Adjuvants' mechanisms

佐剂作用机制

基本信息

批准号：
8428568
负责人：
YAN SHI
金额：
$ 19.58万
依托单位：
UNIVERSITY OF CALGARY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8428568
关键词：
Activation Analysis Address Adjuvant Adjuvanticity Affect Affinity Air Pollution Antibody Formation Antigen Presentation Antigen-Presenting Cells Antigens Atomic Force Microscopy Automobile Driving Binding Biological Assay Categories Cell Surface Receptors Cell membrane Cell surface Cells Cellular Membrane Critical Pathways Cytotoxic T-Lymphocytes Dendritic Cells Dendritic cell activation Disease Drug Delivery Systems Event Histocompatibility Antigens Class I Human ITAM Immune Immune Cell Activation Immune response Implant Inflammation Inflammatory Response Lead Learning Ligands Link Lipid Binding Lipids Lung Inflammation MAPK14 gene MHC Class I Genes Mediating Membrane Membrane Lipids Membrane Microdomains Molecular Outcome Particulate Pathway interactions Phagocytosis Production Proteins Regulation Reporting Research Role Science Selection for Treatments Signal Pathway Signal Transduction Signaling Molecule Solid Sorting - Cell Movement Structure T cell response Time Urate Uric Acid Vaccine Design Work aluminum sulfate antigen processing base human SYK protein immune activation implant material insight macrophage particle receptor response tool vaccine development

项目摘要

DESCRIPTION (provided by applicant): Protein based receptor ligand interactions are universally regarded as the initiating point of immune activation. However, it is questionable if i is applicable to immune recognition of solid structures. This issue is particularly relevant in vaccine design as some of the best known adjuvants are solid crystals, such as alum and monosodium urate. Binding of particulate antigens by antigen presenting cells (APC) is a critical step in immune activation. It has been demonstrated that uric acid and alum crystals are potent adjuvants, initiating a robust adaptive immune response. However, the mechanisms of activation are unknown. Using atomic force microscopy as a tool for real time single cell activation analysis, we have collected evidence that uric acid and alum crystals can directly engage cellular membranes, with a force substantially stronger than protein based cellular contacts. Binding of particulate substances activates Syk kinase-dependent signaling in dendritic cells (DCs). These observations suggest a mechanism whereby immune cell activation can be triggered by solid structures via membrane lipid alteration without the requirement for specific cell surface receptors, and a testable hypothesis for crystal-associated inflammation and adjuvanticity. In this proposal, we extend the findings to study the signaling mechanisms involved, particularly the association between cell surface lipid sorting and downstream signal transduction, critical steps in crystal mediated immune activation, as well as how this mechanism affects antigen presentation. The outcome of this work will impact vaccine development and our understanding of crystal related diseases.

描述（由申请人提供）：基于蛋白质的受体配体相互作用被普遍认为是免疫激活的起始点。然而，i是否适用于固体结构的免疫识别是值得怀疑的。这个问题在疫苗设计中尤其重要，因为一些最著名的佐剂是固体晶体，例如明矾和尿酸钠。抗原呈递细胞 (APC) 与颗粒抗原的结合是免疫激活的关键步骤。已证明尿酸和明矾晶体是有效的佐剂，可引发强大的适应性免疫反应。然而，激活机制尚不清楚。使用原子力显微镜作为实时单细胞激活分析的工具，我们收集了证据表明尿酸和明矾晶体可以直接接合细胞膜，其作用力比基于蛋白质的细胞接触强得多。颗粒物质的结合激活树突状细胞 (DC) 中的 Syk 激酶依赖性信号传导。这些观察结果表明了一种机制，即固体结构可以通过膜脂改变来触发免疫细胞激活，而不需要特定的细胞表面受体，以及晶体相关炎症和佐剂性的可检验假设。在本提案中，我们将研究结果扩展到研究所涉及的信号传导机制，特别是细胞表面脂质分选与下游信号转导之间的关联、晶体介导的免疫激活的关键步骤，以及该机制如何影响抗原呈递。这项工作的结果将影响疫苗的开发和我们对晶体相关疾病的理解。