Asthma affects millions of individuals in the US. It is a disease propagated by the immune system in interaction with itself and components of the lung. Despite decades of study, there has previously been little methodology to study the dynamics of the key members of the immune response at the living-tissue level, particularly in subclasses of asthma. Thus, treatment strategies have not profited from an understanding of how very specific subsets of immune infiltrates interact with the tissue, deposit cytokines upon them and propagate the allergic state. This project will apply advanced real-time imaging methodologies to determine how and where the immune response takes place in real-time. We will characterize both IL4/13 and IL-17 producing cell types and will include analyses of adaptive (T cells) and innate (e.g. eosinophils, Ih2). We will determine how and when they interact with one another within the tissue and how and when cytokine exchanges take place. We will then transfer this technology to the analysis of human lungs from the shared Clinical Subject and Biospecimen Core. These studies will in turn allow us to understand the homing and interaction zones for two specific classes of T helper cells, secreting IL13 and IL17. These analyses will take place in living lung biopsies and will develop technologies for visualizing ongoing biology in clinically relevant subclasses of asthma; notably before/after allergen challenge, before/after inhaled corticosteroid and in severe asthmatic lung. Together with critical reagent and method development that will be useful for many other asthma and lung applications, this proposal will provide exquisite insight into how the immune system propagates the allergic state in a variety of clinically-relevant settings.
This study will provide real-time 3 dimensional understanding of T cells, antigen-presenting cells and, importantly, the structural cells ofthe lung. It will do so in mouse models and, profiting from the tissue core of the associated U19 projects, it will exploit parallel methods in human tissue biopsies from well-characterized asthmatic lungs. These studies will be formative in directing therapies and in understanding key differences in asthma presentation
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