RESUMEN
BACKGROUND: Altered epithelial physical and functional barrier properties along with TH1/TH2 immune dysregulation are features of allergic asthma. Regulation of junction proteins to improve barrier function of airway epithelial cells has the potential for alleviation of allergic airway inflammation. OBJECTIVE: We sought to determine the immunomodulatory effect of knob protein of the adenoviral capsid on allergic asthma and to investigate its mechanism of action on airway epithelial junction proteins and barrier function. METHODS: Airway inflammation, including junction protein expression, was evaluated in allergen-challenged mice with and without treatment with knob. Human bronchial epithelial cells were exposed to knob, and its effects on expression of junction proteins and barrier integrity were determined. RESULTS: Administration of knob to allergen-challenged mice suppressed airway inflammation (eosinophilia, airway hyperresponsiveness, and IL-5 levels) and prevented allergen-induced loss of airway epithelial occludin and E-cadherin expression. Additionally, knob decreased expression of TH2-promoting inflammatory mediators, specifically IL-33, by murine lung epithelial cells. At a cellular level, treatment of human bronchial epithelial cells with knob activated c-Jun N-terminal kinase, increased expression of occludin and E-cadherin, and enhanced epithelial barrier integrity. CONCLUSION: Increased expression of junction proteins mediated by knob leading to enhanced epithelial barrier function might mitigate the allergen-induced airway inflammatory response, including asthma.
Asunto(s)
Proteínas de la Cápside/farmacología , Proteínas de la Cápside/uso terapéutico , Células Epiteliales/efectos de los fármacos , Adenoviridae , Anciano , Animales , Bronquios/citología , Líquido del Lavado Bronquioalveolar/inmunología , Cadherinas/metabolismo , Línea Celular , Citocinas/inmunología , Eosinofilia/inmunología , Células Epiteliales/metabolismo , Femenino , Humanos , Masculino , Ratones Endogámicos BALB C , Persona de Mediana Edad , Ocludina/metabolismo , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Hipersensibilidad Respiratoria/tratamiento farmacológico , Hipersensibilidad Respiratoria/inmunologíaRESUMEN
The effect of sustained exposure to nicotine, a major constituent of cigarette smoke, on hematopoiesis in the bone marrow (BM) and spleen was evaluated in a murine model. BALB/c mice were exposed to nicotine subcutaneously using 21-day slow-release pellets. Exposure to nicotine had no effect on the proliferation of long-term BM cultures or on their ability to form colonies. However, there was a significant decrease in the generation of lineage-specific progenitor cells, specifically eosinophil (colony-forming unit [CFU]-Eos) progenitors, in the BM of nicotine-exposed mice compared with control mice. Surprisingly, sustained exposure of mice to nicotine was found to induce significant hematopoiesis in the spleen. There was a significant increase in total colony formation as well as eosinophil-, granulocyte-macrophage-, and B-lymphocyte-specific progenitors (CFU-Eos, CFU-GM, and CFU-B, respectively) in nicotine-exposed mice but not in control mice. Sustained exposure to nicotine was associated with significant inhibition of rolling and migration of enriched hematopoietic stem/progenitor cells (HSPCs) across BM endothelial cells (BMECs) in vitro as well as decreased expression of beta2 integrin on the surface of these cells. Although sustained exposure to nicotine has only a modest effect on BM hematopoiesis, our studies indicate that it significantly induces extramedullary hematopoiesis in the spleen. Decreased interaction of nicotine-exposed HSPCs with BMECs (i.e., rolling and migration) may result in altered BM homing of these cells, leading to their seeding and proliferation at extramedullary sites such as the spleen.
Asunto(s)
Células de la Médula Ósea/efectos de los fármacos , Hematopoyesis Extramedular/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Nicotina/farmacología , Bazo/efectos de los fármacos , Animales , Células de la Médula Ósea/inmunología , Antígenos CD18/análisis , Adhesión Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Línea Celular , Linaje de la Célula , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Hematopoyesis/efectos de los fármacos , Células Madre Hematopoyéticas/inmunología , Ratones , Ratones Endogámicos BALB C , Modelos Animales , Fumar/efectos adversos , Bazo/inmunología , Bazo/patologíaRESUMEN
During the past 20 years, the development of HIV vaccines has come a long way. The focus has progressively changed from the traditional protein-based HIV vaccines that induce humoral immunity to the live recombinant viral vector-based HIV vaccines capable of eliciting both cellular and humoral immune responses. These new viral vector-based vaccines encoding multiple HIV antigens, delivered either alone or in heterologous prime-boost modalities elicited antigen-specific CTL responses in immunized hosts and protected animals from disease. The viral vector-based vaccines have proven to be potent vaccines in pre-clinical studies and foster the hope to put an end to the ever-increasing threat of the AIDS epidemic. Several unique features of viral vector-based HIV vaccines have contributed to their success, including their intrinsic immune-modulating properties, high transduction efficiency, and in vivo production of immunogens within the cell mimicking a natural infection without the associated health risks. In this review, we will discuss the characteristics of non-replicating viral vectors most commonly used for HIV vaccines with a particular focus on immune responses elicited by the vector particles alone and their effect on the potency of viral vector-based HIV vaccines.