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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

基本信息

批准号：
8263369
负责人：
Karen M Haas
金额：
$ 18.5万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-15 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8263369
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 public health relevance receptor response selective expression small molecule

项目摘要

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（由申请方提供）：本提案的目的是评价阻断PD-1免疫抑制受体及其配体之间的相互作用作为增强对肺炎链球菌荚膜中发现的肺炎球菌多糖（PPS）的保护性抗体应答的策略的可行性。S.肺炎继续构成全球威胁，并且是儿童发病率和死亡率的主要原因之一。PPS疫苗在成人中提供针对特定型侵袭性肺炎球菌疾病的显著保护，但对非侵袭性疾病的有效性较低，并且在非常年轻、老年和免疫功能低下的人群中刺激保护性抗体应答较差。了解PPS的保护性抗体反应是如何调节的，是设计更有效疫苗的关键。PPS通常引发T细胞非依赖性2型（TI-2）抗体应答，其与对蛋白抗原的抗体应答不同地被调节。我们以前发现，一个独特的B细胞亚群，称为B-1 B细胞，是产生抗体的关键3型PPS（PPS-3）和其他TI-2抗原的小鼠。我们的初步数据显示，抗原特异性B-1 B细胞在TI-2抗原免疫后上调免疫抑制受体PD-1，并且阻断PD-1与其配体相互作用显著增加了针对TI-2 Ag（包括PPS-3）的IgG应答。尽管人们对开发PD-1相关生物制剂和小分子抑制剂用于治疗慢性病毒感染和恶性肿瘤非常感兴趣，但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。本提案中的研究旨在探索：1）抑制PD-1功能如何影响PPS-3抗体应答的数量、持续性和保护能力，2）PD-1调节当前肺炎球菌疫苗中不同类型PPS抗体应答的程度，3）B细胞特异性PD-1表达在调节PPS抗体应答中的作用。最后，由于PD-1表达仅在小鼠中TI-2抗原免疫后在抗原特异性B-1 B b细胞上显著诱导，因此我们将探索B-1样细胞对非人灵长类动物（非洲绿色猴; AGM）中TI-2抗体应答的功能贡献以及PD-1类似调节这些细胞的潜力。这些探索性研究的结果将证明PD-1调节途径对产生对S.本研究将揭示B细胞特异性PD-1表达在小鼠的这一过程中的重要性。最后，该项目将进一步开发AGM作为替代非人灵长类动物模型，以评估B细胞亚群和有助于调节针对PPS和其他临床相关TI-2抗原的抗体应答的因素。最终，这些研究可能会导致PD-1治疗剂在增强PPS疫苗对S.肺炎。公共卫生相关性：本申请中提出的研究目标是了解免疫系统如何被调节以响应针对肺炎链球菌的疫苗。从这些研究中获得的知识可能会导致改进的疫苗，从而增强对目前威胁全球公共卫生的肺炎球菌感染的保护。