Novel Roles for Mucosal Tissue Eosinophils in Dissemination of Type 2 Immunity

About This Grant

Abstract Allergic diseases including food allergies and allergic asthma represent a substantial health and economic burden, with the US Centers for Disease Control (CDC) estimating more than 50 million people within the US suffering from some form of allergic disease. Their natural history reveals a natural progression of co-morbid allergic diseases along the skin – gut – lung axis within the same individual commonly referred to as the “allergic march”. Systemic mechanisms that underscore allergic march progressions remain poorly understood, representing a critical knowledge gap. In prior work we demonstrated mouse models of food allergy activate small intestinal cellular and molecular circuits that coordinately disseminate an intestinal type 2 immune response and exacerbate allergic susceptibility of remote (allergen non-exposed) airways via dysregulation of lung tissue eosinophils. Strikingly, we found different functional phenotypes of tissue eosinophils, shaped by their local tissue microenvironments, to differentially influence intestine- and lung-localized aspects of this type 2 immune gut – lung axis. Based on these findings, this proposal will explore novel contributions of intestinal and lung tissue eosinophils to allergic march progressions along the gut – lung axis through two specific aims. Aim 1 will leverage new mouse lines exhibiting eosinophil-targeted deletion of key receptors and signaling molecules and allergen- dependent and -independent in vivo models to unravel the mechanistic underpinnings of an observed negative regulation of type 2 immune dissemination mediated by a subset of intestine-adapted, resident eosinophils. Aim 2 will apply pulse chase and lineage tracing approaches to determine the origin, phenotype, and tissue retention behavior of a subset of food allergen-elicited, remote lung-infiltrating eosinophils with putative type 2 exacerbating functions. In parallel translational subaims embedded within both aims 1 & 2 we will complement the manipulatable in vivo mouse models with analysis of cellular and molecular markers from duodenal biopsies and blood samples from patients with or without food allergies seen in our gastrointestinal eosinophilic diseases program (GEDP) clinic. Together these studies will provide new insights into the cellular and molecular circuitry that underscores enhanced vulnerability of some allergic patients to allergic march progressions and reveal homeostatic and pathologic contributions of tissue eosinophils to the systemic dissemination of type 2 immunity. In addition to mechanistic insights to instruct the development of novel therapeutic strategies aimed at interrupting the allergic march, these studies hold important considerations related to potential impacts of long-term use of anti- IL-5 biologics in allergic patients that aim to globally delete eosinophils.