Lamina Propria Antigen Acquisition Pathways and Outcomes

固有层抗原获取途径和结果

• 批准号: 8870277
• 负责人: MARK James MILLER
• 金额: $ 29.54万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8870277
• 关键词: Activities of Daily Living; Antigen Presentation; Antigens; Bacteria; Behavior; CX3CL1 gene; Characteristics; Charge; Chronic; Data; Dendritic Cells; Disease; Drug or chemical Tissue Distribution; Enteral; Epithelial; Epithelium; Equilibrium; Event; Failure; Flow Cytometry; Homeostasis; Imaging technology; Immune response; Immune system; Immunity; Immunohistochemistry; In Vitro; Infection; Infection Control; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intestines; Knowledge; Laboratories; Lamina Propria; Life; Lymphocyte; Microscopy; Modeling; Mucous Membrane; Mus; Outcome; Pathway interactions; Phenotype; Population; Principal Investigator; Production; Reporter; Research; Rest; Role; Shapes; Small Intestines; Structure of aggregated lymphoid follicle of small intestine; Surface; T-Lymphocyte; Vaccine Therapy; Villus; Viral Tumor Antigens; behavioral response; cell mediated immune response; cell motility; chemokine; food antigen; improved; in vivo; killings; migration; mucosal vaccine; novel; pathogen; pathogenic bacteria; prevent; response; trafficking; two-photon

DESCRIPTION (provided by applicant): The intestinal immune system is charged with the difficult task of protecting a large environmentally exposed surface from potential pathogens, while simultaneously preventing inflammatory responses to innocuous foreign antigen from food and commensal microbiota. Failure to appropriately protect the mucosa can result in life-threatening enteric infection, and failure to control intestinal immune responses results in chronic debilitating disorders such as inflammatory bowel disease. Recent studies determined that the lamina propria (LP) DC population is primarily comprised of dichotomous (CD103+ tolerogenic or CX3CR1 + inflammatory) DCs. This discovery suggests that the balance between tolerance and immunity rests upon which LP DC subtype participates in the immune responses. However a key and missing component is in vivo knowledge of which LP DC subtypes acquire antigen, the anatomical and cellular context of the each LP DC subtypes' interactions with T cells and microbiota, and the outcomes of these interactions on the character of the cellular immune response. The studies outlined in this proposal will harness the complementary expertise of two laboratories to examine the pathways guiding the delivery of pathogenic and non-pathogenic antigens to LP DCs and the outcomes associated with antigen acquisition by LP DC subtypes. The proposed studies make extensive use of cutting-edge two-photon imaging technology to analyze the trafficking and function of DCs and T cells in the intestine of living mice. The overarching hypothesis of this proposal is that antigen acquisition pathways guide immune responses by delivering antigen to specific LP DC subtypes. The studies in Aim 1 will use complimentary in vivo and in vitro approaches to examine the pathways delivering antigen to LP DC subtypes in the uninfected and infected state. Aim 2 will evaluate LP DC subtype specific responses in the presence and absence of infection. Aim 3 will evaluate the capacity of the LP DC subtypes to shape pre- existing T cell mediated immune responses locally within the intestinal lamina propria. Completion of these studies will put forth a new paradigm demonstrating that antigen acquisition pathways are a controlled proximal mechanism guiding immune response toward tolerance or immunity. RELEVANCE: The intestinal immune system must protect us from a wide array of potential pathogens and simultaneously avoid over-exuberant responses resulting in chronic intestinal inflammation. This study will investigate a novel mechanism for maintaining the balance between immunity and tolerance and will offer new avenues to pursue for improved mucosal vaccine therapy and chronic intestinal inflammation.

描述（由申请人提供）：肠道免疫系统负责保护大型环境暴露的表面免受潜在病原体的影响，同时防止对食物和共生微生物的炎症反应。无法适当保护粘膜会导致威胁生命的肠道感染，而无法控制肠道免疫反应会导致长期衰弱的疾病，例如炎症性肠病。最近的研究确定，固有层（LP）DC种群主要由二分法（CD103 +耐受性或CX3CR1 +炎症性）DC组成。这一发现表明，耐受性和免疫之间的平衡取决于LP DC亚型参与免疫反应。但是，关键和缺失的成分是在体内知识，LP DC亚型获得抗原，抗原是每个LP DC亚型与T细胞和微生物群的相互作用的解剖和细胞上下文，以及这些相互作用在细胞免疫反应的特征上的结果。 该提案中概述的研究将利用两个实验室的互补专业知识，以检查指导致病性和非致病性抗原向LP DC的递送的途径，以及与LP DC亚型抗原获取相关的结果。拟议的研究广泛使用了尖端的两光子成像技术，以分析活小鼠肠中DC和T细胞的运输和功能。该提案的总体假设是抗原采集途径通过将抗原传递到特定的LP DC亚型来指导免疫反应。 AIM 1中的研究将使用免费体内和体外方法来检查在未感染和感染状态下向LP DC亚型传递抗原的途径。 AIM 2将在存在和不存在感染的情况下评估LP DC亚型特异性反应。 AIM 3将评估LP DC亚型的能力，以塑造现有的T细胞介导的免疫反应，肠道层次的局部局部免疫反应。这些研究的完成将提出一个新的范式，证明抗原采集途径是指导免疫反应对耐受性或免疫力的受控近端机制。 相关性：肠道免疫系统必须保护我们免受广泛的潜在病原体的影响，并同时避免过度发达反应，从而导致慢性肠炎。这项研究将调查一种保持免疫力和耐受性之间平衡的新型机制，并将为改善粘膜疫苗疗法和慢性肠炎的新途径提供新的途径。