Dendritic Cell Function in Early Allergic Sensitization

描述(由申请人提供)：先天免疫系统的细胞，抗原提呈细胞(APC)，对于启动幼稚和记忆T细胞对抗原的反应都是关键的。树突状细胞(DC)是APC中功能最强的，它决定了T细胞与抗原相遇的结果是耐受还是免疫。幼稚状态下，DC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，用于监测肺部环境。这个项目的目标是描述出生前和出生后的抗原呈递环境，重点是确定决定早期接触变应原是否会导致T细胞敏化或耐受的因素。他们的想法是，在某些情况下，T细胞敏化可能发生在子宫或出生后早期，导致这些情况的因素在过去20年里有所增加。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，扭转疾病的逐渐增加。在生命早期接触抗原是否会在二次接触同一抗原时导致致敏或耐受，目前仍存在争议，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树突状细胞，因为它们引导T细胞对抗原的反应贯穿一生，可能包括出生前和出生后，其长期后果将在本申请中提出的研究中定义。此外，我们还将确定母体通过转移某些免疫球蛋白亚型和抗原而产生的免疫反应如何影响树突状细胞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，这将使我们能够评估抗原注射的途径、抗原暴露的时间和环境如何决定DC功能，最终导致T细胞在早期生命中的敏感性或耐受性。识别这一过程中的关键因素将增加利用DC作为治疗性免疫调节器改变疾病结果的可能性，或在为易感个体设计疫苗接种策略时使用。为此，我们建议：目的1.测定出生前后树突状细胞提呈抗原和启动T细胞反应的能力。目的2.确定母源免疫复合体在出生前和出生后对树突状细胞功能的作用。目的3.探讨围产期抗原提呈对长期T细胞免疫功能的影响。

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.