Abstract
Background: Food allergy affects up to 8% of the pediatric
population. Despite ongoing efforts, treatment options remain limited.
Novel models of food allergy are needed to study response patterns
downstream of IgE-crosslinking and evaluate drugs modifying acute
events. Here, we report a novel human ex vivo model that displays
acute, allergen-specific, IgE-mediated smooth muscle contractions using
precision cut intestinal slices (PCIS). Methods: PCIS were
generated using gut tissue samples from children who underwent
clinically indicated surgery. Viability and metabolic activity were
assessed from 0-24h. Distribution of relevant cell subsets was confirmed
using single cell nuclear sequencing. PCIS were passively sensitized
using plasma from peanut allergic donors or peanut-sensitized
non-allergic donors, and exposed to various stimuli including serotonin,
histamine, FcɛRI-crosslinker and food allergens. Smooth muscle
contractions and mediator release functioned as readouts. A novel
program designed to measure contractions was developed to quantify
responses. The ability to demonstrate the impact of antihistamines and
immunomodulation from peanut oral immunotherapy (OIT) was assessed.
Results: PCIS viability was maintained for 24h. Cellular
distribution confirmed the presence of key cell subsets including mast
cells. The video analysis tool reliably quantified responses to
different stimulatory conditions. Smooth muscle contractions were
allergen-specific and reflected the clinical phenotype of the plasma
donor. Tryptase measurement confirmed IgE-dependent mast cell-derived
mediator release. Antihistamines suppressed histamine-induced
contraction and plasma from successful peanut OIT suppressed
peanut-specific PCIS contraction. Conclusion: PCIS represent a
novel human tissue-based model to study acute, IgE-mediated food allergy
and pharmaceutical impacts on allergic responses in the gut.