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Role of PD-1/PD ligand system in the pathogenesis of rheumatoid arthritis

PD-1/PD配体系统在类风湿关节炎发病机制中的作用

基本信息

批准号：
14370164
负责人：
KUMAGAI Shunichi
金额：
$ 6.78万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

The aim of the investigation is to clarify whether (1) the abnormalities of the inhibitory co-stimulatory system PD-1/PD-L ligand (PD-L1), which we first described, exist in rheumatoid arthritis (RA) and (2) if so, the abnormalities of PD-1/PD-L system result in the induction of RA. The followings are our achievements ;1. Synovial fluid (SF) from RA patients contained PD-1+CD4+T cells, while such cells were essentially not detected in peripheral blood or SF from osteoarthritis patients. These cells were considered to have the inhibitory function since they also expressed CTLA-4 and were positive for the intracelluar IL-10. Interferon (IFN)-gamma strongly induced the cell-surface expression of PD-L1, but not the other co-stimulatory molecules such as B7.1 and B7.2, on cultivated synovial cells in vitro.2. The expression of PD-1 and PD-L1 in articular tissue of RA patients was examined immunohistochemically using the newly developed monoclonal antibodies. PD-L1 was strongly expressed on the surface layer cells of synovial tissue and the endothelial cells. PD-L1 was also expressed on the majority of infiltrated cells expressed PD-L1. It is currently under examination by the double staining method on frozen samples what kind of cells express PP-I and which cytokines these cells produce.3. On collagen induced arthritis (CIA) mice, synovial cells were positive for PD-L1 while some of the bone marrow cells were PD-L2 positive. Administration of anti PD-L1 antibodies to the CIA mice tended to inhibit the onset of arthritis.4. PD-1 knockout (KO) mice are known to develop arthritis naturally, and it is highly, possible that CIA on these mice is severer than CIA on wild type mice due to the lack of PD-1 system, which again indicate the involvement of PD-1/PD-L1 system on the etiology of RA. The process to make the KO mice specific pathogen free is currently on-going.

本研究的目的是阐明(1)类风湿关节炎(RA)是否存在PD-1/PD-L配体(PD-L1)抑制共刺激系统的异常；(2)如果存在，则PD-1/PD-L系统的异常导致RA的发生。主要研究成果如下：1.RA患者滑液中含有PD-1+CD4+T细胞，而骨性关节炎患者的外周血和滑液中基本未检测到PD-1+CD4+T细胞。这些细胞被认为具有抑制功能，因为它们也表达CTLA-4，细胞内IL-10阳性。结论1.体外培养的滑膜细胞，干扰素-γ能强烈诱导细胞表面PD-L1的表达，但不能诱导其他共刺激分子如B7.1和B7.2的表达。采用免疫组织化学方法检测PD-1和PD-L1在RA患者关节组织中的表达。PD-L1主要表达于滑膜组织表层细胞和内皮细胞。PD-L1在大多数表达PD-L1的浸润性细胞上也有表达。目前正在通过冰冻标本的双重染色方法检测哪些细胞表达PP-I，这些细胞产生哪些细胞因子。胶原诱导性关节炎(CIA)小鼠滑膜细胞PD-L1阳性，部分骨髓细胞PD-L2阳性。给CIA小鼠注射抗PD-L1抗体可以抑制关节炎的发生。PD-1基因敲除(KO)小鼠自然发生关节炎，由于缺乏PD-1系统，这些小鼠的CIA很可能比野生型小鼠的CIA更严重，这再次表明PD-1/PD-L1系统参与了RA的发病机制。使KO小鼠摆脱特定病原体的过程目前正在进行中。