CD40 COSTIMULATION AND TRANSPLANTATION

CD40 联合刺激和移植

• 批准号: 6341724
• 负责人: David Linn Perkins
• 金额: $ 26.06万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6341724
• 关键词: CD40 molecule; T lymphocyte; apoptosis; biological signal transduction; cytokine; gene expression; genetically modified animals; heart transplantation; homologous transplantation; laboratory mouse; leukocyte activation /transformation; lymphocyte proliferation; nuclear factor kappa beta; transplant rejection; transplantation immunology; tumor necrosis factor alpha

DESCRIPTION: (adapted from applicant's abstract) Following transplantation, acute rejection is recognized as the most frequent serious complication and the best predictor of chronic rejection, a major cause of long term graft loss. T cells are essential for initiating and maintaining acute rejection. Early intervention in transplant rejection necessitates understanding the mechanisms of T cell activation, as related to allograft survival. The principal investigator and others have found that blockade of CD40 signals prolongs graft survival. The goal of this proposal is to determine which CD40 regulated functions mediate graft rejection. CD40 signals are transduced by both NF-kB-dependent and -independent mechanisms. The PI has found that in vivo inhibition of NF-kB activation with a dominant negative transgene or by deletion of c-Rel prolongs allograft survival. Thus, one focus will be on the role of CD40-regulated actions that are NF-kB-dependent. The investigators propose the hypothesis that blockade of the CD40/CD40L costimulatory pathway prolongs allograft survival by NF-kB-dependent mechanisms. To test this hypothesis, they will employ an adoptive transfer model of cardiac transplantation using double transgenic lines that express the DO11 TCR transgene, which is cross-reactive with I-Ab, plus null alleles of either CD40, CD40L, c-Rel, or IkBa (DN), a dominant negative inhibitor of NF-kB. Transfer of cells from these animals into Balb/c recipients of C57Bl6 cardiac grafts will provide a means to examine in vivo and in vitro the molecular mechanisms governing CD40/CD40L costimulatory effects. Aim 1 will determine the role of CD40 ligand signals on T cell activation, proliferation, unresponsiveness, and cytokine secretion. Aim 2 will determine the cellular mechanisms by which CD40 expressed on T cells regulates allograft rejection by mechanisms of activation and apoptosis involving FasL and TNF-a signals. Aim 3 will investigate the molecular mechanisms by which activation of NFkB controls allograft survival.

描述：(改编自申请者摘要) 在移植后，急性排斥反应是公认的最多的 常见严重并发症和慢性心绞痛的最佳预测指标 排斥反应，是长期移植物丢失的主要原因。T细胞是必不可少的 引发和维持急性排斥反应。早期干预 移植排斥反应需要了解T细胞的机制 激活，与同种异体移植物存活有关。首席调查员 还有一些人发现，阻断CD40信号可以延长移植物的生长时间 生死存亡。这项提案的目标是确定哪个CD40受到监管 功能调节移植物排斥反应。CD40信号由两者传递 核因子-kB依赖和非依赖机制。私家侦探发现 显性负性转基因体内抑制核因子-kB活性的研究 或c-rel基因缺失可延长同种异体移植物存活时间。因此，一个焦点是 将取决于CD40调节的、依赖于NF-kB的动作的作用。 研究人员提出了一种假设，即阻断CD40/CD40L 依赖核因子-kB的共刺激通路延长同种异体移植物存活 机制。为了检验这一假设，他们将雇佣一名领养人 利用双转基因系建立心脏移植移植模型 表达DO11 TCR转基因，它与I-Ab交叉反应， 加上CD40、CD40L、c-Rel或IkBA(DN)的零等位基因，显性 核因子-kB的阴性抑制物。将这些动物的细胞转移到 接受C57BL6心脏移植的BALB/c将提供一种手段 检测体内和体外控制的分子机制 CD40/CD40L共刺激效应。目标1将确定CD40的作用 T细胞活化、增殖、无反应的配体信号， 和细胞因子的分泌。目标2将通过以下方式确定细胞机制 表达在T细胞上的CD40通过调节同种异体移植排斥反应 涉及FasL和TNF-a信号的激活和凋亡机制。 目标3将研究激活的分子机制 NFkB控制同种异体移植物存活。