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: 9056974
• 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/9056974
• 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; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Development; Disease; Encapsulated; Enhancing Antibodies; Functional disorder; Future; Generations; Goals; Health; 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; PDCD1LG1 gene; 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; 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（由适用提供）：与所有其他可预防疫苗预防的疾病相比，Neumoniae链球菌杀死了更多的人，全世界每年有160万人死亡。当前在成年人中使用的天然肺炎球菌疫苗由衍生自23种不同血清型的囊囊多糖（PPS）组成，因此提供了针对侵入性疾病的广泛覆盖范围。但是，随着抗体滴度的减少，保护最终会减少，通常在疫苗接种后10年。不幸的是，PPS的提升不会引起召回反应。这是大多数多糖（PS）抗原的典型代表。鉴于对肺炎球菌感染的保护有可能减少，这是一个重大问题。与幼儿观察到的相反，PPS蛋白结合疫苗不会有效地提高或产生与成人本地PPS的优越滴度。这是结合疫苗的高成本和有限的血清型覆盖范围，这表明需要采取替代策略来提高PPS疫苗效率。为了改善天然PS疫苗，必须对防止PS特异性抗体回忆反应的因素进行机械理解。我们的数据支持记忆B细胞是根据PS抗原产生的，但是当感染或重新捕获后抗原会产生抗原时，它们在很大程度上没有反应。抗原特异性IgG可以通过抑制PS特异性IgM召回响应来发挥作用。但是，我们的数据支持抑制的其他机制，不仅有助于IgM受损，而且有助于IgG促进PS抗原。在此提案中，我们将检验以下假设：受体介导的免疫抑制的主动机制限制了PS特异性记忆B细胞的产生和对二级抗原相遇的功能反应性。此外，我们将检验以下假设：通过Toll样（TLR）提供的强烈“危险”信号 和C型讲座受体（CLR）可以克服这种抑制。在AIM 1中，我们将研究B7：CD28超家族抑制受体和配体的B细胞中的和 - 超级角色的作用，以抑制PS特异性记忆B细胞形成和效应子功能。在AIM 2中，我们将研究PS特异性抗体抑制增强的机制。在AIM 3中，我们将研究TLR4/RP105和Mincle激动剂协同促进PS特异性记忆B细胞的产生和功能响应能力的程度。我们将研究实现这一目标的机制，包括这些激动剂在目标1和2中所检查的抑制途径的程度。这些研究的完成有望提供有关负责抑制对天然PS的二级抗体反应的机制的重要知识，以及使用TLR和CLR基于基于Clr的辅助组合的可行性，以使这种耐蜂蜜的含量固定效果。预计我们的结果将对使用本机PS的主要促进策略以及更实惠，高效的基于PS的疫苗的使用具有重大影响，并具有最高的血清型覆盖范围。