Novel strategy for the graft rejection by down-regulating MHC class II molecules.

通过下调 MHC II 类分子进行移植物排斥的新策略。

• 批准号: 15591472
• 负责人: SHIONO Hiroyuki
• 金额: $ 2.11万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591472/
• 关键词: lung transplantation; MHC; graft rejection; immunosuppression; rat; HVJ; MHC class II; CIITA; 遺伝子導入; 遺伝子導

Inhibition of the graft rejection is essential for the successful organ transplantation. Although the improvement of immunosuppressants have been made the transplantation safer, more effective methods for the control of rejection are still needed.Our novel strategy for the control of the graft rejection is to down-regulate the expression of MHC class II molecules in the transplanted organs by interfering the function of MHC class II transactivator (CIITA), which is one of the transcription factor of MHC molecules.A deletion mutant protein which express only the biding domain is supposed to work as a dominant negative mutation and to suppress the expression of MHC class II molecules. Dominant mutant cDNA was introduced into Raji cells, the B cell line expressing HLA-DR. Expression of HLA-DR antigen was shown to be significantly suppressed in the stable transfectants.Hemagglutinating virus of Japan (HVJ virus) envelope vector with cDNA was amplified, and infused via a catheter which was inserted into the vein dorsalis penis superficiales of rats. The expression of the protein of inserted cDNA was clearly detected in the alveolar in the rat lungs.These achievement should enable us to develop the rat donor lungs in which HLA class II molecules are down-regulated for the inhibition of the rejection. This novel strategy for the control of the rejection could be useful against any sorts of organ transplants.

抑制移植排斥对于器官移植的成功至关重要。尽管免疫抑制剂的改进使移植更加安全，但仍需要更有效的方法来控制排斥反应。我们控制移植排斥的新策略是通过干扰MHC II类反式激活因子（CIITA）的功能来下调移植器官中MHC II类分子的表达，CIITA是MHC分子的转录因子之一。 仅表达结合结构域的缺失突变蛋白被认为是显性失活突变并抑制 MHC II 类分子的表达。将显性突变体 cDNA 引入 Raji 细胞（表达 HLA-DR 的 B 细胞系）。稳定转染子中HLA-DR抗原的表达明显受到抑制。扩增带有cDNA的日本血凝病毒(HVJ病毒)包膜载体，并通过插入大鼠阴茎表面静脉背侧的导管输注。在大鼠肺的肺泡中清楚地检测到插入的cDNA蛋白的表达。这些成果使我们能够开发出HLA II类分子下调的大鼠供体肺，以抑制排斥反应。这种控制排斥反应的新策略可用于对抗任何类型的器官移植。