Dendritic Cell Function in Early Allergic Sensitization

树突状细胞在早期过敏致敏中的功能

• 批准号: 6944745
• 负责人: Lynn Puddington
• 金额: $ 36.25万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6944745
• 关键词: MHC class II antigen; affinity chromatography; antigen presentation; asthma; cellular immunity; cytotoxic T lymphocyte; dendritic cells; developmental immunology; enzyme linked immunosorbent assay; flow cytometry; genetically modified animals; helper T lymphocyte; immune complex; immune response; immune tolerance /unresponsiveness; immunocytochemistry; immunoglobulin E; immunoglobulin G; laboratory mouse; tetracyclines

DESCRIPTION (provided by applicant): Cells of the innate immune system, antigen-presenting cells (APCs), are critical to the initiation of both naive and memory T cell responses to antigens. Dendritic cells (DCs) are the most competent of the APCs, and it is DCs that dictate whether the outcome of a T cell's encounter with antigen will be tolerance or immunity. In the naive state, DCs are widely distributed in lymphoid and non-lymphoid organs. For example, the respiratory tract contains an extensive network of DCs to monitor the pulmonary environment. The goal of this project is to characterize the antigen-presenting environment in pre- and post-natal life, with the focus on defining factors that dictate whether exposure to allergen in early life induces T cell sensitization or tolerance. The thinking is that in certain circumstances, T cell sensitization can occur in utero or in early post-natal life and that factors responsible for these circumstances have increased in the past 20 years. It has been proposed that this could explain the increased incidence of asthma and other inflammatory diseases. The challenge for scientists is to identify factors that control this process, with the ultimate goal of developing therapeutic strategies to reverse the progressive increase in disease. It is controversial whether exposure to antigen in early life results in sensitization or tolerance upon secondary exposure to the same antigen, and the cell types responsible for these life-long changes in immunity and their mechanisms of action remain to be identified. Our studies will concentrate on DCs as they direct the T cell responses to antigen throughout life, presumably including the pre- and post-natal period, the long term consequences of which will be defined in studies proposed in this application. In addition, we will define how maternal immune responsiveness via maternal transfer of certain Ig isotypes and antigen impacts on the functional capacity of DCs and the development of immune responsiveness in offspring. We have established murine models that will allow us to assess how the route of antigen administration, timing of the antigen exposure, and environment dictate DC function to ultimately result in T cell sensitization or tolerance in early life. Identification of critical factors in this process will enhance the possibility of altering disease outcomes using DCs as therapeutic immunoregulators, or in the design of vaccination strategies for susceptible individuals. To this end, we propose to: AIM 1. Determine the capacity of dendritic cells to present antigen and initiate T cell responses in pre- and post-natal life. AIM 2. Determine the role of maternal-derived immune complexes on dendritic cell function in pre- and post-natal life. AIM 3. Determine the effect of perinatal antigen presentation on long-term T cell immunity.

描述（由申请人提供）：先天免疫系统的细胞，抗原呈递细胞（APC），对于启动对抗原的初始和记忆T细胞应答至关重要。树突状细胞（Dendritic cells，DC）是最有能力的APC，并且它决定T细胞与抗原相遇的结果是耐受还是免疫。在幼稚状态下，DC广泛分布于淋巴和非淋巴器官中。例如，呼吸道包含广泛的DC网络以监测肺环境。该项目的目标是表征产前和产后生活中的抗原呈递环境，重点是定义决定早期接触过敏原是否诱导T细胞致敏或耐受的因素。这种想法是，在某些情况下，T细胞致敏可以发生在子宫内或出生后早期，并且在过去20年中，导致这些情况的因素有所增加。有人提出，这可以解释哮喘和其他炎症性疾病发病率的增加。科学家面临的挑战是确定控制这一过程的因素，最终目标是制定治疗策略，以扭转疾病的逐步增加。在生命早期暴露于抗原是否会导致在二次暴露于相同抗原后的致敏或耐受性是有争议的，并且负责这些免疫力终身变化的细胞类型及其作用机制仍有待确定。我们的研究将集中在DC上，因为它们在整个生命中指导T细胞对抗原的应答，大概包括产前和产后时期，其长期后果将在本申请中提出的研究中定义。此外，我们将确定如何通过母体转移某些IG同种型和抗原的影响，对DC的功能能力和后代的免疫反应性的发展的母体免疫反应。我们已经建立了小鼠模型，这将使我们能够评估抗原给药途径、抗原暴露时间和环境如何决定DC功能，最终导致T细胞致敏或早期耐受。在这个过程中的关键因素的识别将提高使用DC作为治疗性免疫调节剂改变疾病结果的可能性，或在易感个体的疫苗接种策略的设计中。为此，我们建议：目标1。确定树突状细胞在出生前后呈递抗原和启动T细胞应答的能力。AIM 2.确定母亲来源的免疫复合物对出生前和出生后树突状细胞功能的作用。AIM 3.确定围产期抗原呈递对长期T细胞免疫的影响。