Summary: Immune Basis and Clinical Implications of Threshold-Based Phenotypes of Peanut AllergyPeanut allergy (PA) is common, affecting 2-5% of school-age children in the US. The characteristics of PA varywidely among individuals, with some reacting to 1/100th of a peanut and others not having symptoms until theyhave ingested many peanuts. Symptoms can vary from mild rashes to fatal anaphylaxis. There is no FDA-approved treatment, and all patients with PA are managed with strict allergen avoidance. Most research on PAhas focused on those with the most exquisite sensitivity to peanut. Immunotherapy trials commonly excludesubjects with a threshold dose over 1/3 of a peanut (100mg). However, most individuals with PA have higherthresholds of reaction and are excluded from current research approaches. We hypothesize that the naturalheterogeneity of PA is a valuable opportunity for investigation. We have shown that milk or egg allergicindividuals with tolerance to baked forms of these foods not only tolerate their inclusion in the diet, but thisexposure increases the rate of resolution 14-16-fold. We hypothesize that dietary exposure to sub-thresholdlevels of peanut in those with higher threshold levels of reactivity could lead to significant clinical improvement.Furthermore, studying the natural heterogeneity of PA is a valuable opportunity to elucidate mechanisms ofdisease. To study the clinical implications and mechanism of phenotypic heterogeneity in PA, we will conduct arandomized open feeding trial (CAFETERIA trial) to investigate a prototype approach where children withmoderate PA (tolerating at least 100 mg of peanut) ingest a sub-threshold amount daily, with increasing levelstested every 3 months. The impact of dietary intervention will be tested at 1 and 2 years by oral food challenge.The CAFETERIA study will provide a rich biorepository of samples from highly phenotyped subjects. Weanticipate screening 200-250 subjects, including low threshold, high threshold, and sensitized but not allergic,in order to enroll 98 subjects that meet the high threshold criteria for the CAFETERIA trial. We will obtainlongitudinal samples from subjects randomized to dietary therapy or avoidance. We will comprehensivelyprofile antibody responses by high-throughput epitope assay, peanut-specific T cell responses by flowcytometry, and whole blood activation by CyTOF to construct a detailed clinical-immune network of PA, andanalyze the relationship between immune and clinical parameters. We will identify biomarkers and key causaldrivers of PA by performing integrated network-based examination of peripheral blood transcriptomes from PAsubjects, sampled before and after food challenge, and before and after dietary therapy. Successful completionof these aims will result in (1) a simple low-cost treatment option applicable to the majority of those with PA; (2)an identification of immune and molecular mechanisms of PA and response to dietary therapy; (3) peripheralblood biomarkers that will practically impact clinical care of PA; (4) the potential for personalized approaches tothe treatment of PA; and (5) a tremendously rich resource of clinical, immune, and transcriptional data andanalytic tools to be made publicly available to the research community.