Role of Bone Marrow T Cells, Transendothelial Migratory T Cells and Anti-Endothelial Cell Antibodies in the Pathogenesis of Autoimmunity.

骨髓 T 细胞、跨内皮迁移 T 细胞和抗内皮细胞抗体在自身免疫发病机制中的作用。

• 批准号: 09670489
• 负责人: KANO Shogo
• 金额: $ 2.11万
• 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-09670489/
• 关键词: systemic lupus erythematosus; apoptosis; ceramide; rheumatoid arthritis; transendothelial migration; anti-ribosomal P0 protein antibody; 抗リボゾームP0蛋白抗体; 自己免疫; 抗血管内皮細胞抗体; 血管外遊走; FTY720

1. MRL-lpr/lpr mouse has defect in apoptosis due to abnormal Fas gene and develops autoimmune diseases. Ceramide is an important mediator of intracellular signal transduction from Fas-Fas ligand interaction, and the cell membrane-permeable form C2-ceramide induced apoptosis in CD3+CD4-CD8-(DN) T cells from MIRL-lprllpr mice. FTY72O is a novel immunosuppressive agent resembling sphingosine in chemical structure. Oral administration of FTY72O as well as C2-ceramide reduced the number of DN T cells in lymph nodes and spleen of MRL-lpr/lpr mice, and significantly prolonged the survival at nine months.2. A monoclonal antibody (4C8) was established, which inhibits the transendothelial migration of T cells without interfering their adhesion to endothelial cells. The 4C8 molecule also acts as the second signal of T cell activation.3. Significantly elevated level of anti-endothelial cell antibody was found in SLE patients associated with pulmonary hypertension. One of the antigen recognized by anti-endothelial cell antibodies was identified as ribosomal P0 protein. Anti-ribosomal PG protein antibodies were found in sera from the patient with systemic lupus erythematosus(SLE). Positive anti-ribosomal P0 protein antibodies were associated with central nervous system involvement in SLE.A close temporal relationship of liver disease to anti-ribosomal P0 protein antibodies and central nervous system disease was also found in SLE patients.

1. MRL-lpr/lpr小鼠由于Fas基因异常导致细胞凋亡缺陷，发生自身免疫性疾病。神经酰胺是Fas-Fas配体相互作用的细胞内信号转导的重要介质，细胞膜可渗透形式的C2-神经酰胺诱导MIRL-1 prllpr小鼠的CD 3 + CD 4-CD 8-（DN）T细胞凋亡。FTY 72 O是一种新型的免疫抑制剂，其化学结构与鞘氨醇相似。口服FTY 72 O和C2-神经酰胺可减少MRL-lpr/lpr小鼠淋巴结和脾脏中DN T细胞的数量，并显著延长9个月的生存期.建立了一种单克隆抗体（4C 8），它抑制T细胞的跨内皮迁移，而不干扰它们与内皮细胞的粘附。4C 8分子也是T细胞活化的第二信号. SLE合并肺动脉高压患者血清抗内皮细胞抗体水平明显升高。抗内皮细胞抗体识别的抗原之一被鉴定为核糖体P0蛋白。系统性红斑狼疮（SLE）患者血清中存在抗核糖体PG蛋白抗体。SLE患者抗核糖体P0蛋白抗体阳性与中枢神经系统病变相关，SLE患者抗核糖体P0蛋白抗体阳性与中枢神经系统病变也有密切的时间关系。

项目成果

Funayama H,Ikeda U,Takahashi M,Sakata Y,Kitagawa S,Takahashi Y,Masuyama J-I,Furukawa Y,Miura Y,Kano S,Matsuda M and Shimada K: "Human monocyte-endothelial cell interaction induces platelet-derived growth factor expression." Cardiovasc Res. 37. 216-224 (19

Funayama H、Ikeda U、Takahashi M、Sakata Y、Kitakawa S、Takahashi Y、Masuyama J-I、Furukawa Y、Miura Y、Kano S、Matsuda M 和 Shimada K：“人单核细胞-内皮细胞相互作用诱导血小板衍生生长因子表达

Horie S,Nakada K,Masuyama J-I,Yoshio T,Minota S,Wakabayashi Y,Hirose S and Kano S: "Detection of large macrophage colony forming cells in the peripheral blood of patients with rheumatoid arthritis." J Rheumatol. 24. 1517-1521 (1997)

Horie S、Nakada K、Masuyama J-I、Yoshio T、Minota S、Wakabayashi Y、Hirose S 和 Kano S：“类风湿性关节炎患者外周血中大巨噬细胞集落形成细胞的检测”。

Takahashi M, Ikeda U, Masuyama J, Funayama H, Kano S, Shimada K: "Nitric oxide attenuates adhesion molecule expression in human endothelial cells." Cytokine. 8(11). 817-821 (1996)

Takahashi M、Ikeda U、Masuyama J、Funayama H、Kano S、Shimada K：“一氧化氮减弱人内皮细胞中粘附分子的表达。”

Horie S, Nakada K, Masuyama J-I, Yoshio T, Minota S, Wakabayashi Y, Hirose S and Kano S: "Detection of large macrophage colony forming cells in the peripheral blood of patients with rheumatoid arthritis." J Rheumatol. 24. 1517-1521 (1997)

Horie S、Nakada K、Masuyama J-I、Yoshio T、Minota S、Wakabayashi Y、Hirose S 和 Kano S：“类风湿性关节炎患者外周血中大巨噬细胞集落形成细胞的检测”。

Yoshio T,Masuyama J-I,Kohda N,Hirata D,Sato H,Iwamoto M,Mimori A,Takeda A,Minota S and Kano S: "Association of interleukin 6 release from endothelial cells and pulmonary hypertension in SLE." J Rheumatol. 24. 489-495 (1997)

Yoshio T、Masuyama J-I、Kohda N、Hirata D、Sato H、Iwamoto M、Mimori A、Takeda A、Minota S 和 Kano S：“SLE 中内皮细胞释放白细胞介素 6 与肺动脉高压的关联。”