Lymphotoxin and Lymphoid Neogenesis

淋巴毒素和淋巴新生

基本信息

批准号：
7998877
负责人：
Nancy H. Ruddle
金额：
$ 4.86万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-15 至 2010-03-31
项目状态：
已结题

项目摘要

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）：该项目的目的是了解淋巴器官的发育和功能。指向淋巴毒素（LT）（LTA或LTAB）的表达导致异位淋巴聚集体具有淋巴机器人的特征。这些“三级淋巴器官”（TLOS）在自身免疫性的许多慢性炎症中也可以看到，包括胰岛素依赖性糖尿病的早期阶段（IDDM）。高内皮静脉（HEV）基因在发育，TLO和急性炎症中受到调节。成熟的HEV表型，其特征在于PNAD，LTBR和HEV链纤维转移酶（HEC-6ST）的表达取决于正常和HEC6ST-LACZ小鼠中通过LTBR信号传导。免疫后，HEV会瞬时恢复到未成熟的表型，然后恢复。恢复取决于B细胞和LTBR。 TLO和急性炎症也发生淋巴管生成。在免疫后的早期，LV和HEV标记呈阳性的血管的发生取决于LTBR。通过磁共振成像（MRI）和荧光可视化淋巴管的新型双峰树状聚合物的结果表明，缺乏LT的小鼠的LV有缺陷。尚不清楚LT如何促进淋巴管生成。将检验两个假设。假设I.淋巴管受炎症和发育中的LT调节。假设II。通过LT的持续信号传导对于淋巴器官的维持和功能是必要的，尤其是在HEV和LVS方面。具体目的是：1。通过确定B细胞是否产生调节HEV和LVS的LT配体在急性炎症中如何调节HEV和LV，通过评估巨噬细胞在淋巴管生成中的作用，并确定双阳性容器是否代表HEVS的LVS芽; 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信号传导来确定如何在慢性炎症中调节HEV和LV。 3.通过评估LV功能和表型4来确定LT是否和如何通过通过使用LTBR和TNFR抑制剂处理以及通过使用四环素可诱导系统的LTBR和TNFR抑制剂处理LT和OFF，确定是否需要连续的LT信号传导来维持TLOS中的HEV和LV。阐明HEV和LV调节将为抑制自身免疫性提供策略，并允许控制胰岛炎。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lymphocyte traffic in lymphoid organ neogenesis: differential roles of Ltalpha and LTalphabeta.

淋巴器官新生中的淋巴细胞运输：Ltα 和 LTαβ 的不同作用。

DOI：
发表时间：
2002
期刊：
Advances in experimental medicine and biology
影响因子：
0
作者：
Drayton,DanielleL;Chan,Kee;Lesslauer,Werner;Lee,Jason;Ying,XiaoYan;Ruddle,NancyH
通讯作者：
Ruddle,NancyH

Identification of a new stromal cell type involved in the regulation of inflamed B cell follicles.

DOI：
10.1371/journal.pbio.1001672
发表时间：
2013-10
期刊：
PLoS biology
影响因子：
9.8
作者：
Mionnet C;Mondor I;Jorquera A;Loosveld M;Maurizio J;Arcangeli ML;Ruddle NH;Nowak J;Aurrand-Lions M;Luche H;Bajénoff M
通讯作者：
Bajénoff M

Ectopic LT alpha beta directs lymphoid organ neogenesis with concomitant expression of peripheral node addressin and a HEV-restricted sulfotransferase.