BLC AND BLR1 AND IMMUNE FUNCTION AND DYSFUNCTION

BLC 和 BLR1 与免疫功能和功能障碍

• 批准号: 6632078
• 负责人: Jason G Cyster
• 金额: $ 20.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6632078
• 关键词: B lymphocyte; T lymphocyte; cell differentiation; cell migration; chemokine; cytokine receptors; disease /disorder model; gene targeting; genetically modified animals; green fluorescent proteins; inflammation; laboratory mouse; leukocyte activation /transformation; macrophage; pancreatic islet disorder; receptor expression; tissue /cell culture

Chemokines are well characterized as small chemotactic cytokines that recruit cells from the blood to sites of infection. Recent studies have uncovered a role for chemokines in cell trafficking through lymphoid tissues. In mice deficient in Burkitt's Lymphoma Receptor 1 (BLR1/CXC- R5), B cell follicles fail to form in spleen and Peyer's patches and inguinal lymph nodes do not develop. B-Lymphocyte Chemoattractant (BLC/BCA1), the only known ligand for BLR1, is expressed by follicular stromal cells in these tissues. How BLR1 and BLC function to organize cells in follicles is not understood. The long-term objective of this propose is to define the contribution of BLR1/BLC to cell migration and organization in both lymphoid and non-lymphoid tissues. The first of three aims seeks to determine if changes in BLR1 expression or BLC responsiveness contribute to the changes in B cell tropism that occur upon activation and differentiation. Similar studies will also be performed on T cells since T cell migration into follicles is essential for germinal center reactions and may also permit access to antigen trapped on follicular dendritic cells such as HIV in patients with AIDS. Aim 1 will also test if a splice variant of BLR1 in human macrophages is expressed in the mouse and will determine the BLC responsiveness of macrophage subsets. In Aim 2 the mouse BLC gene will be inactivated by gene targeting. BLC-deficient mice are important for reestablishing the role of BLC in follicular compartmentalization of B cells, for determining whether BLC is the only ligand for BLR1 and for characterizing whether BLC has functions in addition to a role in cell homing to follicles. The targeting construct will also introduce the green fluorescent protein gene (GFP) into the BLC locus to permit characterization of BLC expressing cells. In patients suffering chronic inflammatory diseases such as rheumatoid arthritis and diabetes, there are often large accumulations of B cells in the affected tissue. The third aim will explore whether BLC is expressed at sites of chronic inflammation in mouse models and, using the gene targeted mice, test to what extent BLC contributes to the inflammation. This aim will also test the effect of BLC expression to an ectopic site (the pancreatic islets) using a transgenic approach both to determine whether BLC is sufficient to promote follicle formation and to establish a system where the relationship between B cell accumulation and pathology can be studied.

趋化因子被很好地描述为小的趋化细胞因子 从血液中招募细胞到感染部位。最近的研究表明 发现趋化因子在细胞通过淋巴系统运输中的作用 纸巾。在Burkitt淋巴瘤受体1(BLR1/CXC-1)缺陷小鼠中 R5)，B细胞滤泡不能在脾和Peyer‘s斑内形成， 腹股沟淋巴结不发育。B淋巴细胞趋化因子 (BLC/BCA1)是唯一已知的BLR1的配体，在卵泡中表达 这些组织中的基质细胞。BLR1和BLC如何进行组织 卵泡中的细胞还不清楚。这样做的长期目标是 建议定义BLR1/BLC对细胞迁移和 淋巴组织和非淋巴组织中的组织。第一个 三个目标试图确定BLR1表达或BLC的变化 反应性有助于B细胞趋向性的改变 在激活和分化时。类似的研究也将在 对T细胞进行手术，因为T细胞迁移到毛囊是必不可少的 用于生发中心反应，也可以允许访问抗原 艾滋病患者体内的滤泡树突状细胞，如HIV。 AIM 1还将测试人类巨噬细胞中BLR1的剪接变体是否 在小鼠中表达，并将确定BLC对 巨噬细胞亚群。在Aim 2中，小鼠BLC基因将通过以下方式失活 基因打靶。BLC缺陷小鼠对于重建 BLC在B细胞卵泡区域化中的作用 确定BLC是否是BLR1和For的唯一配体 表征BLC是否除了在细胞中的作用外还具有功能 归巢到毛囊。目标构造还将引入 绿色荧光蛋白基因(GFP)进入BLC基因座的许可 表达BLC的细胞的特性。在患有慢性疾病的患者中 炎症性疾病，如类风湿性关节炎和糖尿病 通常是在受影响的组织中大量积累B细胞。这个 第三个目标将探索BLC是否在慢性粒细胞白血病的部位表达 小鼠模型中的炎症，并使用该基因靶向的小鼠，测试 BLC在多大程度上促进了炎症。这一目标也将考验 BLC表达对异位胰岛的影响 使用转基因方法来确定BLC是否足够 促进卵泡的形成，并建立一种制度， 可以研究B细胞积聚与病理的关系。