ROLE OF ANTIGEN TRANSPORT BY DENDRITIC CELLS IN AGING

描述：(改编自申请人的摘要)：至关重要的是 抗原转运至滤泡树突状细胞(FDCs) 维持二次抗体反应的细胞事件 随着年龄的增长而变得有缺陷。接受运输的FDC树枝晶 抗原，成熟并产生冰小体(免疫复合体)， 将抗原运送到滤泡B细胞进行内吞、加工和 呈递给T细胞。这一系列事件--“另一种选择 抗原途径，从传入的运输细胞(ATCs)开始 淋巴，以将抗原输送到滤泡B细胞结束。这个 研究人员将这条通路命名为ATC-FDC-ICCOSome-B细胞轴 抗原运输。与年龄相关的缺陷导致抗原不完整 运输。萎缩和未成熟的FDCs保留的抗原很少， 即使有，也很少产生冰小体。这导致了生发的稀少。 B记忆(BM)细胞形成的中心。在临床上，这与 老年人产生二次抗体反应的能力受抑 用破伤风类毒素等抗原加强免疫。 抗FDC单抗的形态和表型证据 表明ATC是前FDDC。这一点没有得到直接的证实 然而，这可能是一个受衰老影响的主要过程。这个 因此，调查人员假设，ATC在以下条件下成熟为FDDC B细胞和T细胞的影响。这是由重建研究提出的。 骨髓、胸腺、B和T细胞。这些工人还预测， 冰小体对于B细胞对抗体和/或抗原的摄取很重要 BM细胞生产。调查人员提出了两个具体目标：1) 评估ATCs是否自主地或伴随B和T细胞成熟为FDDC 帮助；以及2)评估抗原摄取所需的B细胞胞外体， 抗原提呈、抗体形成和骨髓细胞的产生。他们 将在体外和SCID小鼠身上研究第一个目标，在裸鼠身上， 和体外生发中心。Szakal博士和他的同事将使用老老鼠 作为抗原运输缺陷的模型，并检测其能力 ATC、B和T细胞在上述模型中的表现，以阐明 抗原运输的机制。在第二个目标中，他们将测试 陈旧性B细胞体外提呈体内获得抗原的能力及 B细胞摄取抗原所需的冰小体。演示文稿 抗体的形成和骨髓细胞的产生。为此，他们将使用 利用单抗对ATC/FDC分离群体进行富集化 用于细胞培养、体内细胞转移、抗原呈递、骨髓和 放射免疫分析、免疫细胞化学和电子显微镜检查。

DESCRIPTION: (Adapted from applicant's abstract): It is critical that antigen transport to follicular dendritic cells (FDCs) which initiates cellular events for the maintenance of the secondary antibody response becomes defective with age. FDC dendrites receiving the transported antigen, mature and produce iccosomes (immune complex coated bodies) which deliver the antigen to follicular B cells for endocytosis, processing and presentation to T cells. This sequence of events - the "alternative antigen pathway," begins with the transport cells (ATCs) in the afferent lymph and ends with the delivery of the antigen to follicular B cells. The investigators designated this path the ATC-FDC-iccosome-B cell axis of antigen transport. The age-related defect results in an incomplete antigen transport. The atrophic and immature FDCs retain little antigen and produce few, if any, iccosomes. This results in a paucity of germinal centers where B memory (Bm) cells form. Clinically, this correlates with the depressed ability of the aged to produce a secondary antibody response to booster immunizations with antigens such as tetanus toxoid. Morphological and phenotypic evidence with anti-FDC monoclonal antibodies suggest that ATCs are pre-FDCs. This has not been substantiated by direct experiments, yet it may be a major process affected by aging. The investigators therefore hypothesize that ATCs mature to form FDCs under the influence of B and T cells. This is suggested by reconstitution studies with bone marrow, thymus, B and T cells. These workers also predict that iccosomes are important for antigen uptake by B cells for antibody and/or Bm cell production. The investigators propose two specific aims; 1) to assess whether ATCs mature into FDCs autonomously or with B and T cell help; and 2) to assess B cell iccosome requirements for antigen uptake, antigen presentation and production of antibody forming and Bm cells. They will study the first aim in vitro and in SCID mice, in athymic nude mice, and in vitro germinal centers. Dr. Szakal and coworkers will use old mice as a model of antigen transport deficiency and test the capacity of their ATCs, B and T cells to perform in the above models to elucidate the mechanisms of antigen transport. In the second aim, they will test the ability of old B cells to present in vivo obtained antigen in vitro and the iccosome requirements of B cells for antigen uptake. presentation, antibody forming and Bm cell production. To this end, they will use isolated ATC/FDC populations enriched with the aid of monoclonal antibody for cell culture, in vivo cell transfers, antigen presentation, Bm, and radioimmunoassays, immunocytochemistry and electron microscopy.