ROLE OF CD44 AND CD7 MOLECULES IN MEDIATION OF INFLAMMATORY SYNOVITIS

CD44 和 CD7 分子在调节炎性滑膜炎中的作用

• 批准号: 6348929
• 负责人: Barton F. Haynes
• 金额: $ 21.36万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6348929
• 关键词: CD antigens; CD44 molecule; T cell receptor; T lymphocyte; cell cell interaction; cytokine; genetically modified animals; human T cell lymphotropic virus type 1; human tissue; hyaluronate; hypertrophic osteoarthropathy; immunopathology; interferon gamma; laboratory mouse; monocyte; protein isoforms; rheumatoid arthritis; synovitis; tissue /cell culture

Monocyte-T cell interactions are key events in mediation of pathologic immune responses. The broad objectives of this project are to study roles that T cells and monocytes play in rheumatoid arthritis (RA), by focusing on the roles that CD44 isoforms and CD7 deficient T cells play in the pathogenesis of RA and in animal models of inflammatory synovitis. These objectives will be accomplished by the use of peripheral blood (PB), synovial fluid (SF) and synovial tissue from patients with RA, as well as evaluation of a series of novel CD44 and CD7 deficient mouse strains for their ability to develop synovitis when injected with challenge antigens or when bred to mice susceptible to HTLV-l tax transgenic mouse arthritis. Specific aims for Project l are as follows: l) We will study the roles of cytokines in vivo and in vitro in regulation of hyaluronan (HA) binding to CD44 isoforms on monocytes and other synovial cell types in RA, and in tax transgenic mice and mice with collagen-induced arthritis. Study of the cytokines that regulate HA binding (and therefore HA-induced proinflammatory events) in RA and in animal models of RA-like synovitis are critical to development of novel interventional strategies for treatment of RA. 2) We will define the roles of CD44 isoforms in inflammatory synovitis using: a) total CD44 deficient mice. b) mice selectively deficient only in variant CDT forms (but expressing the standard CD44 form. CD44S), and c) mice only expressing select variant CD44 isoforms. CD44 deficient mice will be studied for their response to antigen-induced arthritis (AIA). and bred on a HTLV-l tax transgenic background to determine the effect of CD44 selective and total deficiencies on arthritis in HTLV- l tax transgenic mice. 3) We will study the roles of CD7 deficient T cells and an altered TCR repertoire in mediation of inflammatory synovitis by isolating CD4+, CD7-, CD28- T cells from RA and OA PBMC. SF and synovial tissue and determining the ability of these T cells to produce IFN-gamma and other cytokines/chemokines in response to T cell activation signals, and by studying CD7 deficient mice, in the presence and absence of abnormal T cell receptor (TCR) repertoires in TCR transgenic mice, for their ability to develop arthritis. Taken together these studies will provide insight into the roles that T cells and monocytes play in inflammatory synovitis. and provide new targets for novel therapeutic interventions in RA.

单核细胞-T细胞相互作用是介导病理性免疫缺陷的关键事件。 免疫反应。该项目的主要目标是研究 T细胞和单核细胞在类风湿性关节炎（RA）中的作用， 关注CD44亚型和CD7缺陷型T细胞的作用 在RA的发病机制和炎症的动物模型中， 滑膜炎这些目标将通过使用 外周血（PB）、滑液（SF）和滑膜组织 RA患者，以及一系列新的CD44和 CD7缺陷型小鼠品系在以下情况下发生滑膜炎的能力： 注射攻击抗原或当与易感 HTLV-ltax转基因小鼠关节炎。项目1的具体目标是 主要内容如下：1）研究细胞因子在体内外的作用 调节透明质酸（HA）与单核细胞上CD44亚型的结合 和其他滑膜细胞类型，以及tax转基因小鼠和 患有胶原性关节炎调节HA的细胞因子的研究 结合（因此HA诱导的促炎事件）在RA和 RA样滑膜炎的动物模型对于开发新的 RA的介入治疗策略。2)我们将定义 CD44亚型在炎性滑膜炎中的作用：a）总CD44 缺陷小鼠B）仅在变体CDT形式中选择性缺陷的小鼠 (but表达标准的CD44形式。CD44S），和c）仅小鼠 表达选择的变体CD44同种型。CD44缺陷型小鼠将 研究它们对抗原诱导的关节炎（AIA）的反应。和长大 在HTLV-1 tax转基因背景下，以确定CD44 HTLV-1 Tax转基因动物关节炎的选择性和总体缺陷 小鼠3)我们将研究CD7缺陷型T细胞的作用， 通过分离CD4+介导炎性滑膜炎的TCR库， 来自RA和OA PBMC的CD7-、CD28-T细胞。SF和滑膜组织，以及 确定这些T细胞产生IFN-γ和其他干扰素的能力， 细胞因子/趋化因子，并通过 研究CD7缺陷小鼠，在存在和不存在异常T细胞的情况下， 细胞受体（TCR）库在TCR转基因小鼠，为他们的 发展关节炎的能力。这些研究将提供 深入了解T细胞和单核细胞在炎症反应中的作用 滑膜炎并为新的治疗干预提供新的靶点 在RA中。