LYMPHOTOXIN AND LYMPHOID NEOGENESIS

淋巴毒素和淋巴新生

• 批准号: 6748471
• 负责人: Nancy H. Ruddle
• 金额: $ 31.8万
• 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 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6748471
• 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。需要检验的假设是，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)的淋巴器官的过程相似，这些淋巴器官具有共同的功能，即递呈和对抗原的反应。在朗格汉斯胰岛、肾脏和皮肤中组成性表达LTalpha的大鼠胰岛素启动子(RIPLT小鼠)控制下的LTalpha转基因小鼠在转基因表达部位出现炎症，在黏附分子、趋化因子和细胞成分的表达方面具有许多淋巴器官的特征。一些细胞(MAdCAM-1、SLC和BLC)是由LTalpha3介导的，而另一些(Pnad；L-选择素高细胞)也需要LTalphaβ。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诱导肠系膜和外周性LN，LTalphabeta诱导外周性LN。RIPLT小鼠是一种独特的试剂，它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.同时表达LTalpha和LTalphabeta是否会导致具有外周淋巴结特征的新生？将分析转RIPLTalpha和RIPLTβ基因的小鼠的浸润液中Pnad和L-选择素、趋化因子、DC和FDC的表达。2.LT诱导的浸润物与功能淋巴器官有多相似？将评估浸润物呈递内源性(Y-Ae)和外源性抗原并对其做出反应的能力。3.LTalpha和LTβ在淋巴新生动力学中的单独作用是什么？维持淋巴器官是否需要维持LT的产生？表达LTalpha和/或LTbeta的RIP特异性和可诱导系统将被开发，随意打开和关闭，并对淋巴新生进行评估。4.LT诱导的NFkappaB活化在淋巴器官发生中的作用是什么？RIPLT小鼠将与表达超抑制物Ikappabpha的小鼠杂交，并评估其对淋巴系新生的影响。这些研究将提供有关细胞因子诱导炎症的机制的信息，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部位新的淋巴器官的建立，深入了解决定子扩散的过程和重要性。