B Cell Mechanisms of Tolerance Following Infant Peanut Consumption

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PROJECT SUMMARY/ABSTRACT This proposal details a 5-year plan to provide the candidate, Dr. Adora Lin, with the knowledge and expertise to become an independent investigator in the field of Allergy and Immunology. The proposed research is a novel investigation of the role of B cells in the development of peanut allergy versus tolerance in infants deemed at high risk for peanut allergy. Although studies suggest that early introduction of peanut to high-risk infants can influence the development of peanut allergy versus tolerance, with accompanying changes in peanut-specific immunoglobulin levels, the biology of the B cells producing these immunoglobulins and regulatory mechanisms mediating these changes are unknown. The candidate will evaluate the B cell response to IL-10, regulatory B cells (B regs), and the B cell transcriptome in samples collected from infants at high risk for peanut allergy, both prior to peanut introduction and during peanut consumption or avoidance. The specific aims of the project are: 1) To determine whether increased B cell responsiveness to IL-10 and increased B reg frequency and function identify infants at high risk for peanut allergy who tolerate peanut, 2) To evaluate whether regular peanut consumption augments B cell responsiveness to IL-10 and B reg frequency and function in infants at high risk for peanut allergy, and 3) To define the B cell transcription signature associated with peanut tolerance. Findings from this research will address significant gaps in our knowledge regarding the impact of B cells during the critical early period that shapes food allergy versus tolerance. These findings may be leveraged into future studies evaluating novel biomarkers for distinguishing food allergy versus tolerance, new diagnostic methods, improved monitoring of allergen immunotherapy, and B cell-targeted interventions for food allergy. This research will also provide new insights into B cell biology, B regs, and the B cell transcriptome during infancy. The candidate has assembled an outstanding team of NIH- funded mentors, who have committed their time, expertise, and resources to facilitate the candidate's research and career goals. Dr. Bollard is a world-renowned translational immunologist and expert in adoptive T cell therapies. Dr. Guerrerio is a leading expert in food allergy pathogenesis. Dr. Freishtat has extensive expertise in transcriptomics and systems biology. The candidate will participate in coursework designed to provide her with further skills in advanced biostatistics, clinical study design, next-generation sequencing, bioinformatics, and various areas of professional development. She will benefit from an ideal scientific, educational, and clinical environment provided by her primary institution, Children's National Medical Center, enhanced by training opportunities at the George Washington University and National Institutes of Health. In summary, this proposal describes a relevant and feasible research project and career development plan that will position the candidate to secure independent NIH funding and establish herself in a niche area of academic food allergy.