B Cell Mechanisms of Tolerance Following Infant Peanut Consumption

婴儿食用花生后 B 细胞的耐受机制

• 批准号: 10039452
• 负责人: Adora A Lin
• 金额: $ 18.04万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10039452
• 关键词: 3 year old; 5 year old; Address; Age-Months; Allergen Immunotherapy; Allergic; Allergy to eggs; Allergy to peanuts; Anaphylaxis; Antibody-Producing Cells; Area; Atopic Dermatitis; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Bioinformatics; Biological Markers; Biology; Biometry; Breastfed infant; Cattle; Cellular biology; Cessation of life; Child; Clinical; Clinical Research; Consumption; Data; Developed Countries; Development; Development Plans; Diagnosis; Diagnostic Procedure; Down-Regulation; Environment; Evaluation; Family; Food; Food Hypersensitivity; Frequencies; Funding; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Goals; Health Care Costs; Hypersensitivity; IgE; IgG4; Immune; Immunoglobulin Class Switching; Immunoglobulins; Immunologics; Immunologist; Immunology; Immunotherapeutic agent; Infant; Institution; Interleukin-10; Intervention; Investigation; Knowledge; Learning; Life; Measurement; Measures; Mediating; Medical; Medical center; Mentors; Milk; Monitor; Oral; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Physicians; Positioning Attribute; Prevalence; Prevention; Production; Quality of life; Research; Research Design; Research Personnel; Research Project Grants; Resources; Risk; Role; Sampling; Scientist; Secure; Serum; Shapes; Systems Biology; T cell therapy; Therapeutic; Time; Training; United States National Institutes of Health; Universities; Washington; atopy; base; career; career development; critical period; cytokine; design; differential expression; egg; experience; food challenge; high risk; high risk infant; improved; infancy; insight; interleukin-10 receptor; next generation sequencing; novel; novel diagnostics; novel marker; oral immunotherapy; psychosocial; receptor expression; response; skills; training opportunity; transcriptome; transcriptome sequencing; transcriptomics

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.

项目概要/摘要 该提案详细介绍了一个五年计划，旨在为候选人 Adora Lin 博士提供知识和专业知识 成为过敏和免疫学领域的独立研究者。拟议的研究是 B 细胞在婴儿花生过敏与耐受性发展中的作用的新研究 被认为是花生过敏的高风险人群。尽管研究表明，早期引入花生给高风险人群 婴儿可能会影响花生过敏与耐受的发展，并伴随着花生过敏的变化 花生特异性免疫球蛋白水平、产生这些免疫球蛋白的 B 细胞的生物学以及 调节这些变化的调节机制尚不清楚。候选人将评估 B 细胞 婴儿样本中对 IL-10、调节性 B 细胞 (B regs) 和 B 细胞转录组的反应 在引入花生之前以及食用或避免花生期间，花生过敏的风险很高。这 该项目的具体目标是： 1) 确定 B 细胞对 IL-10 和 B reg 频率和功能增加可识别对花生过敏且耐受花生的高风险婴儿，2) 评估定期食用花生是否会增强 B 细胞对 IL-10 和 B reg 的反应性 花生过敏高危婴儿的频率和功能，以及 3) 定义 B 细胞转录 与花生耐受性相关的特征。这项研究的结果将弥补我们在 关于 B 细胞在形成食物过敏的关键早期阶段的影响的知识 宽容。这些发现可能会被用于未来的研究，评估新的生物标志物以区分 食物过敏与耐受、新的诊断方法、改进的过敏原免疫治疗监测以及 B 针对食物过敏的细胞靶向干预措施。这项研究还将为 B 细胞生物学、B regs 和婴儿期 B 细胞转录组。该候选人组建了一支优秀的 NIH 团队—— 资助导师，他们投入了时间、专业知识和资源来促进候选人的研究 和职业目标。 Bollard博士是世界著名的转化免疫学家和过继性T细胞专家 疗法。 Guerrerio 博士是食物过敏发病机制方面的领先专家。 Freishtat 博士拥有丰富的专业知识 转录组学和系统生物学。候选人将参加旨在为她提供的课程 拥有高级生物统计学、临床研究设计、下一代测序、生物信息学等方面的进一步技能， 以及各个领域的专业发展。她将受益于理想的科学、教育和 她的主要机构国家儿童医疗中心提供的临床环境，通过 乔治华盛顿大学和国立卫生研究院的培训机会。综上所述，这 提案描述了一个相关且可行的研究项目和职业发展计划，该计划将定位 候选人获得独立的美国国立卫生研究院资助，并在食物过敏学术领域确立自己的地位。