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 LTalpha3 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细胞因子在个体发育（二级淋巴器官）（淋巴器官发生）和炎症（三级淋巴器官）（淋巴新生）中诱导淋巴器官的过程相似，并且这些淋巴器官具有共同的功能，即对抗原的呈递和反应。在大鼠胰岛素启动子控制下的 LTα 转基因小鼠（RIPLT 小鼠）在朗格汉斯岛、肾脏和皮肤中组成型表达 LTα，在转基因表达位点表现出炎症，该位点具有淋巴器官的许多特征。粘附分子、趋化因子和细胞组成的表达。 一些（MAdCAM-1、SLC 和 BLC）由 LTalpha3 介导，而其他（PNAd；L-选择素 hi 细胞）也需要 LTalphabeta。 这些数据和来自选择性缺乏细胞因子或其受体的小鼠的其他数据表明，LTalpha 诱导肠系膜和外周 LN，LTalphabeta 诱导外周 LN。 RIPLT 小鼠是一种独特的试剂，为研究淋巴器官发生的机制、动力学和分子要求提供了一个可访问的系统，将用于回答以下问题： 1. LTalpha 和 LTalphabeta 的同时表达是否会导致具有以下特征的新生周围淋巴结？ 将分析 RIPLTα 和 RIPLTβ 转基因小鼠的浸润物中 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？将评估浸润物呈递和响应内源性（Y-Ae）和外源性抗原的能力。 3. LTalpha 和 LTbeta 在淋巴新生动力学中各自的作用是什么？ 是否需要持续产生 LT 来维持淋巴器官？ 将开发表达 LTalpha 和/或 LTbeta 的 RIP 特异性和诱导系统，随意打开和关闭，并评估淋巴新生。 4. LT 诱导的 NFkappaB 激活在淋巴器官发生中的作用是什么？ RIPLT 小鼠将与表达超级抑制剂 Ikappabalpha 的小鼠杂交，并评估对淋巴新生的影响。这些研究将提供有关细胞因子诱导炎症机制的信息，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部位新淋巴器官的建立，深入了解决定性扩散的过程和重要性。