Immune Basis of FPIES

Food protein induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy with a usual onset in
infancy. FPIES is recognized as an allergic emergency due to severe vomiting, and shock-like symptoms within
1-4 hours of ingestion of the causative food. Symptoms of FPIES resolve within hours following acute exposure
and days following chronic exposure; endoscopy and biopsy of gastrointestinal mucosa are not routinely
performed for the confirmation of diagnosis that is based on the recognition of the constellation of symptoms.
Diagnosis in infancy is based on clinical history, and oral food challenges (OFC) are performed to determine if
outgrowth has occurred. OFC are performed in hospital, with intravenous access in place for rapid fluid
resuscitation. In addition to being highly resource-intensive, they are limited in availability and extremely
unpleasant for the patient and the caregivers, due to the severity of the gastrointestinal symptoms. There is an
unmet need for better approaches for diagnosis, as well as an understanding of the underlying pathophysiology.
In Aim 1, we will randomize participants 1:2 to standard OFC or a novel low-dose multi-day challenge protocol,
in which individuals with a history of FPIES will be challenged on Day 1 with a low-dose (300 mg protein) OFC,
which we expect to be tolerated by most individuals with active FPIES. They will then continue with a daily 300
mg challenge at home for a total of 7 days, while monitoring symptoms. On day 8, participants will return for a
re-evaluation and biospecimen collection. If no objective symptoms were recorded during the at-home challenge,
a regular 3 g OFC will be performed. Objective symptoms at any point of the protocol will result in stopping of
the challenge. We anticipate that the majority of those who will react to the OFC will develop relatively mild but
objective gastrointestinal symptoms (vomiting, diarrhea) during the at home dosing. In Aim 2, we will perform
high dimensional T cell profiling of T cells activated by the low dose chronic antigen challenge. FPIES is
associated with a lack of circulating detectable food-specific T cells, however during symptomatic reactions there
is a systemic innate immune cell activation as well as a Th17 cytokine signature detectable in the plasma,
suggesting a role for tissue resident T cells. As is observed with gluten challenge in celiac disease, we expect to
see an expansion of gut-resident T cells in the periphery in response to a multi-day food challenge. We will sort
these cells and perform spectral cytometry, bulk RNAseq, and single cell RNAseq to generate a full
understanding of the role of these cells in FPIES reactions. In Aim 3, we will examine the role of the purine
metabolism pathway as the mechanistic link between T cell activation and vomiting symptoms in FPIES.
Serotonin from enterochromaffin cells (EC) is thought to drive activation of vagal afferents leading to vomiting,
and EC are responsive to purine metabolites that are elevated during FPIES reactions. In Aim 3, we will use
gastrointestinal biopsies to study the immune regulation of serotonin release from ECs via the purine pathway.
Successful completion of our aims will directly improve patient care and advance our understanding of FPIES.

Grant Number: 5U01AI170836-04
NIH Institute/Center: NIH
Principal Investigator: Cecilia Berin