Lymphotoxin and Lymphoid Neogenesis

淋巴毒素和淋巴新生

• 批准号: 7215306
• 负责人: Nancy H. Ruddle
• 金额: $ 8.24万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215306
• 关键词: antigen presentation; autoimmunity; developmental immunology; genetically modified animals; high endothelial venule; histogenesis; inflammation; laboratory mouse; lymphatic circulation; tumor necrosis factor beta

DESCRIPTION (provided by applicant): The goal of these studies is to gain an understanding of lymphoid organ development and function in embryonic development and in chronic inflammation. Simultaneous expression of LTa and LTb results in the formation of ectopic lymphoid aggregates with the characteristics of lymphoid organs arising through a process termed lymphoid organ neogenesis. These "tertiary lymphoid organs" (TLOs) are seen in autoimmunity, including the early stages of insulin dependent diabetes mellitus (IDDM). TLOs provide information about autoimmunity and serve as models of normal lymphoid development. Studies with transgenic and knock out mice and spontaneous models of autoimmunity have identified the crucial and differential roles of cytokines LTa and the LTab complex in regulation of inflammation and lymphoid organ development, particularly high endothelial venules (HEVs). This renewal application will continue to elucidate the regulation of HEVs and lymphatic vessels (LVs). HEV genes are regulated in development, in TLOs, and in acute inflammation. The mature HEV phenotype depends on signaling through the LTb receptor. Peripheral lymph node HEVs revert transiently to an immature phenotype and permanently if lymphatic vessels are severed, suggesting a requirement for "lymphatic factors" during their maintenance. Thus understanding LV regulation is a crucial aspect of understanding HEV regulation. Several hypotheses will be tested. Hypothesis I. TLOs represent sites of antigen presentation, with LVs and HEVs, and are valid models to study lymphoid organ development. Hypothesis II. Lymphatic vessels are regulated by the LT family and are initiators of lymphoid organs. Hypothesis III. Continual signaling through TNFR and/or LTbR is necessary for maintenance and function of lymphoid organs and HEVs and LVs. The specific aims to test these hypotheses are to: 1. Determine whether the LT induced TLO is a valid model of lymphoid organogenesis. 2. Determine how HEVs and LVs are regulated. 3. Determine if LT is necessary and sufficient for lymphangiogenesis. 4. Determine if continual LT signaling is necessary to maintain HEVs and lymphatic vessel function. These studies are important as they elucidate specific aspects of LN development. Understanding HEV and LV regulation could provide useful strategies for inhibiting TLOs in autoimmunity.

描述（由申请方提供）：这些研究的目的是了解胚胎发育和慢性炎症中淋巴器官的发育和功能。LTa和LTb的同时表达导致异位淋巴聚集体的形成，其具有通过称为淋巴器官新生的过程产生的淋巴器官的特征。这些“三级淋巴器官”（TLO）见于自身免疫，包括胰岛素依赖型糖尿病（IDDM）的早期阶段。TLO提供关于自身免疫的信息，并作为正常淋巴发育的模型。用转基因和敲除小鼠和自发性自身免疫模型的研究已经确定了细胞因子LTa和LTab复合物在炎症和淋巴器官发育（特别是高内皮小静脉（HEV））的调节中的关键和不同作用。该更新申请将继续阐明HEV和淋巴管（LV）的调节。HEV基因在发育、TLO和急性炎症中受到调控。成熟的HEV表型依赖于通过LTb受体的信号传导。外周淋巴结HEV短暂恢复为不成熟表型，如果淋巴管被切断则永久恢复，这表明在其维持期间需要“淋巴因子”。因此，理解LV调节是理解HEV调节的关键方面。几个假设将被测试。假设一TLO代表抗原呈递位点，具有LV和HEV，并且是研究淋巴器官发育的有效模型。假设二。淋巴管由LT家族调节，是淋巴器官的起始者。假设三。通过TNFR和/或LTbR的持续信号传导对于淋巴器官和HEV和LV的维持和功能是必需的。检验这些假设的具体目的是：1。确定LT诱导的TLO是否是淋巴器官发生的有效模型。2.确定HEV和LV是如何调节的。3.确定LT是否是淋巴管生成的必要和充分条件。4.确定是否需要持续的LT信号来维持HEV和淋巴管功能。这些研究很重要，因为它们阐明了LN发展的具体方面。了解HEV和LV的调节可以为抑制自身免疫中的TLO提供有用的策略。