Molecular Mechanisms for Carbohydrate Presentation to CD4+ T cells by MHCII Pathway
Molecular Mechanisms for Carbohydrate Presentation to CD4+ T cells by MHCII Pathway
批准号:
9919487
负责人:
Fikri Y Avci
金额:
$37.5万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-06-06 至 2022-09-16
关键词:
APC VaccineAdaptive Immune SystemAdoptive TransferAntibodiesAntigen-Presenting CellsAntigensB-LymphocytesBacteriaBacterial InfectionsBacterial ModelBacterial PolysaccharidesBindingBiologicalBiological AssayCD4 Positive T LymphocytesCarbohydratesCarrier ProteinsCell surfaceCellsCellular StructuresChemicalsChemistryClone CellsCommunicable DiseasesCompetitive BindingComplexComprehensionConjugate VaccinesDataDisaccharidesEpitopesFutureGenerationsGlycoconjugatesHealthHealth BenefitHelper-Inducer T-LymphocyteHistocompatibility Antigens Class IIHumanImmuneImmune responseImmune systemImmunizationImmunoglobulin Class SwitchingImmunoglobulin GImmunologic SurveillanceKnowledgeLibrariesMajor GrooveMass Spectrum AnalysisMeasurementMediatingMethodsModelingModificationMolecularMolecular StructureMusOligosaccharidesPathogenicityPathway interactionsPeptidesPlayPolysaccharidesPopulationProcessProductionPropertyProteinsRoleStreptococcus pneumoniaeStructureSurfaceSurface AntigensSystemT-Cell ReceptorT-LymphocyteT-Lymphocyte EpitopesTCR ActivationTimeVaccine DesignVaccine ResearchVaccinesadaptive immune responsebaseclinical practicecostdepolymerizationdesignexperimental studyhigh risk populationimmune activationimmune system functionimmunogenicinsightknowledge basemimeticsnovelolder patientpathogenic bacteriapeptide Iresponseuptakevaccine candidate
中文摘要
项目摘要/摘要
大多数致病菌表达表面碳水化合物,称为衣壳多糖(CPSS)。CPSS是
重要的候选疫苗,因为它们位于细菌的最外表面,而且它们有
不同的结构。这两个特征使得它们很容易被免疫系统访问和识别
从而导致B细胞产生CPS特异性抗体。诱导CPS特异性
获得性免疫反应(即T细胞介导的B细胞反应),CPSS与载体蛋白偶联,
这种结合产物被称为糖结合疫苗。由于对他们的了解不够
免疫激活机制,目前的糖结合疫苗策略已经达到饱和,并
对过去的经验共轭方法进行了很大的修改。这一代人的生产
糖结合疫苗是基于试验和错误的,不利用特定的科学知识来
最大限度地刺激与产生保护性免疫球蛋白有关的关键免疫细胞(即辅助T细胞)
抗体。以碳水化合物为基础的疫苗研究急需一个新的视角。具有…的潜力
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
CD4T细胞谱系包含一组碳水化合物特异性T细胞(即Tabs),它们识别
碳水化合物表位。在这里,我们建议扩展我们以前的发现,并定义分子
模型糖结合疫苗碳水化合物表位激活Tcarb的机制。在目标1中
这项建议我们将阐明碳水化合物呈递的主要组织相容性的结构要求
抗原提呈细胞(APC)表面或纯化的MHCII蛋白
蛋白质通过相互作用研究。在目标2中,我们将从结构和功能上描述T细胞受体(TCR)
糖链抗原表位的识别。我们相信,我们提出的研究将创造一个新的平台
开发富含Tcarb功能表位的基于知识的糖结合疫苗。使用
Tcarb激活机制和糖链表位结构的发现,我们可以设计和开发
新一代糖结合疫苗将引发强大和持久的免疫反应以保护
不受细菌感染。
英文摘要
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 they have
distinct structures. These two features make them easily accessible and distinctly recognizable by immune
surveillance, therefore resulting in 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 to 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 carbohydrate-specific T cells (i.e., Tcarbs) that recognize
carbohydrate epitopes. Here, we propose to expand on our previous discovery and define the molecular
mechanisms for Tcarb activation by carbohydrate epitopes from a model glycoconjugate vaccine. In Aim 1 of
this proposal we will elucidate structural requirements for carbohydrate presentation by major histocompatibility
complex class II (MHCII) proteins on the surface of antigen presenting cells (APCs) or as purified MHCII
proteins via interaction studies. In Aim 2 we will structurally and functionally characterize T cell receptor (TCR)
recognition of glycan epitopes by Tcarbs. We believe our proposed studies will create a new platform to
develop knowledge-based glycoconjugate vaccines that are enriched for functional Tcarb epitopes. Using the
discovery of Tcarb activation mechanisms and of structures of glycan epitopes, we can design and develop
new-generation glycoconjugate vaccines that will elicit strong and long lasting immune response to protect
from bacterial infections.
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Molecular Mechanisms for Carbohydrate Presentation to CD4+ T cells by MHCII Pathway
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批准号:9285694
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依托单位:
海外基金