Heterogeneity of the Bone Marrow Plasma Cell Pool

骨髓浆细胞库的异质性

• 批准号: 8397182
• 负责人: Irene Chernova
• 金额: $ 2.87万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397182
• 关键词: Ablation; Affect; Affinity; Antibodies; Antibody Formation; Antigens; Autoimmune Diseases; B-Lymphocytes; Biological Models; Bone Marrow; Cell Communication; Cell Lineage; Cells; Characteristics; Data; Disease; Engineering; Generations; Genes; Heterogeneity; Immunization; Immunoglobulin Somatic Hypermutation; Infection; Kinetics; Life; Maintenance; Mediating; Medicine; Memory B-Lymphocyte; Mission; Modeling; National Heart, Lung, and Blood Institute; Plasma Cells; Play; Population; Receptors, Antigen, B-Cell; Regulation; Rheumatoid Arthritis; Role; Serum; Signal Transduction; Somatic Mutation; Specificity; Structure of germinal center of lymph node; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Testing; Therapeutic; Transfusion; Vaccine Antigen; Vaccine Design; base; defined contribution; design; experience; mouse model; programs; research study

DESCRIPTION (provided by applicant): The signals required to maintain antibody-secreting plasma cell pools and serum antibody titers remain poorly defined. This proposal is focused on definitively determining whether persisting antigen plays a key role in maintaining serum antibody titers. The proposition that maintenance of antigen-specific serum titers requires persistence of antigen would have profound implications for vaccine design as all immunizing antigens would have to be engineered to form a lifelong depot in the body. To eliminate the seeding of the BM PC pool by antigen-stimulated B cell feeder populations, B cells will be deprived of T cell help and the B cell receptor of the memory B cell population will be experimentally revised so as to not be responsive to antigen. If it is found that the BM PC pool needs to be maintained by feeder populations it will be a demonstration of the need for persistent antigen for the maintenance of protective antibody titers. Overall, the experiments within this proposal will serve to better define the requirements for serum antibody maintenance and may suggest new ways to optimize these titers, thereby fulfilling the mission of the Transfusion Medicine and Cellular Therapeutics Program of the NHLBI. PUBLIC HEALTH RELEVANCE: The proposed studies will test whether antigen persistence plays a role in maintaining plasma cell populations and therefore antibody titers. This will inform us about ways to optimize vaccine antigen design. It will also increase our understanding about the regulation of a cell subset that is responsible for the production of antibodies that both mediate autoimmune disease (such as rheumatoid arthritis) and protect our bodies from infection.

描述（由申请人提供）：维持抗体分泌浆细胞池和血清抗体滴度所需的信号仍不清楚。该提案的重点是明确确定持续抗原是否在维持血清抗体滴度中发挥关键作用。维持抗原特异性血清滴度需要抗原持续存在的主张将对疫苗设计产生深远的影响，因为所有免疫抗原都必须经过改造以在体内形成终生储存库。为了消除 BM PC 库中抗原刺激的 B 细胞饲养群的播种，B 细胞将被剥夺 T 细胞的帮助，并且记忆 B 细胞群的 B 细胞受体将通过实验进行修改，以便不对抗原产生反应。如果发现 BM PC 池需要由饲养群体来维持，则这将证明需要持久抗原来维持保护性抗体滴度。总体而言，本提案中的实验将有助于更好地确定血清抗体维持的要求，并可能提出优化这些滴度的新方法，从而实现 NHLBI 输血医学和细胞治疗计划的使命。 公共卫生相关性：拟议的研究将测试抗原持久性是否在维持浆细胞群以及抗体滴度方面发挥作用。这将告知 我们了解优化疫苗抗原设计的方法。它还将增加我们对负责产生抗体的细胞亚群的调节的理解，这些抗体既介导自身免疫性疾病（例如类风湿性关节炎）又保护我们的身体免受感染。