CD40 COSTIMULATION AND TRANSPLANTATION

CD40 联合刺激和移植

• 批准号: 6626350
• 负责人: David Linn Perkins
• 金额: $ 27.54万
• 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/6626350
• 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） 移植后，急性排斥反应被认为是最常见的并发症。 频繁的严重并发症和慢性的最佳预测 排斥反应是长期移植物丢失的主要原因。T细胞至关重要 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。主要研究者 其他人发现，阻断CD 40信号通路， 生存这项提案的目标是确定哪些CD 40调节 功能介导移植物排斥。CD 40信号由两种细胞转导。 NF-κ B依赖和非依赖机制。PI发现，在 用显性负转基因体内抑制NF-κ B活化 或通过c-Rel基因缺失导致同种异体移植物存活。因此，一个焦点 将是对CD 40的作用调节的行动是NF-κ B依赖。 研究者提出了一种假设，即阻断CD 40/CD 40 L， 共刺激通路通过NF-κ B依赖性抑制同种异体移植物存活 机制等为了验证这一假设，他们将雇用一名收养的 双转基因心脏移植模型的建立 表达DO 11 TCR转基因，其与I-Ab交叉反应， 加上CD 40、CD 40 L、c-Rel或IkBa（DN）的无效等位基因， NF-kB的负性抑制剂。将这些动物的细胞转移到 C57 B16心脏移植物的Balb/c受体将提供一种手段， 在体内和体外研究控制 CD 40/CD 40 L共刺激作用。目的1将确定CD 40的作用 配体信号对T细胞活化、增殖、无反应性 和细胞因子分泌。目标2将确定细胞机制， T细胞上表达的CD 40通过以下方式调节同种异体移植物排斥反应： 涉及FasL和TNF-α信号的活化和凋亡机制。 目的3将研究激活的分子机制， NFkB控制同种异体移植物存活。

项目成果

Differentiation of stress, metabolism, communication, and defense responses following transplantation.

移植后应激、新陈代谢、交流和防御反应的分化。

• DOI: 10.1189/jlb.0102052
• 发表时间: 2003
• 期刊: Journal of leukocyte biology
• 影响因子: 5.5
• 作者: Mueller,ThomasF;Ma,Chunyan;Lederer,JamesA;Perkins,DavidL
• 通讯作者: Perkins,DavidL

Analysis of cytokine functions in graft rejection by gene expression profiles.

通过基因表达谱分析移植排斥中细胞因子的功能。

• DOI: 10.1097/01.tp.0000093464.72920.7c
• 发表时间: 2003
• 期刊: Transplantation.
• 作者: Liang,Yurong;Christopher,Kenneth;DeFina,Rachel;Cidado,Justin;He,Hongzhen;Haley,KathleenJ;Finn,PatriciaW;Perkins,DavidL
• 通讯作者: Perkins,DavidL

Analysis of immunoglobulin and T-cell receptor gene deficiency in graft rejection by gene expression profiles.

通过基因表达谱分析移植排斥反应中免疫球蛋白和 T 细胞受体基因缺陷。

• DOI: 10.1097/01.tp.0000113803.45613.f8
• 发表时间: 2004
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: DeFina,RachelA;Liang,Yurong;He,Hongzhen;Haley,KathleenJ;Christopher,Kenneth;Finn,PatriciaW;Perkins,DavidL
• 通讯作者: Perkins,DavidL

Molecular profiling of the role of the NF-kappaB family of transcription factors during alloimmunity.

转录因子 NF-kappaB 家族在同种免疫过程中作用的分子谱分析。

• 发表时间: 2002
• 期刊: Journal of leukocyte biology.
• 作者: Finn,PatriciaW;He,Hongzhen;Ma,Chunyan;Mueller,Thomas;Stone,JamesR;Liou,Hsiou-Chi;Boothby,MarkR;Perkins,DavidL
• 通讯作者: Perkins,DavidL

Analysis of costimulation by 4-1BBL, CD40L, and B7 in graft rejection by gene expression profiles.

通过基因表达谱分析移植排斥中 4-1BBL、CD40L 和 B7 的共刺激。

• DOI: 10.1007/s00109-003-0468-1
• 发表时间: 2003
• 期刊: Journal of molecular medicine (Berlin, Germany)
• 作者: DeFina,Rachel;Christopher,Kenneth;He,Hongzhen;Mandelbrot,Didier;Gu,Yongping;Finn,Patricia;Perkins,DavidL
• 通讯作者: Perkins,DavidL