Modulación de la respuesta inmune con glicolípidos activadores de células iNKT contenidos en liposomas en un modelo de alergia inducida por extractos de ácaro del polvo
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Archivos
Fecha
2023
Autores
Profesor/a Guía
Facultad/escuela
Idioma
es
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Universidad Andrés Bello
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Licencia CC
Licencia CC
Resumen
El sistema inmune es una compleja red de órganos, tejidos, células y moléculas que se
encargan de proteger el organismo contra agentes externos mediante la respuesta inmune.
Esta respuesta se divide en dos: la inmunidad innata y la inmunidad adaptativa. Cuando hay un
desequilibrio en la respuesta inmune, pueden surgir enfermedades autoinmunes y alérgicas,
como es el caso del asma alérgica. Esta condición se caracteriza por una inflamación crónica
de las vías respiratorias debido a una respuesta inmunitaria exacerbada. El asma alérgica es
una enfermedad pulmonar inflamatoria crónica que afecta a millones de personas en todo el
mundo. Aunque en la actualidad existen tratamientos para controlar los síntomas y reducir la
inflamación, como los broncodilatadores y corticosteroides inhalados, todavía se necesitan
nuevas terapias que aborden la respuesta inmunitaria de forma específica y efectiva. A nivel
celular, la respuesta alérgica involucra la interacción de diversas células inmunitarias, como las
células de la inmunidad innata, las células presentadoras de antígeno y los linfocitos T y B,
además de la liberación de mediadores inflamatorios como la histamina, quimioquinas,
citoquinas y leucotrienos. La exposición a alérgenos comunes, como los ácaros del polvo,
desencadena una respuesta inmune exacerbada en personas atópicas, con elevados niveles de
IgE en suero y producción aumentada de citoquinas de tipo Th2. En este trabajo se propuso
dirigirse a células Natural Killer T invariantes (iNKT) para el tratamiento del asma alérgica. Se
ha descrito que el uso de glicolípidos específicos, como el glicolípido alfa-galactosilceramida (α
GalCer) induce la activación de las células iNKT. Esto induce la producción rápida de citoquinas
mixtas con propiedades proinflamatorias y antiinflamatorias definidas como una respuesta
similar a Th0 (IL-4/IFN-γ). Interesantemente, se han sintetizado varios análogos de αGalCer
para inducir una respuesta de citoquinas polarizada, entre ellos AH10-7 y 7DW8-5. En este
trabajo se buscó determinar si la activación de las células NKT con los análogos AH10-7 y
7DW8-5 tienen la capacidad de modular la respuesta alérgica. Los resultados obtenidos in vitro
demuestran la eficacia de las formulaciones liposomales generadas para activar a las células
iNKT de manera dosis dependiente. Además, cuando las preparaciones liposomales se
administraron como tratamiento en el modelo de asma alérgica, se obtuvo que el tratamiento
que contenía el glicolípido 7DW8-5 (Lp/Derp1/7DW8-5) provocó una disminución significativa de
la población de eosinófilos y un aumento de la población de macrófagos intersticiales. Además
de provocar una disminución en la infiltración de células inflamatorias, y, también una
disminución de la inflamación de los bronquiolos. Estos resultados proporcionan aspectos
atractivos para el uso del glicolípido 7DW8-5 contenido en liposomas como tratamiento del
asma alérgica, sin embargo, aún faltan resultados más consistentes para determinar su eficacia.
The immune system is a complex network of organs, tissues, cells, and molecules that work to protect the body against external agents through the immune response. This response is divided into two: innate immunity and adaptive immunity. When there is an imbalance in the immune response, autoimmune and allergic diseases can arise, such as allergic asthma. This condition is characterized by chronic inflammation of the airways due to an exacerbated immune response. Allergic asthma is a chronic inflammatory lung disease that affects millions of people worldwide. Although there are treatments available to control symptoms and reduce inflammation, such as inhaled bronchodilators and corticosteroids, new therapies are still needed to address the immune response in a specific and effective way. At the cellular level, the allergic response involves the interaction of various immune cells, such as cells of innate immunity, antigen-presenting cells, and T and B lymphocytes, in addition to the release of inflammatory mediators such as histamine, chemokines, cytokines, and leukotrienes. Exposure to common allergens, such as dust mites, triggers an exacerbated immune response in atopic individuals, with elevated levels of serum IgE and increased production of Th2-type cytokines. This study aimed to target invariant Natural Killer T (iNKT) cells for the treatment of allergic asthma. It has been described that the use of specific glycolipids, such as alpha galactosylceramide (α-GalCer), induces activation of iNKT cells. This leads to rapid production of mixed cytokines with defined proinflammatory and anti-inflammatory properties defined as a Th0-like response (IL-4/IFN-γ). Interestingly, several analogs of αGalCer have been synthesized to induce a polarized cytokine response, including AH10-7 and 7DW8-5. This study sought to determine if activation of NKT cells with AH10-7 and 7DW8-5 analogs has the ability to modulate the allergic response. The results obtained in vitro demonstrate the efficacy of the generated liposomal formulations to activate iNKT cells in a dose-dependent manner. Furthermore, when liposomal preparations were administered as treatment in the allergic asthma model, it was found that treatment containing the glycolipid 7DW8-5 (Lp/Derp1/7DW8-5) caused a significant decrease in eosinophil population and an increase in interstitial macrophage population. In addition to causing a decrease in inflammatory cell infiltration and also a decrease in bronchiolar inflammation. These results provide attractive aspects for the use of glycolipid 7DW8-5 contained in liposomes as a treatment for allergic asthma; however, more consistent results are still needed to determine its efficacy.
The immune system is a complex network of organs, tissues, cells, and molecules that work to protect the body against external agents through the immune response. This response is divided into two: innate immunity and adaptive immunity. When there is an imbalance in the immune response, autoimmune and allergic diseases can arise, such as allergic asthma. This condition is characterized by chronic inflammation of the airways due to an exacerbated immune response. Allergic asthma is a chronic inflammatory lung disease that affects millions of people worldwide. Although there are treatments available to control symptoms and reduce inflammation, such as inhaled bronchodilators and corticosteroids, new therapies are still needed to address the immune response in a specific and effective way. At the cellular level, the allergic response involves the interaction of various immune cells, such as cells of innate immunity, antigen-presenting cells, and T and B lymphocytes, in addition to the release of inflammatory mediators such as histamine, chemokines, cytokines, and leukotrienes. Exposure to common allergens, such as dust mites, triggers an exacerbated immune response in atopic individuals, with elevated levels of serum IgE and increased production of Th2-type cytokines. This study aimed to target invariant Natural Killer T (iNKT) cells for the treatment of allergic asthma. It has been described that the use of specific glycolipids, such as alpha galactosylceramide (α-GalCer), induces activation of iNKT cells. This leads to rapid production of mixed cytokines with defined proinflammatory and anti-inflammatory properties defined as a Th0-like response (IL-4/IFN-γ). Interestingly, several analogs of αGalCer have been synthesized to induce a polarized cytokine response, including AH10-7 and 7DW8-5. This study sought to determine if activation of NKT cells with AH10-7 and 7DW8-5 analogs has the ability to modulate the allergic response. The results obtained in vitro demonstrate the efficacy of the generated liposomal formulations to activate iNKT cells in a dose-dependent manner. Furthermore, when liposomal preparations were administered as treatment in the allergic asthma model, it was found that treatment containing the glycolipid 7DW8-5 (Lp/Derp1/7DW8-5) caused a significant decrease in eosinophil population and an increase in interstitial macrophage population. In addition to causing a decrease in inflammatory cell infiltration and also a decrease in bronchiolar inflammation. These results provide attractive aspects for the use of glycolipid 7DW8-5 contained in liposomes as a treatment for allergic asthma; however, more consistent results are still needed to determine its efficacy.
Notas
Memoria (Ingeniero en Biotecnología)
Proyectos FONDECYT 1211959, Iniciativa Científica Milenio – ICN09_016: Instituto Milenio en Inmunología e Inmunoterapia (ICN09_016/ ICN 2021_045), FONDEF I+D ID21|10335
Proyectos FONDECYT 1211959, Iniciativa Científica Milenio – ICN09_016: Instituto Milenio en Inmunología e Inmunoterapia (ICN09_016/ ICN 2021_045), FONDEF I+D ID21|10335
Palabras clave
Células Asesinas Naturales, Alergia e Inmunología