Adhesion molecules and soluble factors specifically regulate T lymphocyte function in patients with rheumatoid arthritis.

粘附分子和可溶性因子特异性调节类风湿关节炎患者的 T 淋巴细胞功能。

• 批准号: 05670438
• 负责人: TANAKA Yoshiya
• 金额: $ 1.41万
• 依托单位: University of Occupational & Environmental Health (U.O.E.H.)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05670438/
• 关键词: rheumatoid arthritis; T lymphocyte; endothelium; adhesion molecules; integrin; proteoglycan; MIP-1beta; IL-1; T細胞; 滑膜細胞; サイトカイン; ケモカイン

Synovitis in rheumatoid arthritis (RA) is characterized by infiltration of synovium by T cells as well as the proliferation of synovial lining cells. We have studied the mechanism of circulating T cell migration into synovial tissue and interaction of T cells with synovial cells from the standpoints of adhesion molecules, cytokines and proteoglycan.1.The mechanisms of T cell infiltration into rheumatoid synovium.We have studied the mechanism of T cell adhesion to endothelium and have proposed that it consists of inflammatory adhesion cascade. To clarify the mechanism of T cell migration into synovial tissue, we assessed the adhesion of peripheral T cells to endothelial cells purified from rheumatoid synovium. The endothelial cells expressed heparan sulfate proteoglycan as well as adhesion molecules such as ICAM-1, VCAM-1 and E-selectin. T cells in synovium produced large amounts of inflammatory cytokine MIP-1beta. The MIP-1beta was most effective when immobilized on the heparan sulfate … More expressed on the rheumatoid endothelium to trigger T cell integrin which lead to the induction of high affinity adhesion of T cells to the endothelium. We reasoned that, as cytokines in vivo will be rapidly washed away by blood flow, MIP-1beta can induce T cell adhesion in its immobilized form. The induced T cell adhesion was inhibited by either, the mixture of anti-VLA-4/LFA-1 antibodies, xyloside which inhibits the synthesis of heparan sulfate, or pertussis toxin which blocks signal transduction through G-protein coupled MIP-1beta receptor. These results indicate that MIP-1beta produced from synovial T cells induces integrin-mediated T cell adhesion to endothelium by its immobilized form on heparan sulfate on synovial endothelium. Thus, cytokines and proteoglycan as well as adhesion molecules are involved in T cell migration into synovium, which leads to accumulation of T cells in rheumatoid synovium. Extrapolation to include the results would bring new approaches to clarification of pathogenesis and pharmacological agents in RA.2.The mechanisms of cellular interaetion of T cells with synovial cellsSynovial lining cells and T cells play a central role in rheumatoid synovitis. We studied the interaction between T cells and synovial fibroblasts. T cells adhered to the synovial cells mainly through LFA-1/ICAM-1. Histochemical studies indicated that LFA-1-positive T cells accumulated around ICAM-1-positive synovial cells. We found that T cells activated synovial cells to induce IL-1beta production through the cellular adhesion via LFA-1/ICAM-1. To clarify if ICAM-1 per se on the synovial cells induce activation signals, ICAM-1 on a synovial fibroblast cell line established rocally was cross-linked and IL-1beta production was assessed. Cross-linked ICAM-1 induced transcription of IL-1beta genomic DNA through enhancer regions containing nuclear factor AP-1-binding sites by CAT analysis. The involvement of AP-1 in ICAM-1-induced IL-1beta transcription was confirmed by bandshift assay. These results indicate that adhesion molecules not only function as glue but transduce activation signals which induce cytokine production through nuclear factor in rheumatoid synovial cells. Thus, the significance of T cell adhesion to synovial cells by LFA-1/ICAM-1 pathway in the pathogenesis of synovitis is suggested, which may bring new approaches to the control of synovitis. Less

类风湿性关节炎（RA）滑膜炎的特征是T细胞浸润滑膜以及滑膜衬里细胞增殖。本文从粘附分子、细胞因子和蛋白多糖的角度研究了循环T细胞向滑膜组织迁移的机制以及T细胞与滑膜细胞的相互作用。1. T细胞向类风湿关节炎滑膜浸润的机制研究了T细胞与内皮细胞的粘附机制，提出T细胞与内皮细胞的粘附是由炎性粘附级联反应组成的。为了阐明T细胞迁移到滑膜组织中的机制，我们评估了外周T细胞与从类风湿性滑膜中纯化的内皮细胞的粘附。内皮细胞表达硫酸乙酰肝素蛋白多糖以及粘附分子如ICAM-1、VCAM-1和E-选择素。滑膜中T细胞产生大量炎性细胞因子MIP-1 β。MIP-1 β固定在硫酸乙酰肝素上时最有效 ...更多信息 在类风湿性内皮上表达以触发T细胞整联蛋白，其导致诱导T细胞与内皮的高亲和力粘附。我们推断，由于体内的细胞因子将被血流迅速冲走，MIP-1 β可以以其固定形式诱导T细胞粘附。诱导的T细胞粘附被抗VLA-4/LFA-1抗体的混合物、抑制硫酸乙酰肝素合成的木糖苷或阻断通过G蛋白偶联的MIP-1 β受体的信号转导的百日咳毒素抑制。这些结果表明，从滑膜T细胞产生的MIP-1 β诱导整合素介导的T细胞粘附到内皮细胞上，通过其固定形式在滑膜内皮细胞上的硫酸乙酰肝素上。因此，细胞因子和蛋白聚糖以及粘附分子参与T细胞迁移到滑膜中，从而导致T细胞在类风湿性滑膜中积聚。2. T细胞与滑膜细胞相互作用的机制滑膜衬里细胞和T细胞在类风湿性滑膜炎中起着重要作用。我们研究了T细胞和滑膜成纤维细胞之间的相互作用。T细胞主要通过LFA-1/ICAM-1与滑膜细胞粘附。组织化学研究表明LFA-1阳性T细胞聚集在ICAM-1阳性滑膜细胞周围。我们发现T细胞通过LFA-1/ICAM-1的细胞粘附激活滑膜细胞，诱导IL-1 β的产生。为了阐明滑膜细胞上的ICAM-1本身是否诱导活化信号，将局部建立的滑膜成纤维细胞系上的ICAM-1交联，并评估IL-1 β的产生。通过CAT分析，交联ICAM-1通过含有核因子AP-1结合位点的增强子区域诱导IL-1 β基因组DNA的转录。带移分析证实AP-1参与ICAM-1诱导的IL-1 β转录。这些结果表明，粘附分子不仅作为胶水，但激活信号，诱导细胞因子的产生，通过核因子在类风湿性关节炎滑膜细胞。提示T细胞通过LFA-1/ICAM-1途径与滑膜细胞粘附在滑膜炎发病机制中的意义，为滑膜炎的防治提供新的思路。少

项目成果

Yoshiya Tanaka: "Proteoglycan on endothelial cell present adhesion-inducing cytokines to leukocytes" Immunology Today. 14. 111-115 (1993)

Yoshiya Tanaka：“内皮细胞上的蛋白多糖向白细胞呈现粘附诱导细胞因子”《今日免疫学》。

Tanaka, Y.: "Adhesion molecules in rheumatoid arthritis : mechanisms and new approaches to the therapy." Clin.Immunol.26. 190-197 (1994)

Tanaka, Y.：“类风湿关节炎中的粘附分子：机制和新的治疗方法。”

田中 良哉: "RAにおける接着分子の過剰発現とその制御の可能性" 臨床免疫. 26. 190-197 (1994)

Yoshiya Tanaka：“RA 中粘附分子的过度表达及其调节的可能性”《临床免疫学》26. 190-197 (1994)。

田中良哉: "抗サイトカイン療法.慢性関節リウマチ治療の新たなアプローチ" 先端医学社(印刷中), (1994)

Yoshiya Tanaka：“抗细胞因子疗法。治疗类风湿性关节炎的新方法” Senpai Igakusha（正在出版），（1994）

Shimizu, Y., Newman, W., Tanaka, Y., Shaw, S.: "Lymphocyte interactions with endothelial cells." Immunol.Today. 13. 106-112 (1992)

Shimizu, Y.、Newman, W.、Tanaka, Y.、Shaw, S.：“淋巴细胞与内皮细胞的相互作用。”