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Genetic analysis of the 4C8 antigen on T cells which stimultes production of TNF-a by synoviocytes from patients with rheumatoid arthritis.

对 T 细胞上的 4C8 抗原进行遗传分析，该抗原刺激类风湿关节炎患者滑膜细胞产生 TNF-a。

基本信息

批准号：
09670488
负责人：
MASUYAMA Jun-ichi
金额：
$ 1.92万
依托单位：
Jichi Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670488/
关键词：
Rheumatoid Arthritis TNF-a T cell Synoviocyte transmigration T細胞膜抗原

项目摘要

We developed a monoclonal antibody (mAb), termed anti-4C8, that blocks transmigration but not adhesion in a culture system in which high CD26 expressing (CD26^<hi>) T cells preferentially migrate through human umbilical vein endothelial cell (HUVEC) monolayers cultured on collagen gels. This mAb also appears to inhibit TNF-alphat production by the interaction between T cells and synoviocytes from patients with rheumatoid arthritis. Anti-4C8 reacted with all CD3+ T cells and monocytes, but not neutrophils or HUVECs. The structure defined by this antibody was an 80 kDa molecule. The mAb at 1 mug/ml inhibited 80-90% of migration of CD3+ T cells through unstimulated and IFN-gamma-stimulated HUVEC monolayers without interfering with adhesion and cell motility. When added to the cultures after the adhesion, anti-4C8 completely blocked subsequent transmigration of adherent T cells. Phase-contrast and electron microscopy revealed that T cells are arrested at the intercellular junctions of HUVE … More Cs in the presence of anti-4C8. Anti-4C8 exhibited agonistic effects on resting T cells without other stimuli under culture conditions in which anti-4C8 can stimulate T cells. First, in the checkerboard assay using collagen gels, the antibody promoted chemokinetic migration of the cells in a dose-dependent manner from 0.1 to 10 mug/ml. The predominant population of T cells that migrated into collagen gels with impregnated anti-4C8 were CD26^<hi>. Second, solid-phase immobilized anti-4C8 induced adhesion of T cells to the substrate, often with polarizations in cell shape and large pseudopods rich in filamentous (F-) actin. Third, soluble anti-4C8 augmented F-actin content preferentially in CD26^<hi> T cells when added to T cells at a high dose of 10 gg/ml. These findings suggest that stimulation via the 4C8 antigen increases cell motility of CD26^<hi> cells with profound cytoskeletal changes through signaling pathways including G proteins. The 4C8 antigen may be involved in preferential transmigration of CD26^<hi> cells adherent to HUVEC.The cloning of the gene coding this antigen is proceeding now. Less

我们开发了一种称为抗4C 8的单克隆抗体（mAb），其在培养系统中阻断迁移但不阻断粘附，在所述培养系统中，高表达CD 26（CD 26 ^<hi>）的T细胞优先迁移通过在胶原凝胶上培养的人脐静脉内皮细胞（HUVEC）单层。该mAb似乎还通过类风湿性关节炎患者的T细胞和滑膜细胞之间的相互作用抑制TNF-α at的产生。抗4C 8抗体与所有CD 3 + T细胞和单核细胞反应，但不与中性粒细胞或HUVEC反应。由该抗体定义的结构是80 kDa分子。1 μ g/ml的mAb抑制80-90%的CD 3 + T细胞通过未刺激和IFN-γ刺激的HUVEC单层的迁移，而不干扰粘附和细胞运动。当在粘附后添加到培养物中时，抗4C 8完全阻断粘附T细胞随后的迁移。相差显微镜和电子显微镜显示T细胞在HUVE的细胞间连接处被阻滞 ...更多信息 Cs在抗4C 8存在下。在抗4C 8可刺激T细胞的培养条件下，抗4C 8在无其他刺激的情况下对静息T细胞表现出激动作用。首先，在使用胶原凝胶的棋盘测定中，抗体在0.1至10 μ g/ml以剂量依赖性方式促进细胞的化学动力学迁移。迁移到具有浸渍的抗4C 8的胶原凝胶中的T细胞的主要群体是CD 26+<hi>。第二，固相固定化抗4C 8诱导T细胞粘附到基底上，通常具有细胞形状的极化和富含丝状（F-）肌动蛋白的大伪足。第三，<hi>当以10 μ g/ml的高剂量添加到T细胞中时，可溶性抗4C 8优先增加CD 26 + T细胞中的F-肌动蛋白含量。这些发现表明，通过4C 8抗原的刺激增加了CD 26+细胞的细胞运动性<hi>，并通过包括G蛋白的信号传导途径发生了深刻的细胞骨架变化。4C 8抗原可能参与粘附于HUVEC的CD 26+细胞的优先迁移<hi>，编码该抗原的基因的克隆正在进行中。少