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。 要检验的假说是，LT/TNF细胞因子在个体发育（二次淋巴机构）（淋巴器官发生）和炎症（第三型淋巴机器人器官）（淋巴样新生）（淋巴机新发生）（淋巴样新生）（淋巴样）（淋巴样）（淋巴样）（淋巴样）和这些反应型溶剂的功能相似的过程相似。小鼠在大鼠胰岛素启动子（RIPLT小鼠）控制下的小鼠转基因，在兰格汉（Langerhans）的胰岛（肾脏和皮肤）在转基因表达的部位表现出炎症，这些表达具有许多特征，这些特征是淋巴机构的表达与粘合分子的表达相对于粘合剂的表达，并且在化合物中表现出炎症。 某些（MADCAM-1，SLC和BLC）由ltalpha3介导，而另一些（PNAD； L-亚纤维蛋白HI细胞）也需要ltalphabeta。 这些数据以及来自细胞因子或其受体缺陷的小鼠的其他数据表明，ltalpha诱导肠系膜和周围LN和LTALPHABETA诱导周围LN。 RIPLT小鼠是一种独特的试剂，它为研究机制，动力学和分子要求提供了可访问的系统，对淋巴机器发生，将用于回答以下问题：1。同时表达ltalpha和ltalphabeta，导致新生殖，导致新生发生的特征，并导致外周淋巴结的特征？ 将分析用于RIPLTALPHA和RIPLTBETA的小鼠转基因的浸润，以表达PNAD和L-选择素，趋化因子，DC和FDC的表达。 2。LT诱导的浸润液的精确程度类似于功能性淋巴器官？将评估浸润物出现和响应内源性（Y-AE）和外源性抗原的能力。 3。ltalpha和ltbeta在淋巴新生殖动力学中的个体作用是什么？ 是否需要维持LT生产才能维持淋巴器官？ 将开发表达LTALPHA和/或LTBETA的RIP特异性和诱导系统，并随意打开和关闭，并评估淋巴样新生殖。 4。LT诱导的NFKAPPAB激活在淋巴器官发生中的作用是什么？ RIPLT小鼠将与表达超抑制剂Ikappabalpha的小鼠交叉，并评估了对淋巴新生殖的影响。这些研究将提供有关细胞因子诱导的炎症机制的信息，并确定疾病中治疗剂的靶标，并通过阐明在炎症自身免疫性疾病的局部部位建立新的淋巴机器人的疾病的过程和重要性。