Alum's adjuvanticity

明矾的佐剂作用

• 批准号: 7949067
• 负责人: YAN SHI
• 金额: $ 13.5万
• 依托单位: UNIVERSITY OF CALGARY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7949067
• 关键词: Activation Analysis; Address; Adjuvant; Adjuvanticity; Aluminum; Antigen-Presenting Cells; Antigens; Atomic Force Microscopy; Binding; Biological Assay; CD8B1 gene; Cell Communication; Cell Surface Receptors; Cell surface; Cells; Cellular Membrane; Cholesterol; Comprehension; Dendritic Cells; Dendritic cell activation; Disease; Event; FDA approved; Fluorescence; General Population; Goals; Grant; Health; Human; Immune; Immune Cell Activation; Immune response; Immune system; Immunization; Inflammation; Inflammatory; Investigation; Knockout Mice; Label; Latex Bead; Lead; Ligands; Lipids; Mediating; Membrane; Membrane Lipids; Membrane Microdomains; Methods; Mononuclear; Outcome; Particulate; Pathway interactions; Personal Satisfaction; Poliomyelitis; Population; Prophylactic treatment; Proteins; Radio; Recruitment Activity; Regulation; Research; Salts; Signal Pathway; Signal Transduction; Signaling Molecule; Solid; Sorting - Cell Movement; Structure; Surface; T cell response; Techniques; Time; Tissues; Uric Acid; Vaccination; Vaccines; Work; aluminum sulfate; arthropathies; base; cytokine; design; human SYK protein; immune activation; immune function; immunogenicity; in vivo; innovation; monocyte; novel; novel vaccines; population based; public health relevance; receptor; research study; response; tool; vaccine development

DESCRIPTION (provided by applicant): Protein based receptor ligand interactions are universally regarded as the initiating point of immune activation. However, it is questionable if it is applicable to immune recognition of solid structures. Binding of particulate antigens by antigen presenting cells (APC) is a critical step in immune activation. Previously, we demonstrated that uric acid 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 crystals can directly engage cellular membranes, particularly the cholesterol components, 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 arthropathies, inflammation and adjuvanticity. In this proposal, we extend our work to study how alum interacts with the immune system and to reveal if such a lipid based mechanism is applicable in alum's adjuvanticity. We will also study the association between cell surface lipid sorting and Nalp3 inflammasome activation, a critical step in uric acid crystal mediated cell activation. We will further study a set of immune activation events unrelated to inflammasome regulation in order to establish a complete picture of alum's immune regulating capacities. The outcome of this work will impact vaccine development and our understanding of crystal related diseases. PUBLIC HEALTH RELEVANCE: This project deals with the basic mechanism for the immune recognition of alum. It has high relevance in the vaccine development and crystal related diseases. Its outcomes will lead to better understanding of the immune system and suggest new methods for population based immunizations.

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，它是否适用于固体结构的免疫识别是值得怀疑的。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。此前，我们证明尿酸晶体是有效的佐剂，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晶体可以直接接合细胞膜，特别是胆固醇成分，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，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，并且为晶体相关的关节病、炎症和佐剂性提供了可检验的假设。在这项提案中，我们将工作扩展到研究明矾如何与免疫系统相互作用，并揭示这种基于脂质的机制是否适用于明矾的佐剂作用。我们还将研究细胞表面脂质分选与 Nalp3 炎性体激活之间的关联，Nalp3 炎性体激活是尿酸晶体介导的细胞激活的关键步骤。我们将进一步研究一组与炎症小体调节无关的免疫激活事件，以便全面了解明矾的免疫调节能力。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。 公共健康相关性：该项目涉及明矾免疫识别的基本机制。它在疫苗开发和晶体相关疾病方面具有高度相关性。其结果将有助于更好地了解免疫系统，并为基于人群的免疫接种提出新方法。