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

项目总结/摘要 大多数病原菌表达称为荚膜多糖（CPS）的表面碳水化合物。CPS是 重要的疫苗候选物，因为它们位于细菌的最外表面，并且具有不同的 结构.这两个特征使它们很容易被免疫系统访问和识别。 监视，因此导致B细胞产生CPS特异性抗体。诱导CPS- 特异性适应性免疫应答（即，T细胞介导的B细胞应答），CPS与载体缀合 蛋白质，并且缀合产物被称为糖缀合物疫苗。由于对 由于其免疫激活机制，目前的糖缀合物疫苗策略已达到饱和， 主要是对过去经验共轭方法的修改。当前一代的生产 糖缀合物疫苗是基于试验和错误，不利用特定的科学知识， 使关键免疫细胞的刺激最大化（即，辅助性T细胞）参与产生保护性IgG 抗体的我们迫切需要一个新的视角来研究碳水化合物疫苗。发生可能 建立一个新的范例，我们以前的发现和初步数据表明，哺乳动物 CD 4 + T细胞库包含识别糖缀合物的碳水化合物表位的T细胞群 称为Tcarbs的疫苗。在我们以前的机制工作的基础上，我们建议建立一个平台， 设计和开发结构确定的糖缀合物疫苗，优化其免疫原性， 抗原组分以持续有效地引发保护性免疫。该提案还涉及 控制偶联疫苗免疫原性的另一个关键参数是鉴定免疫原性。 与糖缀合物疫苗免疫诱导的保护相关。在临床实践中， 测量CPS特异性抗体滴度和体外调理吞噬活性作为免疫相关物， 保护是实现可靠的临床疗效预测的重要里程碑。我们建议 鉴定对疫苗效力至关重要的关键辅助性T细胞群，作为新的免疫相关物， 保护从两种高致病性肺炎链球菌（Spn）血清型Spn 3中开发CPS 和Spn 14-在我们已发表和未发表的初步研究的基础上，我们将建立一个新的， 广泛适用缀合疫苗平台和表征由这些产生的免疫应答 疫苗有两个具体目标。目的1：建立基于知识的结合疫苗平台 由与CPS化学酶结合的内溶酶体可裂解多肽链组成。目标二： 分离人Tcarb克隆并对其诱导保护性体液免疫的能力进行功能表征