Lymphotoxin and Lymphoid Neogenesis

淋巴毒素和淋巴新生

• 批准号: 7655268
• 负责人: Nancy H. Ruddle
• 金额: $ 33.25万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7655268
• 关键词: Acute; Autoimmunity; B-Lymphocytes; Characteristics; Chronic; Development; Fluorescence; Genes; Goals; Growth; High Endothelial Venule; Immunization; Inflammation; Insulin-Dependent Diabetes Mellitus; LacZ Genes; Ligands; Lymphangiogenesis; Lymphatic vessel; Lymphoid; Magnetic Resonance Imaging; Maintenance; Mus; Organ; PNAd; Phenotype; Recovery; Regulation; Role; Signal Transduction; Staging; System; Testing; Tetracyclines; Time; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-Beta; density; inhibitor/antagonist; macrophage; novel; sulfotransferase

DESCRIPTION (provided by applicant): The goal of this project is to understand lymphoid organ development and function in ontogeny and inflammation. Directed over expression of lymphotoxin (LT) (either LTa or LTab) results in ectopic lymphoid aggregates with the characteristics of lymphoid organs. These "tertiary lymphoid organs" (TLOs) are also seen in many situations of chronic inflammation in autoimmunity, including the early stages of insulin dependent diabetes mellitus (IDDM). High endothelial venule (HEV) genes are regulated in development, in TLOs, and in acute inflammation. The mature HEV phenotype, characterized by expression of PNAd, LTbR, and a HEV suIfotransferase (HEC-6ST) depends on signaling through the LTbR in normal and HEC6ST- lacZ mice. After immunization, HEVs revert transiently to an immature phenotype and then recover. The recovery is dependent on B cells and LTbR. Lymphangiogenesis also occurs in TLOs and in acute inflammation. At early times after immunization, the occurrence of vessels that are positive for both LV and HEV markers is dependent on LTbR. Results with a novel bimodal dendrimer that visualizes lymphatic vessels by magnetic resonance imaging (MRI) and fluorescence suggest that mice deficient in LT have defective LVs. It is not known how LT contributes to lymphangiogenesis. Two hypotheses will be tested. Hypothesis I. Lymphatic vessels are regulated by LT in inflammation and development; Hypothesis II. Continual signaling through LT is necessary for maintenance and function of lymphoid organs particularly in respect to HEVs and LVs. The specific aims are to: 1. Determine how HEVs and LVs are regulated in acute inflammation by determining if B cells produce the LT ligand that regulates HEVs and LVs, by evaluating the role of macrophages in lymphangiogenesis, and by determining if the double positive vessels represent LVs budding from HEVs; 2. Determine how HEVs and LVs are regulated in chronic inflammation by evaluating vessel phenotype, density, and function, the role of macrophages, and LTbR and TNFR signaling; 3. Determine if and how LT influences constitutive LVs by evaluating LV function and phenotype 4. Determine if continual LT signaling is necessary to maintain HEVs and LVs in TLOs by treatment with LTbR and TNFR inhibitors and by turning LT on and off with a tetracycline inducible system. Elucidation of HEV and LV regulation will provide strategies for their inhibition in autoimmunity and allow control of insulitis.

描述（由申请人提供）：该项目的目标是了解淋巴器官的发育以及个体发育和炎症中的功能。淋巴毒素 (LT)（LTa 或 LTab）的定向过度表达会导致具有淋巴器官特征的异位淋巴聚集体。这些“三级淋巴器官”（TLO）也见于许多自身免疫性慢性炎症的情况，包括胰岛素依赖型糖尿病（IDDM）的早期阶段。高内皮微静脉 (HEV) 基因在发育、TLO 和急性炎症中受到调节。成熟的 HEV 表型以 PNAd、LTbR 和 HEV 磺基转移酶 (HEC-6ST) 的表达为特征，依赖于正常小鼠和 HEC6ST-lacZ 小鼠中通过 LTbR 的信号传导。免疫后，HEV 暂时恢复到不成熟的表型，然后恢复。恢复取决于 B 细胞和 LTbR。淋巴管生成也发生在 TLO 和急性炎症中。在免疫后早期，LV 和 HEV 标记物均呈阳性的血管的出现取决于 LTbR。一种新型双峰树枝状聚合物通过磁共振成像 (MRI) 和荧光可视化淋巴管，结果表明缺乏 LT 的小鼠的左心室有缺陷。目前尚不清楚 LT 如何促进淋巴管生成。将测试两个假设。假设一：淋巴管在炎症和发育过程中受LT调节；假设二。通过 LT 的持续信号对于淋巴器官的维持和功能是必要的，特别是在 HEV 和 LV 方面。具体目标是： 1. 通过确定 B 细胞是否产生调节 HEV 和 LV 的 LT 配体、评估巨噬细胞在淋巴管生成中的作用以及确定双阳性血管是否产生急性炎症，确定 HEV 和 LV 是如何调节的代表从 HEV 发展而来的 LV； 2. 通过评估血管表型、密度和功能、巨噬细胞的作用以及 LTbR 和 TNFR 信号传导，确定 HEV 和 LV 在慢性炎症中的调节方式； 3. 通过评估 LV 功能和表型，确定 LT 是否以及如何影响组成性 LV 4. 通过用 LTbR 和 TNFR 抑制剂治疗以及用四环素诱导剂打开和关闭 LT，确定是否需要持续的 LT 信号传导以维持 TLO 中的 HEV 和 LV系统。 HEV 和 LV 调节的阐明将为抑制自身免疫并控制胰岛素炎提供策略。