CD40 COSTIMULATION AND TRANSPLANTATION

CD40 联合刺激和移植

• 批准号: 6137277
• 负责人: David Linn Perkins
• 金额: $ 25.3万
• 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/6137277
• 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：（改编自申请人摘要）