Lymphotoxin and Lymphoid Neogenesis

描述(申请人提供)：这些研究的目标是了解淋巴器官在胚胎发育和慢性炎症中的发育和功能。LTA和LTB的同时表达导致异位淋巴聚集体的形成，具有淋巴器官的特征，这一过程被称为淋巴器官新生。这些“第三淋巴器官”(TLO)见于自身免疫，包括早期的胰岛素依赖型糖尿病(IDDM)。TLOS提供了有关自身免疫的信息，可作为正常淋巴发育的模型。对转基因和敲除小鼠的研究以及自发的自身免疫模型已经证实，细胞因子LTA和LTab复合体在调节炎症和淋巴器官发育，特别是高内皮微静脉(HEV)方面发挥着关键和不同的作用。这一续期申请将继续阐明HEV和淋巴管(LV)的监管。HEV基因在发育、TLO和急性炎症中受到调节。成熟的HEV表型依赖于通过LTB受体的信号传递。如果淋巴管被切断，外周淋巴结HEV会暂时恢复到未成熟的表型，并永久恢复，这表明在它们的维护过程中需要“淋巴因素”。因此，了解LV调节是理解HEV调节的关键方面。几个假说将会得到检验。假设一、TLO代表抗原提呈部位，有LV和HEV，是研究淋巴器官发育的有效模型。假设II：淋巴管由LT家族调节，是淋巴器官的始发者。假设III：通过TNFR和/或LTbR的持续信号对于淋巴器官、HEV和LV的维持和功能是必要的。验证这些假说的具体目的是：1.确定LT诱导的TLO是否是一种有效的淋巴器官发生模型。2.确定如何监管HEV和LV。3.确定LT对淋巴管生成是否必要和充分。4.确定维持HEV和淋巴管功能是否需要持续的LT信号。这些研究很重要，因为它们阐明了LN发展的特定方面。了解HEV和LV的调控可以为抑制自身免疫中的TLO提供有用的策略。

DESCRIPTION (provided by applicant): The goal of these studies is to gain an understanding of lymphoid organ development and function in embryonic development and in chronic inflammation. Simultaneous expression of LTa and LTb results in the formation of ectopic lymphoid aggregates with the characteristics of lymphoid organs arising through a process termed lymphoid organ neogenesis. These "tertiary lymphoid organs" (TLOs) are seen in autoimmunity, including the early stages of insulin dependent diabetes mellitus (IDDM). TLOs provide information about autoimmunity and serve as models of normal lymphoid development. Studies with transgenic and knock out mice and spontaneous models of autoimmunity have identified the crucial and differential roles of cytokines LTa and the LTab complex in regulation of inflammation and lymphoid organ development, particularly high endothelial venules (HEVs). This renewal application will continue to elucidate the regulation of HEVs and lymphatic vessels (LVs). HEV genes are regulated in development, in TLOs, and in acute inflammation. The mature HEV phenotype depends on signaling through the LTb receptor. Peripheral lymph node HEVs revert transiently to an immature phenotype and permanently if lymphatic vessels are severed, suggesting a requirement for "lymphatic factors" during their maintenance. Thus understanding LV regulation is a crucial aspect of understanding HEV regulation. Several hypotheses will be tested. Hypothesis I. TLOs represent sites of antigen presentation, with LVs and HEVs, and are valid models to study lymphoid organ development. Hypothesis II. Lymphatic vessels are regulated by the LT family and are initiators of lymphoid organs. Hypothesis III. Continual signaling through TNFR and/or LTbR is necessary for maintenance and function of lymphoid organs and HEVs and LVs. The specific aims to test these hypotheses are to: 1. Determine whether the LT induced TLO is a valid model of lymphoid organogenesis. 2. Determine how HEVs and LVs are regulated. 3. Determine if LT is necessary and sufficient for lymphangiogenesis. 4. Determine if continual LT signaling is necessary to maintain HEVs and lymphatic vessel function. These studies are important as they elucidate specific aspects of LN development. Understanding HEV and LV regulation could provide useful strategies for inhibiting TLOs in autoimmunity.