Project ID CM-HD2024_25


Co Supervisor 1A Faculty of Dentistry, Oral & Craniofacial Sciences, Centre for Host-Microbiome InteractionsWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Peter Gorer Department of ImmunobiologyWebsite

The role of the intestinal epithelium in immune responses to food allergens

Food allergy affects 3-10% of children and up to 10% of adults and can cause severe allergic reactions and fatal anaphylaxis. There is currently no curative treatment for food allergy. Understanding the immune mechanisms underlying food allergy and oral tolerance could enable us to identify novel targets for definitive treatment.
Complex intestinal organoid models derived from human biopsies have been developed by us and will be used as a surrogate for human intestine to study, the interactions between intestinal epithelium, food allergens and immune cells during the establishment of normal oral tolerance or aberrant allergic response to foods. Using this innovative intestinal organoid approach blood and intestinal samples from allergic and non-allergic children being assessed for cow’s milk, egg, or peanut allergies, as part of ongoing clinical studies, will be studied through a variety of approaches.

The successful student will acquire theoretical and practical skills in cell biology (cell isolation and culture, generation of gut organoids, flow cytometry, microscopy), functional genomics (scRNAseq), and molecular immunology (RT-PCR, siRNA, lentiviral overexpression, CRISPR) as well as translational research skills in allergy and clinical immunology and bioinformatics.

Objectives for each year:
• Aim 1 (year 1): Establish intestinal organoids from children’s intestinal biopsies and determine the impact of food allergens on epithelial functions.
• Aim 2 (years 2/3): Compare intestinal epithelial functions of food allergic and non-allergic children using organoid models.
• Aim 3 (years 3/4): Assess how the immune cells respond to food allergens by co-culturing lymphocytes with intestinal organoids.
This project is suitable for a 3+1 and 4 years PhD.

Representative Publications

Jowett GM, Read E, Roberts LB, Coman D, González MV, Zabinski T, Nazi U, Reis R, Trieu TJ, Danovi D, Gentleman, Vallier L, E, Curtis MA, Lord GM*, Neves JF*. Organoids capture tissue-specific innate lymphoid cell development in mice and humans. Cell Reports. 2022 Aug 30;40(9):111281. doi: 10.1016/j.celrep.2022.111281. * These authors contributed equally for this work Jowett GM, Coales I, Neves JF. Organoids as a tool for understanding immune-mediated intestinal regeneration and development. Development. 2022 Apr 15;149(8):dev199904. doi: 10.1242/dev.199904. Jowett GM, Norman MDA, Yu TTL, Rosell Arévalo P, Hoogland D, Lust ST, Read E, Hamrud E, Walters NJ, Niazi U, Chung MWH, Marciano D, Omer OS, Zabinski T, Danovi D, Lord GM, Hilborn J, Evans ND, Dreiss CA, Bozec L, Oommen OP, Lorenz CD, da Silva RMP, Neves JF*, Gentleman E*. ILC1 drive intestinal epithelial and matrix remodelling. Nat Mater. 2021 Feb;20(2):250-259. doi: 10.1038/s41563-020-0783-8 *these senior authors contributed equally for this work & are joint corresponding authors
Hemmings O, Niazi U, Kwok M, James LK, Lack G, Santos AF*. Peanut diversity and specific activity are the dominant IgE characteristics for effector cell activation in children. J Allergy Clin Immunol 2021 148(2):495-505.e14. doi: 10.1016/j.jaci.2021.02.029. *Corresponding author Hemmings O, Du Toit G, Radulovic S, Lack G, Santos AF*. Ara h 2 is the dominant peanut allergen despite similarities with Ara h 6. J Allergy Clin Immunol 2020;146(3):621-630.e5. doi: 10.1016/j.jaci.2020.03.026. *Corresponding author Santos AF*, Barbosa-Morais NL, Hurlburt BK, Ramaswamy S, Kwok M, Cheng H, James L, Gould H, Sutton B, Maleki S, Lack G. IgE to epitopes of Ara h 2 enhance the diagnostic accuracy of Ara h 2-specific IgE. Allergy 2020; 75(9):2309-2318. doi: 10.1111/all.14301. *Corresponding author