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

基本信息

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
项目类别：
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

项目摘要

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

项目概要/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。重要的候选疫苗，因为它们位于细菌的最外层表面，并且具有独特的特性这两个特征使它们易于被免疫系统识别和识别。监视，因此导致 B 细胞产生 CPS 特异性抗体以诱导 CPS-。特异性适应性免疫反应（即 T 细胞介导的 B 细胞反应），CPS 与载体缀合由于对蛋白质的了解不够，其结合产物被称为糖结合疫苗。由于其免疫激活机制，目前的糖复合物疫苗策略已达到饱和，很大程度上是对过去经验共轭方法的修改。糖复合物疫苗基于反复试验，不利用特定的科学知识最大限度地刺激参与产生保护性 IgG 的关键免疫细胞（即辅助 T 细胞）鉴于碳水化合物疫苗研究的潜力，我们非常需要新的视角。建立一个新的范式，我们之前的发现和初步数据表明，哺乳动物 CD4+ T 细胞库包含识别糖复合物碳水化合物表位的 T 细胞群在我们之前的机械工作的基础上，我们建议建立一个平台来开发疫苗，称为 Tcarbs。设计和开发结构明确的糖复合物疫苗，并针对其免疫原性和该提案还提出了持续有效地诱导保护性免疫的抗原成分。控制结合疫苗免疫原性的另一个关键参数是识别免疫原性。糖复合物疫苗免疫诱导的保护的相关性在临床实践中得到改善。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性我们建议，保护是实现可靠预测临床疗效的一个重要里程碑。确定对疫苗功效至关重要的关键辅助 T 细胞群，作为疫苗的新免疫相关因素利用两种高致病性肺炎链球菌 (Spn) 血清型 — Spn3 的 CPS 和 Spn14——并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和广泛适用的结合疫苗平台并表征由此产生的免疫反应通过两个具体目标开发疫苗。目标 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的多肽链组成目标 2：分离人类 Tcarb 克隆并对其进行功能表征，了解其诱导保护性体液免疫的能力