S. aureus and Regulatory T cells in the Failure of Oral Tolerance

金黄色葡萄球菌和调节性 T 细胞在口服耐受失败中的作用

基本信息

  • 批准号:
    8581436
  • 负责人:
  • 金额:
    $ 13.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-07-01 至 2018-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Anne Marie Singh, a pediatric allergist-immunologist at Northwestern Feinberg School of Medicine. Dr. Singh is young investigator in patient-oriented translational research of food allergy. Her previous research studying the phenotypic expression of early eczema and role of regulatory T cells in allergy makes her uniquely qualified to study early mechanisms of loss of tolerance. Food allergy affects over 12 million Americans, and prevalence in children has increased by 18% from 1997-2007. Food allergy-induced anaphylaxis is often life threatening, and food allergy is an important risk factor for the future development of asthma and allergic rhinitis. Despite its significant impact, little is known regarding the cellular and immunologic mechanisms in the initiation of food allergy in children. Food allergy results from a loss of oral tolerance t ingested antigens, leading to the pathologic immune response. Regulatory T (Treg) cells are important in balancing immune responses, and dysregulation of these cells may play an important role in the pathogenesis of food allergy. It has recently been shown that oral exposure to Staphylcoccal enterotoxin B, SEB, breaks oral tolerance in mice, promoting food allergy-associated responses. Exciting new preliminary data demonstrate increased Staphylococcus aureus burden in the gut of patients with food allergy, and previous work has also illustrated increased IL-10 producing Tregs in formally egg allergic children as they acquire tolerance. It has been shown that topical S. aureus plays a crucial role in the cutaneous inflammation of atopic eczema and activation of CD25+ Treg cells with S. aureus enterotoxin B (SEB) abrogated their suppressive phenotype. Together, these data support the following hypothesis: colonization of children with Staphylococcus aureus abrogates Treg function, inhibiting oral tolerance, and thereby promotes allergic inflammation and the development of food allergy. To test this hypothesis we propose to characterize the Treg cells by flow cytometry in children with food allergy compared to non-food allergic children, determine the colonization and enterotoxin production of S. aureus in food allergic and non-food allergic children through microbiome analysis, and determine the effect of food antigen and microbial exposure on Treg function in vitro in these children. This proposal focuses on the role of Treg cells and S. aureus in the attendant loss of tolerance, and will open approaches to prevent the development of food allergy or increase treatment options beyond antigen avoidance. Through the proposed research, Dr. Singh will work towards her long-term goal of becoming an independent translational physician-investigator, studying cellular mechanisms of early life exposures on the development of atopy. Short term goals are to: (1) develop research skills of regulatory T cell analysis, transcription factor analysis and next-generation sequencing, (2) establish bioinformatics skills to analyze microbiota data sets and (3) develop biostatistical and clinical trial skills for study design and implementation. After completion of this award, Dr. Singh, will have had the training to design and implement studies on the immune effects of bacterial and environment exposures, including the acquisition of microbiota over time and the mechanisms that microbial and other environmental exposures impact the regulation of the immune response. To achieve these goals, a top-notch mentoring team has been assembled. The primary mentor, Robert Schleimer, PhD, Chief, Division of Allergy-Immunology (Department of Medicine) has a strong track record of translational research in allergy and has successfully trained many academicians. Co-mentors include Paul J. Bryce, PhD, Associate Professor, with expertise in mouse models of food allergy and regulatory T cell studies~ Jacqueline Pongracic, MD, Chief, Division of Allergy-Immunology (Department of Pediatrics) who has multicenter clinical trial experience in pediatric allergy patients~ Lewis Smith, MD, Associate Vice Chair for Research, with extensive clinical and laboratory-based research programs studying asthma pathogenesis~ and Mitchell L. Sogin, PhD, Director, Marine Biology Laboratory, a pioneer in studies of bacterial communities, including bioinformatics analysis of human microbiota. The mentoring team will oversee Dr. Singh's progress to study the effects of S. aureus on regulatory T cell function in food allergy.
描述(由申请人提供):这是为西北大学范伯格医学院的儿科过敏学家和免疫学家安妮·玛丽·辛格博士申请K23奖项。辛格博士是面向患者的食物过敏转化研究的年轻研究员。她之前对早期湿疹的表型表达和调节性T细胞在过敏中的作用的研究使她成为唯一有资格研究早期耐受性丧失机制的人。食物过敏影响了1200多万美国人,从1997年到2007年,儿童的患病率增加了18%。食物过敏引起的过敏反应往往危及生命,食物过敏是哮喘和过敏性鼻炎未来发展的重要危险因素。尽管它有重大影响,但人们对儿童食物过敏的细胞和免疫学机制知之甚少。食物过敏是由于对摄入的抗原失去口服耐受性而导致的病理性免疫反应。调节性T(Treg)细胞在平衡免疫反应中起重要作用,这些细胞的失调可能在食物过敏的发病机制中发挥重要作用。最近有研究表明,口服葡萄球菌肠毒素B(SEB)打破了小鼠的口服耐受性,促进了食物过敏相关反应。令人兴奋的新的初步数据表明,食物过敏患者肠道中金黄色葡萄球菌的负担增加,以前的工作也表明,在对鸡蛋过敏的儿童获得耐受性后,IL-10产生的Tregs增加。研究表明,外用金黄色葡萄球菌在特应性湿疹的皮肤炎中起重要作用,金黄色葡萄球菌肠毒素B(SEB)激活CD25+Treg细胞可抑制其表型。综上所述,这些数据支持以下假设:金黄色葡萄球菌感染儿童的定植丧失了Treg功能,抑制了口服耐受性,从而促进了过敏性炎症和食物过敏的发展。为了验证这一假说,我们建议用流式细胞术比较食物过敏儿童和非食物过敏儿童Treg细胞的特征,通过微生物组分析确定金黄色葡萄球菌在食物过敏和非食物过敏儿童中的定植和肠毒素产生,并确定食物抗原和微生物暴露对这些儿童体外Treg功能的影响。这项建议侧重于Treg细胞和金黄色葡萄球菌在伴随而来的耐受性丧失中的作用,并将开辟防止食物过敏发展或增加抗原回避以外的治疗选择的方法。通过这项拟议中的研究,辛格博士将朝着她的长期目标努力,成为一名独立的转化型医生兼研究员,研究早期生命暴露对特应性疾病发展的细胞机制。短期目标是:(1)发展调节性T细胞分析、转录因子分析和下一代测序的研究技能,(2)建立生物信息学技能来分析微生物区系数据集,(3)为研究设计和实施发展生物统计学和临床试验技能。在完成这一奖项后,辛格博士将接受培训,设计和实施关于细菌和环境暴露的免疫影响的研究,包括随着时间的推移获得微生物区系,以及微生物和其他环境暴露影响免疫反应调节的机制。为了实现这些目标,已经组建了一支顶尖的指导团队。主要导师罗伯特·施莱默博士,过敏免疫科(医学部)主任,在过敏翻译研究方面有着良好的记录,并成功培训了许多院士。共同导师包括Paul J.Bryce博士,副教授,在食物过敏小鼠模型和调节性T细胞研究方面具有专业知识~Jacqueline Pongracic,医学博士,过敏-免疫科(儿科)主任,具有儿科过敏患者多中心临床试验经验~Lewis Smith,医学博士,研究助理副主席,拥有广泛的临床和实验室研究项目,研究哮喘发病机制~和Mitchell L.Sogin博士,海洋生物实验室主任,细菌群落研究的先驱,包括人体微生物区系的生物信息学分析。指导小组将监督辛格博士在研究金黄色葡萄球菌对食物过敏中调节性T细胞功能的影响方面的进展。

项目成果

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Anne Marie Singh其他文献

Anne Marie Singh的其他文献

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{{ truncateString('Anne Marie Singh', 18)}}的其他基金

Childhood Allergy and the NeOnatal Environment (CANOE) ECHO Pediatric Follow-Up and New Enrollment
儿童过敏和新生儿环境 (CANOE) ECHO 儿科随访和新入组
  • 批准号:
    10744839
  • 财政年份:
    2023
  • 资助金额:
    $ 13.05万
  • 项目类别:
S. aureus and Regulatory T cells in the Failure of Oral Tolerance
金黄色葡萄球菌和调节性 T 细胞在口服耐受失败中的作用
  • 批准号:
    8664793
  • 财政年份:
    2013
  • 资助金额:
    $ 13.05万
  • 项目类别:

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