ROLE OF ANTIGEN TRANSPORT BY DENDRITIC CELLS IN AGING

树突状细胞抗原运输在衰老中的作用

• 批准号: 3115985
• 负责人: ANDRAS K. SZAKAL
• 金额: $ 13.69万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-30 至 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3115985
• 关键词: B lymphocyte; CD antigens; T lymphocyte; aging; antigen presentation; antigens; athymic mouse; biological transport; cell age; cell differentiation; cell growth regulation; dendritic cells; electron microscopy; endocytosis; genetic strain; immune complex; immunocytochemistry; immunologic memory; in situ hybridization; laboratory mouse; lymph nodes; lymphocyte; monoclonal antibody; phagocytosis; radioimmunoassay; single cell analysis; tissue /cell culture

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.

描述：（改编自申请人摘要）：关键是 抗原转运至滤泡树突状细胞（FDC）， 维持二次抗体应答的细胞事件 随着年龄的增长而变得有缺陷。 FDC树突接受转运的 抗原，成熟并产生iccosomes（免疫复合物包被体）， 将抗原递送至滤泡B细胞用于内吞、加工和 呈递给T细胞。 这一系列事件-“替代方案” 抗原途径”始于传入神经中的转运细胞（ATC）， 淋巴中，并以将抗原递送至滤泡B细胞结束。 的 研究人员将这一途径命名为ATC-FDC-iccosome-B细胞轴， 抗原转运 年龄相关的缺陷导致抗原不完全 运输 萎缩和不成熟的FDC保留很少的抗原， 产生很少的，如果有的话，iccosomes。 这就导致了老年人的缺乏 B记忆（Bm）细胞形成的中心。 临床上，这与 老年人产生二次抗体反应的能力降低 用抗原如破伤风类毒素加强免疫。 抗FDC单克隆抗体的形态学和表型证据 表明ATC是前FDC。 这一点没有得到直接证实。 实验，但它可能是一个受衰老影响的主要过程。 的 因此，研究人员假设，在生长期内，ATC成熟形成FDC， B和T细胞影响。 这是由重建研究提出的 骨髓胸腺B和T细胞 这些工作人员还预测， 微粒体对于B细胞对抗体和/或 BM细胞生产。 研究人员提出了两个具体目标：1） 评估ATC是否自主成熟为FDC或与B和T细胞 帮助;和2）评估B细胞微粒体对抗原摄取的需求， 抗原呈递和抗体形成和Bm细胞的产生。 他们 将在体外和SCID小鼠中研究第一个目标，在无胸腺裸鼠中， 和体外生殖中心。 Szakal博士和他的同事们会用老老鼠 作为抗原转运缺陷的模型，并测试其 ATC、B和T细胞在上述模型中的表现，以阐明 抗原转运机制。 在第二个目标中，他们将测试 老年B细胞在体内呈递体外获得的抗原的能力， B细胞对抗原摄取的微粒体要求。 演示文稿， 抗体形成和Bm细胞产生。 为此，他们将利用 借助单克隆抗体富集的分离的ATC/FDC群体 用于细胞培养、体内细胞转移、抗原呈递、Bm和 放射免疫分析、免疫细胞化学和电子显微镜。