L’immunothérapie orale pour le traitement des allergies alimentaires multiples

The prevalence of IgE-mediated food allergies has tripled over the last decade with prospective studies indicating that up to 8% of children may be affected in North America. There is currently no cure for food allergy but oral immunotherapy (OIT) is an experimental approach to treat food allergies.  It consists in the progressive administration from minute to large amounts of the allergenic food by the mouth over a prolonged period of time to induce a state of desensitization and possibly sustained tolerance.  This approach has been shown to be safe and to allow desensitization to high doses in over 80% of participants allergic to peanuts, milk or egg.     In this thesis, we present two phase 1 trials on OIT protocols designed to efficiently treat multiple foods allergies. About 30% of children with food allergy are allergic to more than one food. This proportion increases to 70% when considering the most severe cases. Children with multiple food allergies are at higher risk of accidental reactions and suffer from greater impact on quality of life than those with single food allergies. By creating a customized treatment mix with a 1:1 stoichiometric ratio for the child’s relevant food proteins, we were first able to safely desensitize up to 5 foods simultaneously with a safety profile similar to single allergen therapy and a minimal increase in time to maintenance.    Then, taking advantage of recent evidence showing that omalizumab, an anti-IgE receptor monoclonal antibody, can significantly raise reaction thresholds in food allergic subjects, we used short courses of omalizumab to allow very rapid oral desensitization to various foods in a second phase 1 study.  When compared to “standard” multi-OIT, the omalizumab-enabled rush protocol resulted in a decreased time to maintenance from a median of 21 to 4 months.    While these studies provide reasonable clinical approaches to this population, many questions remain, especially with regards to long term tolerance.  A major limit to our progress in improving these protocols stems from our lack of understanding of the underlying immune mechanisms of oral immunotherapy. Taking advantage of well phenotyped samples from the afore-mentioned trials, we used next-generation high-throughput TCR sequencing to follow clonal distribution of peanut specific T cells during oral immunotherapy.  We found that OIT is associated with significant changes in food-specific clonal frequencies, suggesting clonal exhaustion and replacement as an underlying mechanism of OIT. In addition, we show that the proliferation assay which is traditionally used to assess the cellular response is dominated by a highly non-specific polyclonal distribution.  This observation has important implications considering most of the current literature on T cell response to immunotherapy is based on this assay.  This highlights the need for the development of new tools to assess the cellular allergic response. Overall this thesis lays the ground for further comprehensive translational research programs on the treatment of food allergy.

Keyphrases: Tolérance soutenue, Allergies multiples, Omalizumab, IgE, TCR, Food allergy, Sustained tolerance, Oral immunotherapy, Multiple allergies, Clonal exhaustion, Proliferation assay