LYMPHOTOXIN AND LYMPHOID NEOGENESIS

淋巴毒素和淋巴新生

• 批准号: 6517755
• 负责人: Nancy H. Ruddle
• 金额: $ 31.88万
• 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 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6517755
• 关键词: T lymphocyte; antigen presentation; chemokine; dendritic cells; genetically modified animals; histogenesis; inflammation; laboratory mouse; lymph nodes; nuclear factor kappa beta; selectins; tumor necrosis factor beta

The goal of these studies is to understand the mechanisms and relationships of lymphoid organ development and inflammation as mediated by LTalpha3 and LTalphaB. The hypothesis to be tested is that the processes are similar by which LT/TNF cytokines induce lymphoid organs in ontogeny (secondary lymphoid organs) (lymphoid organogenesis) and inflammation (tertiary lymphoid organs) (lymphoid neogenesis) and that these lymphoid organs have common functions, i.e. presentation and response to antigen. Mice transgenic for LTalpha under the control of the rat insulin promoter (RIPLT mouse) that expresses LTalpha constitutively in the islets of Langerhans, the kidney, and skin, exhibit inflammation at the sites of transgene expression that has many characteristics of lymphoid organs with regard to expression of adhesion molecules, chemokines, and cellular composition. Some (MAdCAM-1, SLC, and BLC) are mediated by LTalpha3, whereas others (PNAd; L-selectin hi cells) require LTalphabeta as well. These data and others from mice selectively deficient in cytokines or their receptors suggest that LTalpha induces mesenteric and peripheral LN and LTalphabeta induces peripheral LN. The RIPLT mouse is a unique reagent that provides an accessible system to study mechanisms, kinetics, and molecular requirements for lymphoid organogenesis which will be used to answer the following questions: 1. Does the simultaneous expression of LTalpha and LTalphabeta result in neogenesis with the characteristics of peripheral lymph nodes? The infiltrates of mice transgenic for RIPLTalpha and RIPLTbeta will be analyzed for expression of PNAd and L-selectin, chemokines, DC, and FDC. 2. How precisely does the LT-induced infiltrate resemble a functional lymphoid organ? The ability of the infiltrates to present and respond to endogenous (Y-Ae) and exogenous antigen will be evaluated. 3. What are the individual roles of LTalpha and LTbeta in the kinetics of lymphoid neogenesis? Does LT production need to be sustained to maintain a lymphoid organ? RIP specific and inducible systems that express LTalpha and/or LTbeta will be developed, turned on and off at will and evaluated for lymphoid neogenesis. 4. What is the role of LT-induced NFkappaB activation in lymphoid organogenesis? RIPLT mice will be crossed with mice expressing a superinhibitor Ikappabalpha and the effect on lymphoid neogenesis evaluated. These studies will provide information regarding the mechanisms of cytokine induced inflammation and identify targets for therapeutics in disease and provide insight into the process and importance of determinant spreading by elucidating the establishment of a new lymphoid organ at the local site in inflammatory autoimmune diseases.

这些研究的目的是了解LTalpha 3和LTalphaB介导的淋巴器官发育和炎症的机制和关系。 待检验的假设是，LT/TNF细胞因子诱导个体发育（次级淋巴器官）（淋巴器官发生）和炎症（三级淋巴器官）（淋巴新生）中淋巴器官的过程相似，并且这些淋巴器官具有共同的功能，即对抗原的呈递和应答。在大鼠胰岛素启动子（在胰岛、肾脏和皮肤中组成型表达LT α）控制下的LT α转基因小鼠（RIPLT小鼠）在转基因表达部位表现出炎症，其在粘附分子、趋化因子和细胞组成的表达方面具有淋巴器官的许多特征。 一些（MAdCAM-1、SLC和BLC）由LTalpha 3介导，而另一些（PNAd; L-选择素hi细胞）也需要LTalpha 3。 这些数据和来自细胞因子或其受体选择性缺陷小鼠的其他数据表明，LT α诱导肠系膜和外周LN，LT α诱导外周LN。 RIPLT小鼠是一种独特的试剂，提供了一个可访问的系统来研究淋巴器官发生的机制、动力学和分子要求，将用于回答以下问题：1. LT α和LT α β的同时表达是否导致具有外周淋巴结特征的新生？ 将分析RIPLT α和RIPLT β转基因小鼠的浸润中PNAd和L-选择素、趋化因子、DC和FDC的表达。 2. LT诱导的浸润与功能性淋巴器官的相似程度如何？将评价浸润细胞呈递和应答内源性（Y-Ae）和外源性抗原的能力。 3. LT α和LT β在淋巴新生动力学中的作用是什么？ 是否需要维持LT的产生以维持淋巴器官？ 将开发表达LT α和/或LT β的RIP特异性和诱导性系统，随意开启和关闭，并评价淋巴新生。 4. LT诱导的NF κ B活化在淋巴器官发生中的作用是什么？将RIPLT小鼠与表达超级抑制剂Ikappab α的小鼠杂交，并评价对淋巴新生的影响。这些研究将提供有关细胞因子诱导的炎症机制的信息，并确定疾病治疗的靶点，并通过阐明炎症性自身免疫性疾病局部新淋巴器官的建立，深入了解决定簇传播的过程和重要性。