Dendritic Cell Function in Early Allergic Sensitization

描述（由申请人提供）：先天免疫系统的细胞，抗原呈递细胞（APCs），对于启动初始和记忆T细胞对抗原的反应至关重要。树突状细胞（dc）是apc中最有能力的，它决定了T细胞与抗原相遇的结果是耐受还是免疫。在初始状态下，树突状细胞广泛分布于淋巴和非淋巴器官。例如，呼吸道包含一个广泛的dc网络来监测肺部环境。该项目的目标是表征产前和产后生活中的抗原呈递环境，重点是确定决定早期暴露于过敏原是否诱导T细胞致敏或耐受的因素。人们认为，在某些情况下，T细胞敏化可能发生在子宫内或产后早期，而导致这些情况的因素在过去20年中有所增加。有人提出，这可以解释哮喘和其他炎症性疾病发病率增加的原因。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来逆转疾病的逐渐增加。早期暴露于抗原是否会导致二次暴露于相同抗原后的致敏或耐受性存在争议，导致这些终生免疫变化的细胞类型及其作用机制仍有待确定。我们的研究将集中于dc，因为它们指导T细胞对抗原的整个生命反应，可能包括产前和产后，其长期后果将在本申请中提出的研究中定义。此外，我们将定义母体免疫反应如何通过母体转移某些Ig同种型和抗原影响dc的功能能力和后代免疫反应的发展。我们已经建立了小鼠模型，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，最终导致早期T细胞致敏或耐受。确定这一过程中的关键因素将增加使用dc作为治疗性免疫调节剂来改变疾病结局的可能性，或在易感个体的疫苗接种策略设计中。为此，我们建议：AIM 1。在产前和产后确定树突状细胞呈递抗原和启动T细胞反应的能力。目标2。确定母源性免疫复合物在产前和产后树突状细胞功能中的作用。目标3。确定围产期抗原呈递对长期T细胞免疫的影响。

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.