Targeting airway lymphocytes in asthma and biologics treatment

Descripción del proyecto

Mejorar el tratamiento del asma grave

El asma grave afecta a millones de personas en todo el mundo y, aunque los nuevos tratamientos biológicos han traído esperanza, muchos pacientes no responden a ellos. Para entender por qué es necesario conocer mejor el comportamiento de las células inmunitarias en los tejidos de las vías respiratorias y cómo les afectan los productos biológicos. El equipo del proyecto TARGET-AIR-LAB, financiado por el CEI, investiga el papel de los linfocitos de tipo 2 implicados en la inflamación de las vías respiratorias. Los investigadores dilucidarán cómo los tratamientos biológicos alteran el movimiento, la diferenciación y la función de los linfocitos de tipo 2 utilizando muestras únicas de tejido de las vías respiratorias de pacientes con asma antes y durante el tratamiento. En el proyecto también se proporcionará información sobre los cambios epigenéticos y transcripcionales que los productos biológicos inducen en estas células. Se espera que los resultados revelen nuevas dianas terapéuticas y estrategias para adaptar los tratamientos biológicos y, en última instancia, mejorar los resultados clínicos.

Objetivo

The development of biologics targeting cytokines involved in type 2 lymphocyte function and activation offers new hope for more than 16 million patients living with severe asthma, but not all patients respond, and none are cured. This calls for increased understanding of airway tissue type 2 lymphocytes and how they are regulated by novel biologics in severe asthma. I discovered human innate lymphoid cells type 2 (ILC2), and have shown how they, in addition to T helper 2 (Th2) cells, orchestrate type 2 immunity in tissues. Building on our unexpected finding that treatment with anti-interleukin (IL)-5 biologics causes an increase in circulating type 2 lymphocytes with modified tissue homing receptor expression, I propose that biologics disrupt airway chemoattractants, lymphocyte trafficking, differentiation, and function, including the underlying epigenetic, transcriptional and functional regulation. To test this innovative hypothesis, I will capitalize on leading a clinical asthma research unit, performing pioneering immunological studies using unique airway tissue samples from patients with severe asthma before and during biologics treatment. My translational team of clinical, immunology and computational researchers will uncover the unique features of airway resident lymphocytes and the epigenetic and transcriptional effects of biologics on circulating and airway resident lymphocytes. We will also dissect the molecular and functional mechanisms involved in lymphocyte trafficking and differentiation in the airways. My studies will break new ground by increased understanding of human airway lymphocyte diversification, trafficking, differentiation and function in relation to biologics treatment efficacy. I will thereby reveal new targets for treatment and means to better tailor the use of biologics. Building on the outcomes of this proposal, my long-term goal is to advance the possibilities for induction of remission in severe asthma by targeting airway lymphocytes.