Targeting airway lymphocytes in asthma and biologics treatment

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.