Structural determinants of human immunity to anthrax

人体炭疽免疫力的结构决定因素

• 批准号: 6820498
• 负责人: Donald C Reason
• 金额: $ 40.03万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6820498
• 关键词: anthrax; anthrax toxin; anthrax vaccines; antigen antibody reaction; bioterrorism /chemical warfare; calorimetry; clinical research; human subject; immune response; immunity; immunogenetics; immunoglobulin structure; immunoglobulins; molecular cloning; monoclonal antibody; patient oriented research; protein engineering; protein sequence; vaccine development; vaccine evaluation

DESCRIPTION (provided by applicant): The recent, intentional dissemination of Bacillus anthracis caused significant morbidity and mortality, as well as widespread and costly disruption of essential public services. The resulting re-evaluation of current methods for the prevention and treatment of anthrax has revealed significant gaps in our knowledge of the basic immunobiology of this disease, and highlighted the need to develop methodologies for establishing vaccine efficacy in the absence of clinical trials. The research described in this proposal will define the molecular and structural characteristics of the protective antibody response elicited by the currently licensed human anthrax vaccine. Methods of repertoire cloning recently developed in our laboratory will be used to establish at the molecular level the structural diversity, variable gene usage, and somatic maturational history of the human antibody repertoire specific for the protective antigen (PA) of B. anthracis. The extent to which different individuals utilize the same immunoglobulin variable gene products to bind specific epitopes on the antigen will be determined. Through sequence analysis, the degree to which responding antibody clones have undergone somatic maturation will be ascertained. Clonally derived PA-specific binding domains will be expressed in vitro, the subset capable of blocking PA functional activity identified, and affinity and valence requirements for functionality established. Cloned antibody binding domains will be used to define the PA-associated antigenic epitopes recognized by the human immune response, and to pinpoint those PA-associated epitopes that elicit neutralizing antibodies. Our findings will be crucial for the rational design of PA subunit vaccines, and will aid in establishing in vitro correlates of protective immunity to B. anthracis infection. In addition, the antibodies isolated will constitute a panel of fully human monoclonal binding domains with potential for therapeutic use as passive immunogens.

描述（由申请人提供）：最近的故意传播炭疽芽孢杆菌引起了显着的发病率和死亡率，以及对基本公共服务的广泛和昂贵的破坏。当前对预防和治疗炭疽治疗的方法的重新评估表明，我们对这种疾病的基本免疫生物学的了解有很大的差距，并强调了在没有临床试验的情况下开发建立疫苗功效的方法。该提案中描述的研究将定义当前许可的人类炭疽疫苗引起的保护性抗体反应的分子和结构特征。最近在我们的实验室中开发的曲目克隆方法将用于在分子水平上建立人类抗体库的结构多样性，可变基因使用和对植物保护性抗原（PA）的人类抗体库的体细胞成熟史。不同个体利用相同的免疫球蛋白可变基因产物在抗原上结合特定表位的程度。通过序列分析，将确定反应抗体克隆的体细胞成熟程度。克隆得出的PA特异性结合结构域将在体外表达，该子集能够阻止PA功能活性，以及​​对功能的亲和力和价要求。克隆的抗体结合结构域将用于定义通过人免疫反应识别的与PA相关的抗原表位，并查明引起中和抗体的那些与PA相关的表位。我们的发现对于PA亚基疫苗的合理设计至关重要，并将有助于建立与炭疽芽孢杆菌感染的保护性免疫的体外相关性。此外，分离的抗体将构成一个完全人类的单克隆结合结构域，其潜在用作被动免疫原子。