Humoral mechanisms of tolerance in peanut oral immunotherapy

花生口服免疫疗法耐受的体液机制

• 批准号: 9013624
• 负责人: Sarita U Patil
• 金额: $ 18.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-07 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9013624
• 关键词: Address; Adopted; Advisory Committees; Affect; Affinity; Allergens; Allergic; Allergic Disease; Allergic Reaction; Allergy to peanuts; Antibodies; Antibody Repertoire; Antigens; B cell repertoire; B-Lymphocytes; Basic Science; Bioinformatics; Biological; Biological Markers; Cells; Characteristics; Child; Classification; Clinical; Clinical Research; Clinical Trials; Complement; Computational Biology; Development; Disease; Effector Cell; Environment; Fellowship; Flow Cytometry; Food; Food Hypersensitivity; Foundations; Frequencies; Future; General Hospitals; Homing; Human; Hypersensitivity; IgE; IgG4; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulins; Immunology; Immunotherapy; Individual; Inflammatory; Institutes; Life; Love; Maps; Mass Spectrum Analysis; Massachusetts; Measures; Mediating; Medicine; Memory; Memory B-Lymphocyte; Mentors; Mentorship; Mutate; Oral; Outcome; Patients; Phenotype; Physicians; Plasma Cells; Play; Population; Positioning Attribute; Prevalence; Prognostic Marker; Proteomics; Public Health; Public Health Schools; Reaction; Receptors, Antigen, B-Cell; Recombinant Antibody; Recombinants; Reporting; Research; Research Personnel; Resources; Risk; Role; Scientist; Sequence Analysis; Serum; Specificity; Surface; Techniques; Technology; Tetanus; Therapeutic; Therapeutic Agents; Training Activity; Translational Research; Vaccines; Work; base; career; catalyst; clinical biomarkers; deep sequencing; desensitization; functional outcomes; glycosylation; human subject; improved; insight; instructor; medical schools; multidisciplinary; next generation sequencing; novel strategies; oral immunotherapy; public health relevance; response; statistics; transcriptome sequencing

 DESCRIPTION (provided by applicant): Candidate: Sarita Patil, MD is a staff physician in Allergy and Immunology at Massachusetts General Hospital (MGH) and a junior investigator as an Instructor in Medicine at Harvard Medical School (HMS). During her fellowship, she conducted translational research, which led to the development of a fluorescent allergen- specific B cell tetramer that could successfully identify peanut-specific B cells in the periphery f peanut- allergic patients undergoing immunotherapy. Building on that technology, this K23 application aims to understand the role of the humoral response in oral food immunotherapy, specifically investigating the immunoglobulin response to the peanut allergen Ara h 2 on a clonal level, allowing for greater insight into mechanisms of immunotherapy in human patients with food allergy. The proposed project combines research in clinical trials, basic science, and bioinformatics to develop a unique expertise in translational research. The work, training activities, and mentoring plan outlined in this proposal will successfully position Dr. Patil for hr first R01 application and an independent career as a physician-scientist. Mentorship, Training Activities, and Environment: Dr. Patil will perform the proposed project in the Center for Immunology and Inflammatory Diseases (CIID) at MGH under the mentorship of Dr. Wayne Shreffler and at Massachusetts Institute of Technology (MIT) under the co-mentorship of Dr. J. Christopher Love. The CIID is a multidisciplinary basic science center that serves as the foundation of immunology research at MGH. In addition, Dr. Robert Anthony at MGH and Dr. Steven Kleinstein at Yale School of Medicine will serve on Dr. Patil's Advisory Committee to provide expertise on immunoglobulin glycosylation in allergic diseases as well as immunoglobulin repertoire analysis using computational biology approaches, respectively. To complement her proposed projects and the expertise of her mentors, Dr. Patil will complete didactic courses in translational research, statistics, sequencing, proteomics, and bioinformatics through the Harvard School of Public Health and the Harvard Catalyst. The collaborative opportunities, intellectual environment and resources available to Dr. Patil are outstanding. Research: IgE-mediated peanut allergy poses a significant public health risk, as minute peanut exposures can cause severe allergic reactions. Clinical trials of peanut oral immunotherapy (PNOIT) with gradual incremental peanut exposure under careful observation in children have been successful in inducing desensitization; however, only a fraction of these children have long-lived tolerance. Patients undergoing PNOIT often have a decrease in their peanut-specific IgE and a gradual increase in their peanut-specific IgG and IgG4 levels, but the mechanistic contribution of these changes in peanut-specific immunoglobulins to long-term tolerance is still unknown. This project addresses how PNOIT affects the B cell repertoire and how those changes correlate to the heterogeneous clinical outcomes that are expected. We hypothesize that long-lasting clinical tolerance following PNOIT directly correlates with, and is partially dueto the induction of high affinity and oligoclonal allergen-specific functional antibodies. Using a fluorescent tetramer-based approach for the identification of allergen-specific B cells, we hope to identify clinical prognostic markers, and improve our understanding of the mechanism of immunotherapy, specifically the pathophysiological role of antibodies and their potential as both biomarkers of tolerance and therapeutic agents. To do so, we propose mapping the allergen-specific B cell repertoire using proteomics and next- generation sequencing in PNOIT patients. We also propose functional studies of recombinant antibodies from the allergen-specific B cells to explore the underlying mechanism of tolerance in PNOIT. By studying both peanut allergic patients who develop variable tolerance during PNOIT as well as peanut allergic patients who naturally outgrew their allergies, we hope to elucidate the contribution of the B cell repertoire t the induction of long-lived tolerance in peanut allergy. These efforts may help identify relevant clinical biomarkers and potential therapeutic avenues for the improvement of PNOIT for the treatment of peanut allergy.

 描述（由适用提供）：候选人：马萨诸塞州萨里塔·帕蒂尔（Sarita Patil）是马萨诸塞州综合医院（MGH）的过敏和免疫学人员，也是哈佛医学院（HMS）医学教练的初级研究员。在奖学金期间，她进行了转化研究，这导致了荧光过敏原B细胞四聚体的发展，该四聚体可以成功地鉴定出接受免疫疗法的外周lip-F花生过敏患者中的花生特异性B细胞。在该技术的基础上，该K23应用旨在了解人类反应在口服食品免疫疗法中的作用，专门研究了克隆水平上对花生过敏原ARA H 2的免疫球蛋白反应，从而可以更深入地了解人类患者免疫疗法的机制。拟议的项目结合了临床试验，基础科学和生物信息学的研究，以开发转化研究中的独特专业知识。该提案中概述的工作，培训活动和心理计划将成功地将Patil博士定位为HR首次R01应用程序，并从事独立职业作为身体科学家。指导，培训活动和环境：帕蒂尔博士将在MGH的免疫学和炎症性疾病中心（CIID）在Wayne Shreffler博士和马萨诸塞州技术研究所（MIT）的遗产下执行拟议项目。 CIID是一个多学科基础科学中心，是MGH免疫研究的基础。此外，MGH的Robert Anthony博士和耶鲁大学医学院的Steven Kleinstein博士将在Patil博士的咨询委员会任职，以分别使用计算生物学方法来提供过敏性疾病中的免疫球蛋白糖基化以及免疫球蛋白库存分析的专业知识。为了补充她提出的项目和导师的专业知识，Patil博士将通过哈佛公共卫生学院和哈佛催化剂完成翻译研究，统计，测序，蛋白质组学和生物信息学的教学课程。 Patil博士可用的协作机会，智力环境和资源非常出色。研究：IgE介导的花生过敏会带来重大的公共卫生风险，因为微小的花生暴露会导致严重的过敏反应。在儿童仔细观察的情况下，花生口服免疫疗法（PNOIT）的临床试验成功地诱导了脱敏。但是，只有一小部分这些孩子具有长期的宽容。接受PNOIT的患者通常会降低花生特异性IgE，而花生特异性IgG和IgG4水平的成绩增加，但是这些变化在花生特异性免疫球蛋白对长期耐受性的机械贡献仍然不明。该项目解决了PNOIT如何影响B细胞库以及这些变化如何与预期的异质临床结果相关。我们假设PNOIT后持久的临床耐受性与高亲和力和寡克隆过敏原特异性抗体的诱导直接相关，部分原因是。我们希望使用基于荧光四聚体的方法来鉴定过敏原特异性B细胞，我们希望鉴定临床预后标记物，并提高我们对免疫疗法机制的理解，特别是抗体的病理生理作用及其潜在的耐受性和治疗的潜力。代理商。为此，我们建议使用PNOIT患者中使用蛋白质组学和下一代测序来映射过敏原特异性B细胞库。我们还提出了来自过敏原特异性B细胞重组抗体的功能研究，以探索PNOIT中耐受性的潜在机制。通过研究在PNOIT期间发展出可变耐受性的花生过敏患者以及自然胜过过敏的花生过敏患者，我们希望阐明B细胞曲目在花生过敏中诱导长期寿命的耐受性的贡献。这些努力可能有助于确定相关的临床生物标志物和潜在的治疗途径，以改善PNOIT以治疗花生过敏。