Immunological and molecular biological analyzes of cell surface antigens associated with T cell activation and function

与 T 细胞活化和功能相关的细胞表面抗原的免疫学和分子生物学分析

• 批准号: 06670242
• 负责人: NAGATA Norikazu
• 金额: $ 1.34万
• 依托单位: Kansai Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06670242/
• 关键词: Autoimmune disease; Monoclonal antibody; T cell subsets; Glomerulonephritis; Cell surface antigens; T細胞亜系; T細胞; クローニング; 自己反応性; Th2; Th1

Autoimmune diseases result from self-tissue destruction caused by auto-reactive immune responses which are not elicited in normal human and mine. We have analyzed immunological abnormalities in autoimmune-prone MRL/lpr mice, particularly graft-versus-host disease (GVHD) -like disorders obeserved in [MRL/lpr -> MRL/+] bone marrow chimeras. In these studies, two interesting monoclonal autoantibodies (25T3 and F6C7) reactive with white blood cells have been established. 25T3 monoclonal antibody (mAb) (IgM,k) is specific for T cells, and reacts to 70-80% peripheral CD8^+ T cells and 30% peripheral CD4^+ T cells. 25T3^+CD4^+T cells secret more IL-2 than 25T3^-CD4^+T cels, and 25T3^-CD4^+T cells secret more IL-4 than 25T3^+CD4^+T cells after in vitro stimulation with anti-CD3 mAb. Therefore, 25T3 mAb may divide CD4^+T cells into Th1 and Th2 subpopulaitons. The 25T3-reactive antigen is approximately 70 kDa. F6C7 mAb (IgG2b, k) strongly reacts to blastic T cells activated by autologous MLR and … More some blastic T cells of MRL/lpr mice. The F6C7-reactive antigen is a heterodimer of approximately 78 and 70 kDa. Although these antigens are not cloned, these mAbs are usuful for analyzing T cell abnormalities in immunological disorders. We have further established nephritogenic mAbs from FGS or (NZW X BXSB) F1 mice which spontaneously develop glomerulonephritis. When the mAbs are transplanted into SCID mice, the mice show proteinuria and glomerulonephritis. FG1H5 mAb (IgM,k) reacts both ssDNA and glomerulus (mainly mesangium), and deposits in the glomeruli. The FG1H5 reactive antigen is approximately 28 kDa. W/B4A9 mAb (IgM,k) deposits along systemic capillary walls in cluding kidney, heart and etc. The mAb reacts to approximately 25 kDa plasma protein. W/B2A4 mAb (IgG3, k) is a cryoglobulin, deposits mainly in glomerular capillary walls and induced high level of proteinuria. These nephritogenic mAbs may elucidate the nephritogenic antigens and contribute to understanding the mechanisms underlying the development of glomerulonephritis. Less

自身免疫性疾病是由自身免疫反应引起的自身组织破坏引起的，而正常人和我的体内不会引起这种免疫反应。我们分析了自身免疫易感MRL/lpr小鼠的免疫异常，特别是在[MRL/lpr -> MRL/+]骨髓嵌合体中观察到的移植物抗宿主病（GVHD）样疾病。在这些研究中，两个有趣的单克隆自身抗体（25 T3和F6 C7）反应的白色血细胞已经建立。25 T3单克隆抗体（mAb）（IgM，k）对T细胞具有特异性，可与70-80%的外周血CD 8 ^+ T细胞和30%的外周血CD 4 ^+ T细胞反应。在体外用抗CD 3 mAb刺激后，25 T3 ^+ CD 4 ^+T细胞比25 T3 ^-CD 4 ^+ T细胞分泌更多的IL-2，25 T3 ^-CD 4 ^+T细胞比25 T3 ^+ CD 4 ^+T细胞分泌更多的IL-4。因此，25 T3 mAb可将CD 4 ^+T细胞分为Th 1和Th 2亚群。25 T3反应性抗原约为70 kDa。F6 C7 mAb（IgG 2b，k）与自体MLR激活的原始T细胞强烈反应， ...更多信息 MRL/lpr小鼠的一些原始T细胞。F6 C7反应性抗原是约78和70 kDa的异源二聚体。虽然这些抗原没有被克隆，但这些mAb用于分析免疫性疾病中的T细胞异常。我们进一步从自发发生肾小球肾炎的FGS或（NZW X BXSB）F1小鼠中建立了致肾炎单克隆抗体。当将mAb移植到SCID小鼠中时，小鼠显示蛋白尿和肾小球肾炎。FG 1H 5 mAb（IgM，k）与ssDNA和肾小球（主要是系膜）反应，并沉积在肾小球中。FG 1H 5反应性抗原约为28 kDa。W/B4 A9 mAb（IgM，k）可沿着全身毛细血管壁沉积，包括肾脏、心脏等。mAb可与约25 kDa的血浆蛋白反应。W/B2 A4 mAb（IgG 3，k）是一种cryocellulin，主要沉积在肾小球毛细血管壁，并引起高水平的蛋白尿。这些致肾炎单克隆抗体可以阐明致肾炎抗原，并有助于了解肾小球肾炎发生的机制。少

项目成果

Hosaka N,Nose M,Nagata N,et al.: "Aging of the thymus is a critical factor in successful bone marrow transplantation : Bone marrow transplantation plus fetal thymus grafts as a strategy for treatment of autoimmune diseases in old MRL/+ mice." Proc. Natl.

Hosaka N、Nose M、Nagata N 等人：“胸腺老化是骨髓移植成功的关键因素：骨髓移植加胎儿胸腺移植作为治疗老年 MRL/小鼠自身免疫性疾病的策略。”

Hosaka N,Nose M,Nagata N,Miyashima S,Kyogoku M,Ikehara S: "Aging of the thymus is a critical factor in successful bone marrow transplantation : bone marrow Transplantation plus fetal thymus graft as a strategy for treatment of autoimmune disease in old MR

Hosaka N，Nose M，Nagata N，Miyashima S，Kyogoku M，Ikehara S：“胸腺的老化是成功骨髓移植的关键因素：骨髓移植加胎儿胸腺移植作为治疗老年自身免疫性疾病的策略

Hosaka N,Nagata N,et al.: "Attenuation of lpr-GVHD in MRL/lpr spleen cell-injected SCID mice by in vivo treatment with anti-Vβ8.1,2 monoclonal antibody." Clin. Exp. Immunol.96. 500-507 (1994)

Hosaka N、Nagata N 等人：“通过抗 Vβ8.1,2 单克隆抗体体内治疗来减弱 MRL/lpr 脾细胞注射的 SCID 小鼠中的 lpr-GVHD”。 500-507 (1994)

Ishida T,Inaba M,Hisha H,Sugiura K,Adachi Y,Nagata N,Ogawa R,Good R A,Ikehara S: "Requirement of donor-derived stromal cells in the bone marrow for successful allogeneic bone marrow transplantation : complete prevention of recurrence of autoimmune disease

Ishida T，Inaba M，Hisha H，Sugiura K，Adachi Y，Nagata N，Okawa R，Good RA，Ikehara S：“成功同种异体骨髓移植需要骨髓中的供体来源的基质细胞：完全预防复发

Nishimura M,Toki J,Sugiura K,Hashimoto F,Tomita T,Fujishima H,Hiramatsu Y,Nishioka N,Nagata N,Takahashi Y,Ikehara S: "Focal segmental glomerular sclerosis, a type of intractable chronic glomerulonephritis, is a stem cell disorder." J.Exp.Med.179 (3). 1053

Nishimura M，Toki J，Sugiura K，Hashimoto F，Tomita T，Fujishima H，Hiramatsu Y，Nishioka N，Nagata N，Takahashi Y，Ikehara S：“局灶节段性肾小球硬化症，一种顽固性慢性肾小球肾炎，是一种干细胞