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: 8820783
• 负责人: Karen M Haas
• 金额: $ 25.9万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8820783
• 关键词: Adjuvant; Adult; Agonist; Antibodies; Antibody Formation; Antibody-Producing Cells; Antigens; B Cell Proliferation; B-Lymphocytes; Bacteria; C Type Lectin Receptors; CD28 gene; CD80 gene; CTLA4 gene; Cessation of life; Child; Conjugate Vaccines; Data; Defect; Disease; Encapsulated; Enhancing Antibodies; Functional disorder; Future; Generations; Goals; Health; Immune response; Immune system; Immunization; Immunosuppression; In Vitro; Infection; Knowledge; Lead; Life; Ligands; Mediating; Memory; Memory B-Lymphocyte; Pathway interactions; Pattern recognition receptor; Pneumococcal Infections; Pneumococcal vaccine; Pneumovax; Polysaccharides; Polyvalent pneumococcal vaccine; Problem Solving; Proteins; Public Health; Publishing; Receptor Signaling; Regulation; Regulatory Pathway; Research; Role; Secondary to; Serotyping; Signal Transduction; Streptococcus pneumoniae; TLR4 gene; Testing; Trehalose; Vaccination; Vaccines; base; cell type; cost; design; improved; killings; member; monophosphoryl lipid A; pathogen; prevent; receptor; response; vaccine efficacy

DESCRIPTION (provided by applicant): Streptococcus pneumoniae kills more people in the U.S. than all other vaccine-preventable diseases combined and is estimated to cause 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-immunization. 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. Our data also suggest that select adjuvant combinations may overcome this defect and enable successful boosting. In this proposal, we will test the hypothesis that active mechanisms of immune suppression limit Ps-specific memory B cell generation and functional responsiveness to secondary antigen encounter. In addition, we will test the hypothesis that "danger" signals supplied through toll-like (TLR) and C-type lectin receptors (CLR) can overcome this suppression. In Aim 1, we will specifically 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 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 effects of B7:CD28 superfamily receptors. Completion of these studies is expected to provide us with 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超过所有其他疫苗可预防疾病的总和，估计每年在全球造成160多万人死亡。目前用于成人的天然肺炎球菌疫苗由来自23种不同血清型的荚膜多糖（PPS）组成，因此可广泛覆盖侵袭性疾病。然而，随着抗体滴度的降低，保护作用最终会减弱，通常在免疫后10年。不幸的是，PPS提升并不能诱导回忆反应。这是大多数多糖（Ps）抗原的典型特征。考虑到对肺炎球菌感染的保护可能减少，这是一个重大问题。与在幼儿中观察到的情况相反，PPS-蛋白缀合物疫苗在成人中不能有效地增强或产生比天然PPS更上级的滴度。沿着结合疫苗的高成本和有限的血清型覆盖，这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，必须对阻止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细胞产生的Ps抗原的反应，但它们在很大程度上是无反应的抗原感染或再接种后再次遇到。我们的数据还表明，选择佐剂组合可以克服这一缺陷，并使成功的加强。在这个建议中，我们将测试的假设，即免疫抑制的主动机制限制PS-特异性记忆B细胞的产生和功能性反应的第二抗原遇到。此外，我们将测试的假设，即“危险”信号提供通过Toll样（TLR）和C型凝集素受体（TLR）可以克服这种抑制。在目的1中，我们将专门研究B7：CD 28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。在目的2中，我们将检查TLR 4/RP 105和Mincle激动剂协同促进Ps特异性记忆B细胞生成和加强期间的功能应答的程度。我们将研究实现这一目标的机制，包括这些激动剂克服B7：CD 28超家族受体抑制作用的程度。这些研究的完成预计将为我们提供关键知识的机制，负责抑制二抗反应的天然Ps，以及使用TLR和CLR为基础的佐剂组合，以克服这一障碍，有效的疫苗接种的可行性。我们的研究结果预计将有一个显着的影响，使用初免-加强策略，采用本地Ps，以及未来的设计更实惠，更有效的Ps为基础的疫苗，尽可能高的血清型覆盖率。