The broad goals of the Mechanistic Core are the following: 1) to continue mechanistic studies from the prior granting period aimed at defining the mechanisms underlying the development of food allergy and """"""""natural"""""""" or immunotherapeutically-induced tolerance, 2) to provide a platform for every project within this new proposal to achieve these goals and 3) to utilize the information gathered during the initial granting period to establish new hypotheses and provide new avenues for investigation. During the initial granting period we established uniform reproducible technology across 5 sites allowing for the study of sensitization and T-cell activation, and assessment of the development of tolerance. There were several findings that caused us to question some of the previous dogma including the fact that a large cohort of milk and egg allergic children were already sensitized to peanut at an early age, that the GATA-3 transcription factor may play less of a role in allergic sensitization in humans than previously thought and that there was a high likelihood of a non- T cell origin for IL-4 (and consequent IgE) in these patients. The current proposal seeks to continue the current studies focused on the role of T cells vs. APCs in allergic sensitization and tolerance, as well as expand studies on the role of basophils in this process. In addition, we now plan to specifically explore the expression and regulation of GATA-3 in T and non-T cells, initiate studies attempting to correlate the expression of food allergy as either atopic, i.e. atopic dermatitis, asthma or allergic rhinitis, vs eosinophilic esophagitis using the immunologic parameters previously described, and finally to use a microarray approach to define novel pathways and markers of atopic disease, disease resolution and tolerance and the distinct expression of disease phenotypes (AD vs EE). These ongoing and new studies should enhance our understanding of the pathogenesis of atopic disease based upon human study.
The results of these studies should help us to gain insights into mechanisms of action of three novel immunotherapeutic approaches to treat peanut allergy, allow us to define pathways whereby novel interventions can be approached, and provide insights into mechanisms and biomarkers associated with the natural development and loss of food allergies.
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