Molecular Mechanisms for Carbohydrate Presentation to CD4+ T cells by MHCII Pathway

通过 MHCII 途径将碳水化合物呈递给 CD4 T 细胞的分子机制

• 批准号: 10587072
• 负责人: Fikri Y Avci
• 金额: $ 46.51万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-06 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587072
• 关键词: Address; Affinity; Antibodies; Antibody titer measurement; Antigen-Presenting Cells; Antigens; B-Cell Activation; B-Lymphocytes; Bacteria; Bacterial Infections; Benchmarking; Biological Assay; CD4 Positive T Lymphocytes; Carbohydrates; Carrier Proteins; Cells; Chemicals; Chemistry; Clinical; Communicable Diseases; Complex; Conjugate Vaccines; Coupling; Data; Epitopes; Funding; Future; Generations; Glycoconjugates; Health Benefit; Helper-Inducer T-Lymphocyte; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunization; Immunoglobulin Class Switching; Immunoglobulin G; Immunologic Surveillance; In Vitro; Investigation; Knowledge; Maps; Measures; Mediating; Memory B-Lymphocyte; Methods; Modeling; Modification; Molecular; Mus; Pathogenicity; Pathway interactions; Peptides; Plasma Cells; Polysaccharides; Population; Process; Production; Publishing; Research; Serotyping; Streptococcus pneumoniae; Structure; Surface; Surface Antigens; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; Vaccine Design; Vaccine Research; Vaccines; Work; adaptive immune response; base; clinical efficacy; clinical practice; cost; cross reacting material 197; depolymerization; design; high risk population; immune activation; immunogenic; immunogenicity; improved; in vivo; knowledge base; microorganism; novel; older patient; pathogenic bacteria; polypeptide; response; success; vaccination outcome; vaccine candidate; vaccine development; vaccine efficacy; vaccine immunogenicity; vaccine platform; vaccine strategy

Project Summary/Abstract Most pathogenic bacteria express surface carbohydrates called capsular polysaccharides (CPSs). CPSs are important vaccine candidates given that they are located on the outermost surface of bacteria and have distinct structures. These two features make them easily accessible and distinctly recognizable by immune surveillance, therefore resulting in the production of CPS-specific antibodies by B cells. To induce a CPS- specific adaptive immune response (i.e., T cell-mediated B cell response), CPSs are conjugated with carrier proteins, and the conjugation products are called glycoconjugate vaccines. Due to insufficient understanding of their immune activation mechanisms, current glycoconjugate vaccine strategies have reached saturation and are largely modifications of past empirical conjugation methods. The production of the current generation of glycoconjugate vaccines is based on trial and error and does not make use of specific scientific knowledge to maximize stimulation of critical immune cells (i.e., helper T cells) involved in producing protective IgG antibodies. A new perspective on carbohydrate-based vaccine research is much needed. With the potential of establishing a new paradigm, our previous discovery and preliminary data demonstrate that the mammalian CD4+ T cell repertoire contains a population of T cells that recognize carbohydrate epitopes of glycoconjugate vaccines, called Tcarbs. Building on our previous mechanistic work, we propose establishing a platform to design and develop structurally defined glycoconjugate vaccines optimized for their immunogenic and antigenic components to elicit protective immunity consistently and effectively. This proposal also addresses another key parameter controlling the immunogenicity of conjugate vaccines, which is to identify the immune correlates of protection induced by glycoconjugate vaccine immunization. In clinical practice, improving on measuring CPS-specific antibody titers and the in vitro opsonophagocytic activity as immune correlates of protection is an essential milestone to achieve for the reliable prediction of clinical efficacy. We propose to identify key helper T cell populations that are essential for vaccine efficacy as a new immune correlate of protection. Exploiting CPSs from two highly pathogenic Streptococcus pneumoniae (Spn) serotypes—Spn3 and Spn14—and building on our published and unpublished preliminary studies, we will establish a new and broadly applicable conjugate vaccine platform and characterize immune responses that result from these vaccines through two specific aims. Aim 1: Establish a knowledge-based conjugate vaccine platform composed of endolysosome-cleavable polypeptide chains chemoenzymatically conjugated with CPSs. Aim 2: Isolate and functionally characterize human Tcarb clones for their ability to induce protective humoral immunity

项目摘要/摘要 大多数致病性细菌表达表面碳水化合物称为囊状多糖（CPSS）。 CPS是 重要的候选疫苗鉴于它们位于细菌的最外面，并且具有不同的 结构。这两个功能使它们易于访问，并且可以通过免疫识别出明显的识别 因此，监视，导致B细胞生产CPS特异性抗体。诱导CPS- 特定的适应性免疫响应（即T细胞介导的B细胞反应），CPS与载体结合 蛋白质和共轭产物称为糖缀合物疫苗。由于对 它们的免疫激活机制，当前的糖缀合物疫苗策略已达到满意，并且 是过去经验共轭方法的很大程度上的修改。当前一代的生产 糖缀合疫苗是基于反复试验的，并且不利用特定的科学知识来 最大程度地刺激参与受保护IgG的临界免疫细胞（即辅助T细胞） 抗体。非常需要对基于碳水化的疫苗研究的新观点。有潜力 建立新的范式，我们以前的发现和初步数据表明哺乳动物 CD4+ T细胞库中包含识别糖缀合物的碳氢化表位的T细胞群 疫苗，称为TCARBS。在我们以前的机械工作的基础上，我们建议建立一个平台 设计和开发针对其免疫原性和 抗原成分始终有效地引起保护免疫。该提议也解决了 控制结合疫苗免疫原性的另一个关键参数，这是识别免疫的 糖缀合物疫苗免疫引起的保护相关。在临床实践中，改善 测量CPS特异性抗体滴度和体外调眼吞噬活性作为免疫相关性 保护是实现可靠预测临床效率的重要里程碑。我们建议 确定对疫苗效率至关重要的关键助手T细胞群作为一种新的免疫相关性 保护。从两个高度致病的肺炎链球菌（SPN）血清型-SPN3中利用CPS 和SPN14 - 在我们发表和未发表的初步研究的基础上，我们将建立一个新的和 广泛适用的共轭疫苗平台，并表征由这些平台产生的免疫反应 通过两个具体目标进行疫苗。目标1：建立基于知识的共轭疫苗平台 由内溶性可裂解的多肽链组成的化学酶与CPS结合。目标2： 分离株和功能表征人类TCARB克隆的能力，其能够诱导受保护的体液免疫性史