group. This study demonstrates that a therapy designed to target IL-13-responsive cells in the lung ameliorates established fungal-induced allergic airway disease in mice.


Assuntos
ADP Ribose Transferases , Aspergilose Broncopulmonar Alérgica/terapia , Toxinas Bacterianas/genética , Toxinas Bacterianas/imunologia , Exotoxinas/genética , Exotoxinas/imunologia , Interleucina-13/genética , Interleucina-13/imunologia , Proteínas Recombinantes de Fusão/imunologia , Fatores de Virulência , Adjuvantes Imunológicos/uso terapêutico , Administração Intranasal , Animais , Aspergilose Broncopulmonar Alérgica/imunologia , Aspergilose Broncopulmonar Alérgica/patologia , Toxinas Bacterianas/administração & dosagem , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/terapia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Doença Crônica , Relação Dose-Resposta Imunológica , Exotoxinas/administração & dosagem , Feminino , Fibrose , Células Caliciformes/patologia , Humanos , Hiperplasia , Imunoglobulina E/biossíntese , Imunoglobulina E/sangue , Imunoglobulina G/biossíntese , Inflamação/imunologia , Inflamação/terapia , Interferon gama/biossíntese , Interleucina-12/biossíntese , Interleucina-13/administração & dosagem , Interleucina-13/biossíntese , Subunidade alfa1 de Receptor de Interleucina-13 , Interleucina-4/biossíntese , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos CBA , Projetos Piloto , Pseudomonas aeruginosa/imunologia , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/biossíntese , Receptores de Interleucina/antagonistas & inibidores , Receptores de Interleucina/genética , Receptores de Interleucina-13 , Receptores de Interleucina-4/antagonistas & inibidores , Receptores de Interleucina-4/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Linfócitos T/patologia , Exotoxina A de Pseudomonas aeruginosa
5.
Mol Cell Biochem ; 166(1-2): 111-6, 1997 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9046027

RESUMO

A glycoprotein antigen with an apparent mw of 45 kD was observed to be predominant in the circulating immune complexes isolated from patients of allergic bronchopulmonary aspergillosis as well as in the immune complexes prepared in vitro. Further characterisation of 45 kD antigen with trypsin showed four immunologically active peptides with mw 43, 36, 33 and 16 kD. Carbohydrate characterization using various lectins (Maackia amurensis agglutinin, Sambucus nigra agglutinin, Peanut agglutinin, Galanthus nivalis agglutinin and Datura stramonium agglutinin) showed presence of both N-linked and O-linked sugar moieties such as mannose, glucose, galactose and N-acetyl glucosamine. Predominant presence of 45 kD antigen in immune complexes, recognition of 45 kD by monoclonal antibodies raised against glycoprotein rich fraction of A. fumigatus and presence of elastinolytic protease activity indicate that 45 kD antigen is probably a potent virulence factor and may be contributing to the pathogenesis of ABPA by its biological as well as immunological activities.


Assuntos
Antígenos de Fungos/isolamento & purificação , Aspergilose Broncopulmonar Alérgica/imunologia , Adulto , Complexo Antígeno-Anticorpo/sangue , Complexo Antígeno-Anticorpo/isolamento & purificação , Feminino , Galanthus , Humanos , Lectinas/metabolismo , Masculino , Peso Molecular , Lectinas de Plantas , Tripsina
6.
J Med Vet Mycol ; 34(6): 421-6, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8971632

RESUMO

A glycoprotein with an apparent molecular weight of 93 kDa was purified from a water-soluble extract of Aspergillus fumigatus NCPF 2109 by single step affinity chromatography using the mannose-specific snowdrop (Galanthus nivalis) lectin coupled to agarose. The carbohydrate moiety contained only mannose and galactose. Partial sequencing of cyanogen bromide fragments of the antigen yielded two sequences, KQNKP and GEIPMKF?PQL, with no homology to any reported proteins. In a preliminary evaluation of its diagnostic potential the 93 kDa antigen was recognized by the sera of four patients with allergic bronchopulmonary aspergillosis, in addition to a monoclonal antibody raised against a partially purified fraction of the A. fumigatus water-soluble extract.


Assuntos
Anticorpos Antifúngicos/sangue , Antígenos de Fungos/isolamento & purificação , Aspergilose Broncopulmonar Alérgica/diagnóstico , Aspergillus fumigatus/imunologia , Sequência de Aminoácidos , Anticorpos Monoclonais , Antígenos de Fungos/química , Aspergilose Broncopulmonar Alérgica/sangue , Aspergilose Broncopulmonar Alérgica/imunologia , Aspergillus fumigatus/isolamento & purificação , Cromatografia de Afinidade , Cromatografia em Gel , Eletroforese em Gel de Poliacrilamida , Galanthus , Humanos , Lectinas , Peso Molecular , Lectinas de Plantas
7.
Prim Care ; 12(2): 353-68, 1985 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-3892565

RESUMO

The recognition of aspergillus in all its clinical disguises remains a challenge to clinicians in all fields of medicine. Fortunately, aspergillus has low pathogenicity for humans and requires very heavy inoculum of spores (aspergillary pneumonitis) in order to infect those whose pulmonary defense mechanisms, inherent structure, and physiology are intact. Patients with problems from aspergillus may be seen in either inpatient or outpatient clinical practice. The patient with fibrotic or cavitary lung disease finds himself at risk to be colonized and develop an aspergilloma (fungus ball). Conservative therapy (that is, antibiotics, pulmonary hygiene) or simple observation is often all that is required. With significant hemoptysis, surgical removal could be definitive treatment; but these patients often have such compromised pulmonary function that alternative therapies like infusion of antifungal agents locally are tempting. Part of the problem of the patient with asthma or COPD may actually be secondary to hypersensitivity to aspergillus (ABPA), which exacerbates bronchospasm and adds "pulmonary infiltrates" to the underlying disease. The recognition of this entity and then the judicious use of corticosteroids to control the symptoms will stabilize the clinical course of the disease. The immunocompromised patient may be relatively free of pulmonary disease.; but aspergillus, waiting until cytotoxic agents, corticosteroids, granulocytopenia, broad-spectrum antibiotics, and previous pneumonias destroy the local lung defense mechanisms, will then attack with a vengeance. The resultant invasive pulmonary aspergillosis requires treatment with amphotericin B, along with its own inherent toxicity.


Assuntos
Aspergilose Broncopulmonar Alérgica , Aspergilose , Pneumopatias Fúngicas , Doença Aguda , Adulto , Idoso , Aspergilose/diagnóstico , Aspergilose/tratamento farmacológico , Aspergilose Broncopulmonar Alérgica/diagnóstico , Aspergilose Broncopulmonar Alérgica/imunologia , Aspergillus fumigatus/isolamento & purificação , Diagnóstico Diferencial , Feminino , Humanos , Pneumopatias Fúngicas/diagnóstico , Pneumopatias Fúngicas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Recidiva , Escarro/microbiologia
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