Unravelling the Immune Mechanisms of Oral Tolerance to Find a Cure for Food Allergy

Food allergies are increasing, affect 8% of children and 10% of adults and can be life-threatening. With no cure, patients must avoid allergens and carry emergency medication, leading to restricted social lives and anxiety. While immunotherapy can raise the reaction threshold, it does not eliminate life-style limitations and risk of reactions. Urgent action is needed to develop definitive treatments for food allergies. Exposure to food allergens through the gastrointestinal tract is tolerogenic. Peanut consumption from the first year of life reduced peanut allergy by 81% in a randomised-controlled trial. This impressive effect was allergen-specific and sustained over time. However, the underlying immune mechanisms of oral tolerance induction to peanut are not well understood. This is due to limited access to the tissue where oral tolerance develops: the gut. We have developed a novel in vitro model using human gut organoids populated with blood immune cells, which mimics children’s intestinal environment and allows us to explore immune mechanisms of oral tolerance and food allergy in humans. Oral tolerance to food antigens occurs in the duodenum and involves various immune cell populations to actively suppress allergic responses, locally and systemically. Revealing the mechanisms that initiate this process will identify targets to halt food allergy. Innate lymphoid cells (ILC) are crucial first responders. In murine models, ILC2 have been implicated in the inception of food allergy mainly through secretion of Th2 cytokines. Conversely, ILC3 have been shown to be important in tolerance to gut commensals, namely through the induction of regulatory T cells. Overall, this evidence led us to hypothesise that ILC2 drive food allergic responses whilst ILC3 drive oral tolerance to food allergens in humans. ILC closely interact with the intestinal epithelium in a bidirectional mode and thus these immune mechanisms may likely be influenced by the epithelium. In this research programme, we will use unique samples from young children undergoing their first oral exposure to peanut and our novel co-culture of human gut organoid models with patients’ immune cells. This will allow us to pinpoint key pathways involved in establishing oral tolerance to food allergens and explore how they can be modulated to develop curative treatments for food allergies. Specifically, we will compare peanut-specific immune responses between peanut-allergic and peanut-sensitised-tolerant children during their first oral exposure to peanuts via oral food challenge (OFC). Blood samples collected before and after the OFC will be used to analyse systemic immunological changes (Aim 1). Gut organoids and duodenal tissue will be utilised to examine how intestinal ILCs are altered following exposure to peanut allergens (Aim 2). We will investigate the direct effects of peanut allergens on the intestinal barrier and ILC-epithelium interactions (Aim 3), as well as gut ILC-T cell interactions (Aim 4). Finally, we will identify key immune pathways activated or suppressed by peanut allergens and explore their pharmacological modulation using blood samples from peanut-allergic children and adults to assess whether the allergic response can be suppressed and oral tolerance induced (Aim 5). By the end of this research programme, we will have fundamentally changed our understanding immune responses to food allergens in the human gut and will have identified specific targets for the much-needed curative treatment of food allergy. This will benefit food allergic patients and their families, the food industry and academic-industry partnerships to pursue identified targeted therapies.