Regulation of Memory B Cell Responses to Polysaccharide Antigens

记忆 B 细胞对多糖抗原反应的调节

• 批准号: 8944119
• 负责人: Karen M Haas
• 金额: $ 38.44万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8944119
• 关键词: Adjuvant; Adult; Agonist; Antibodies; Antibody Formation; Antibody Response; Antigens; B-Lymphocytes; Bacteria; Binding; C Type Lectin Receptors; CD22 gene; CD28 gene; CD80 gene; CTLA4 gene; Carbohydrates; Cell division; Cells; Cessation of life; Child; Communicable Diseases; Complement; Complex; Conjugate Vaccines; Data; Development; Disease; Encapsulated; Enhancing Antibodies; Functional disorder; Future; Generations; Goals; Immune system; Immunization; Immunoglobulin G; Immunoglobulin M; Immunoglobulin-Secreting Cells; Immunoglobulins; Immunosuppression; Individual; Infection; Knowledge; Lead; Lectin; Lectin Receptors; Ligands; Link; Lipid A; Mediating; Memory; Memory B-Lymphocyte; Modification; Pathway interactions; Pattern recognition receptor; Play; Pneumococcal Infections; Pneumococcal vaccine; Pneumovax; Polysaccharides; Polyvalent pneumococcal vaccine; Problem Solving; Proteins; Public Health; Regulation; Regulatory Pathway; Research; Research Personnel; Role; Secondary Immunization; Secondary to; Serotyping; Sialic Acids; Signal Transduction; Streptococcus; Streptococcus pneumoniae; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; TLR4 gene; Testing; Time; Toll-like receptors; Trehalose; Ursidae Family; Vaccination; Vaccines; Work; base; cancer therapy; cost; design; improved; killings; prevent; public health relevance; receptor; response; sialic acid receptor; sialylation; trafficking; vaccine efficacy

 DESCRIPTION (provided by applicant): Streptococcus neumoniae kills more people in the U.S. than all other vaccine-preventable diseases combined and causes over 1.6 million deaths/year worldwide. The native pneumococcal vaccine currently used in adults consists of capsular polysaccharides (PPS) derived from 23 different serotypes and therefore provides broad coverage against invasive disease. Nonetheless, protection eventually wanes as antibody titers diminish, typically by 10 years post-vaccination. Unfortunately, PPS boosting does not induce recall responses. This is typical of most polysaccharide (Ps) antigens. This is a significant concern given the potential for diminished protection against pneumococcal infections. PPS-protein conjugate vaccines do not effectively boost or yield superior titers to native PPS in adults, in contrast to what is observed in young children. This, along with the high cost and limited serotype coverage of conjugate vaccines, suggests that alternative strategies are needed to enhance PPS vaccine efficacy. To improve native Ps vaccines, it is imperative to develop a mechanistic understanding of the factors preventing Ps-specific antibody recall responses. Our data supports that memory B cells are generated in response to Ps antigens but that they are largely unresponsive when antigen is re- encountered following infection or revaccination. Antigen-specific IgG may play a part by suppressing Ps- specific IgM recall responses. However, our data supports additional mechanisms of suppression contribute to not only to impaired IgM, but IgG, boosting to Ps antigens. In this proposal, we will test the hypothesis that active mechanisms of receptor-mediated immune suppression limit Ps-specific memory B cell generation and functional responsiveness to secondary antigen encounter. In addition, we will test the hypothesis that strong "danger" signals supplied through toll-like (TLR) and C-type lectin receptors (CLR) can overcome this suppression. In Aim 1, we will examine the B cell-intrinsic and -extrinsic roles for B7:CD28 superfamily inhibitory receptors and ligands in suppressing Ps-specific memory B cell formation and effector function. In Aim 2, we will investigate mechanisms by which Ps-specific antibody suppresses boosting. In Aim 3, we will examine the extent to which TLR4/RP105 and Mincle agonists synergize to promote Ps-specific memory B cell generation and functional responsiveness during boosting. We will examine the mechanisms by which this is achieved, including the extent to which these agonists overcome the inhibitory pathways examined in Aims 1 and 2. Completion of these studies is expected to provide critical knowledge regarding the mechanisms responsible for suppressed secondary antibody responses to native Ps as well as the feasibility of using TLR and CLR-based adjuvant combinations to overcome this barrier to effective vaccination. Our results are expected to have a significant impact on the use of prime-boost strategies employing native Ps, as well as the future design of more affordable and efficacious Ps-based vaccines with the highest possible serotype coverage.

 描述（由申请人提供）：肺炎链球菌在美国造成的死亡人数比所有其他疫苗可预防疾病的总和还要多，并且每年在全球造成超过 160 万人死亡。目前用于成人的天然肺炎球菌疫苗由源自 23 种不同血清型的荚膜多糖 (PPS) 组成，因此可广泛预防侵袭性疾病。尽管如此，随着抗体滴度的降低，保护作用最终会减弱，通常是在疫苗接种后 10 年。不幸的是，PPS 增强不会引起回忆反应。这是大多数多糖 (Ps) 抗原的典型特征。鉴于对肺炎球菌感染的保护作用可能减弱，这是一个重大问题。与幼儿中观察到的情况相反，PPS-蛋白结合疫苗在成人中不能有效增强或产生优于天然 PPS 的滴度。再加上结合疫苗的高成本和有限的血清型覆盖率，表明需要替代策略来增强 PPS 疫苗的功效。为了改进天然 Ps 疫苗，必须从机制上了解阻止 Ps 特异性抗体回忆反应的因素。我们的数据支持记忆 B 细胞是响应 Ps 抗原而产生的，但当感染或重新接种疫苗后再次遇到抗原时，它们基本上没有反应。抗原特异性 IgG 可能通过抑制 Ps 特异性 IgM 回忆反应发挥作用。然而，我们的数据支持其他抑制机制不仅会导致 IgM 受损，还会导致 IgG 受损，从而增强 Ps 抗原。在本提案中，我们将测试以下假设：受体介导的免疫抑制的主动机制限制 Ps 特异性记忆 B 细胞的生成和对二次抗原相遇的功能反应。此外，我们将测试通过收费类（TLR）提供强“危险”信号的假设 而C型凝集素受体（CLR）可以克服这种抑制。在目标 1 中，我们将检查 B7:CD28 超家族抑制性受体和配体在抑制 Ps 特异性记忆 B 细胞形成和效应器功能中的 B 细胞内在和外在作用。在目标 2 中，我们将研究 Ps 特异性抗体抑制增强的机制。在目标 3 中，我们将研究 TLR4/RP105 和 Mincle 激动剂在增强过程中协同促进 Ps 特异性记忆 B 细胞生成和功能反应的程度。我们将研究实现这一目标的机制，包括这些激动剂克服目标 1 和 2 中检查的抑制途径的程度。这些研究的完成预计将提供有关抑制二抗对天然 Ps 反应的机制的关键知识，以及使用基于 TLR 和 CLR 的佐剂组合来克服有效疫苗接种障碍的可行性。我们的结果预计将对采用天然 Ps 的初免-加强策略的使用，以及未来设计更实惠、更有效、具有最高可能血清型覆盖率的 Ps 疫苗产生重大影响。