Unique Surface Structures on Synovial Cells

滑膜细胞独特的表面结构

• 批准号: 6738962
• 负责人: David Alan Fox
• 金额: $ 28.76万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6738962
• 关键词: CD antigens; T lymphocyte; apoptosis; biomarker; cell adhesion molecules; cell cell interaction; cell morphology; clinical research; cytokine; disease /disorder model; fibroblasts; gene expression; human subject; human tissue; leukocyte activation /transformation; microarray technology; monoclonal antibody; patient oriented research; rheumatoid arthritis; synovial membrane

DESCRIPTION (provided by the applicant): In rheumatoid arthritis (RA) inflammation and ultimate destruction of articular structures are accompanied by extensive infiltration of synovium by T lymphocytes and macrophages, and hyperplasia of synovial fibroblasts (SF). The role of T lymphocytes remains controversial, with no conclusive proof for T cell directed autoimmunity as the cause of RA. We have taken several approaches to better understand pathways of T cell activation and of the role of T cells in RA, including generation of monoclonal antibodies to novel T cell surface antigens, and ligands of surface structures important for T cell activation, including ligands expressed on SF. In addition we have developed evidence that T cells, even resting T cells, can interact with SF in a bi-directional manner. Thus SF can function as potent accessory cells for T cell activation, while resting T cells can stimulate a proinflammatory pattern of gene expression in SF, even in the absence of stimuli that activate the T cell. We have termed this ability of unactivated T lymphocytes to stimulate the SF "effector function of resting T cells." We now propose that a significant component of the aggressive behavior of SF in RA arises from direct interactions between T cells and RA SF. We also hypothesize that the molecular basis for this unusual and pathogenic program of cell differentiation arises from a unique immunologic synapse formed between the T lymphocyte and the SF. The current proposal would further analyze the molecular interactions between T cells and SF and the functional consequences of these interactions, using both morphologic and immunologic approaches. A novel ligand of CD6 expressed by SF will be molecularly characterized and functionally studied. New antibodies will be generated to analyze the T cell/SF microarray analysis of SF gene expression, and quantitative interaction, directed at both known and novel cell surface molecules and at the secreted CD26-related cell interaction molecule attractin. Activation of SF will be studied using measurement of relevant RNA species and protein products, such as osteoclast differentiation factor, cytokines, and tissue destructive proteases. The proposed studies represent a fresh approach to understanding RA.

描述（由申请人提供）：类风湿性关节炎（RA） 伴随着炎症和关节结构的最终破坏 T淋巴细胞和巨噬细胞对滑膜的广泛浸润，以及 滑膜成纤维细胞（SF）增生。 T淋巴细胞的作用仍然存在 有争议，没有确凿的证据证明 T 细胞定向的自身免疫 RA 的病因。我们采取了多种方法来更好地了解 T 细胞激活以及 T 细胞在 RA 中的作用，包括生成 针对新型 T 细胞表面抗原及其表面配体的单克隆抗体 对 T 细胞激活很重要的结构，包括 SF 上表达的配体。 此外，我们还发现证据表明 T 细胞，甚至是静息 T 细胞，可以 与 SF 进行双向交互。因此 SF 可以起到有效的作用 辅助细胞用于 T 细胞激活，而静息 T 细胞可以刺激 SF 中的促炎基因表达模式，即使不存在 激活 T 细胞的刺激。我们将这种能力称为未激活的 T 淋巴细胞刺激 SF“静息 T 细胞的效应功能”。我们现在 提出 RA 中 SF 攻击行为的一个重要组成部分 产生于 T 细胞和 RA SF 之间的直接相互作用。我们还假设 这种不寻常的致病性细胞程序的分子基础 分化源于 T 细胞之间形成的独特免疫突触 淋巴细胞和 SF。目前的提案将进一步分析分子 T 细胞和 SF 之间的相互作用以及这些相互作用的功能后果 相互作用，使用形态学和免疫学方法。一种新型配体 SF 表达的 CD6 将进行分子特征和功能分析 研究过。将产生新的抗体来分析 T 细胞/SF 微阵列 SF 基因表达和定量相互作用分析，针对两者 已知和新颖的细胞表面分子以及分泌的 CD26 相关细胞 相互作用分子吸引素。将使用以下方法研究 SF 的激活 相关RNA种类和蛋白质产物的测量，例如破骨细胞 分化因子、细胞因子和组织破坏性蛋白酶。这 拟议的研究代表了理解 RA 的一种新方法。