REGULATION OF PROTECTIVE HUMORAL IMMUNITY TO STREPTOCOCCUS PNEUMONIAE BY PD-1

PD-1对肺炎链球菌保护性体液免疫的调节

• 批准号: 8173470
• 负责人: Karen M Haas
• 金额: $ 22.2万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173470
• 关键词: Adult; Affinity; Antibodies; Antibody Formation; Antigens; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; Bacteria; Biological; Bone Marrow; Cell physiology; Cells; Cercopithecus pygerythrus; Child; Chronic; Data; Disease; Elderly; Encapsulated; Focal Infection; Generations; Goals; Health Care Costs; Host Defense; Human; Humoral Immunities; Immune response; Immune system; Immunity; Immunization; Immunocompromised Host; Immunoglobulin G; Immunoglobulin M; In Vitro; Infection; Knowledge; Lead; Life; Ligands; Malignant Neoplasms; Mediating; Modeling; Morbidity - disease rate; Mus; Nature; Pathway interactions; Play; Pneumococcal Infections; Pneumococcal vaccine; Polysaccharides; Polyvalent pneumococcal vaccine; Population; Primates; Process; Production; Proteins; Public Health; Publishing; Regulation; Regulatory Pathway; Research; Role; Serotyping; Streptococcus pneumoniae; T-Lymphocyte; TI 2 Antigens; Testing; Therapeutic; Vaccines; Virus Diseases; base; capsule; cell type; clinically relevant; combat; cost effective; design; global health; immunogenic; immunogenicity; improved; inhibitor/antagonist; interest; mortality; nonhuman primate; receptor; response; selective expression; small molecule

DESCRIPTION (provided by applicant): The goal of this proposal is to evaluate the feasibility of blocking interactions between the PD-1 immunoinhibitory receptor and its ligands as a strategy to enhance protective antibody responses to pneumococcal polysaccharides (PPSs) found in the capsule of Streptococcus pneumoniae. S. pneumoniae continues to pose a global threat and is one of the leading causes of morbidity and mortality among children. PPS vaccines provide significant protection against serotype-specific invasive pneumococcal disease in adults, but are less efficacious against non-invasive disease and poorly stimulate protective antibody responses in very young, elderly, and immunocompromised populations. Understanding how protective antibody responses to PPS are regulated is key to devising more efficacious vaccines. PPSs typically elicit T cell independent type 2 (TI-2) antibody responses, which are regulated distinctly from antibody responses to protein antigens. We previously identified that a unique subset of B cells, termed B-1b cells, is critical for producing antibodies against type 3 PPS (PPS-3) and other TI-2 antigens in mice. Our preliminary data shows that antigen-specific B-1b cells upregulate the immunoinhibitory receptor PD-1 following TI-2 antigen immunization, and that blocking PD-1 from interacting with its ligands significantly increases IgG responses against TI-2 Ags, including PPS-3. Despite the intense interest in developing PD-1-related biologics and small molecule inhibitors for treatment of chronic viral infections and malignancies, very little is known about how these therapies may influence B cell function or host defense against bacteria. Studies in this proposal are designed to explore: 1) how inhibiting PD-1 function influences the quantity, persistence, and protective capacity of antibody responses to PPS-3, 2) the extent to which PD-1 regulates antibody responses to distinct types of PPS found in the current pneumococcal vaccine, and 3) the role B-cell-specific PD-1 expression plays in the regulation of PPS antibody responses. Finally, since PD-1 expression is only significantly induced on antigen-specific B-1b cells following TI-2 antigen immunization in mice, we will explore the functional contribution B-1-like cells make to TI-2 antibody responses in non-human primates (African Green monkeys; AGM) and the potential for PD-1 to similarly regulate these cells. The results of these exploratory studies will demonstrate the significance the PD-1 regulatory pathway has on the generation of protective humoral immunity to S. pneumoniae and will reveal the importance B cell-specific PD-1 expression plays in this process in mice. Finally, this project will further develop the AGM as an alternative non-human primate model in which to assess B cell subsets and factors contributing to the regulation of antibody responses against PPS and other clinically relevant TI-2 antigens. Ultimately, these studies may lead to new applications for PD-1 therapeutics in enhancing the efficacy of PPS-based vaccines against S. pneumoniae. PUBLIC HEALTH RELEVANCE: The goal of the research proposed in the current application is to understand how the immune system is regulated to respond to vaccines against Streptococcus pneumoniae. The knowledge gained from these studies may lead to improved vaccines that provide enhanced protection against pneumococcal infections currently threatening global public health.

描述(由申请人提供)：这项建议的目标是评估阻断PD-1免疫抑制受体及其配体之间的相互作用作为一种策略来增强对肺炎链球菌胶囊中发现的肺炎球菌多糖(PPS)的保护性抗体反应的可行性。肺炎链球菌继续构成全球威胁，是儿童发病率和死亡率的主要原因之一。PPS疫苗在成人中对特定血清型的侵袭性肺炎球菌疾病提供了显著的保护，但对非侵袭性疾病的效果较差，并且在非常年轻、老年和免疫受损的人群中刺激保护性抗体反应较差。了解对PPS的保护性抗体反应是如何调节的，这是设计更有效疫苗的关键。PPS典型地激发非依赖T细胞的2型(TI-2)抗体反应，这种抗体反应与对蛋白质抗原的抗体反应不同。我们以前发现，一种独特的B细胞亚群，称为B-1b细胞，对于在小鼠中产生抗3型PPS(PPS-3)和其他TI-2抗原的抗体至关重要。我们的初步数据显示，在TI-2抗原免疫后，抗原特异性B-1b细胞上调免疫抑制受体PD-1，并且阻止PD-1与其配体相互作用显著增加针对TI-2抗原(包括PPS-3)的免疫球蛋白G反应。尽管人们对开发PD-1相关生物制品和小分子抑制剂用于治疗慢性病毒感染和恶性肿瘤有着浓厚的兴趣，但人们对这些疗法如何影响B细胞功能或宿主对细菌的防御知之甚少。这项研究旨在探索：1)抑制PD-1功能如何影响对PPS-3的抗体反应的数量、持久性和保护能力，2)PD-1调节对当前肺炎球菌疫苗中不同类型PPS的抗体反应的程度，以及3)B细胞特异性PD-1表达在调节PPS抗体反应中所起的作用。最后，由于PD-1仅在小鼠TI-2抗原免疫后抗原特异性B-1b细胞上显著诱导表达，我们将探索B-1样细胞对非人类灵长类动物(非洲绿猴；AGM)的TI-2抗体反应的功能贡献，以及PD-1类似地调节这些细胞的可能性。这些探索性研究的结果将证明PD-1调节通路在产生对肺炎链球菌的保护性体液免疫中的重要性，并将揭示B细胞特异性PD-1表达在这一过程中的重要性。最后，该项目将进一步发展AGM作为一种替代的非人类灵长类动物模型，在该模型中评估B细胞亚群和有助于调节针对PPS和其他临床相关的TI-2抗原的抗体反应的因素。最终，这些研究可能导致PD-1疗法在提高以PPS为基础的肺炎链球菌疫苗的有效性方面的新应用。 公共卫生相关性：目前申请中提出的这项研究的目标是了解免疫系统是如何调节以应对肺炎链球菌疫苗的。从这些研究中获得的知识可能导致改进的疫苗，以加强对目前威胁全球公共卫生的肺炎球菌感染的保护。