APCs in Chronic Heart Rejection

慢性心脏排斥反应中的 APC

• 批准号: 6334816
• 负责人: Bruce R. Rosengard
• 金额: $ 35.66万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6334816
• 关键词: CD40 molecule; CD8 molecule; CD95 molecule; antigen presenting cell; arteriosclerosis; biological models; cytotoxic T lymphocyte; cytotoxicity; flow cytometry; graft versus host disease; heart transplantation; helper T lymphocyte; histocompatibility; laboratory mouse; leukocyte activation /transformation; lymphocyte proliferation; pathologic process; tissue /cell culture; transplant rejection; vascular endothelium

DESCRIPTION (Verbatim from the Applicant's Abstract): Cardiac transplantation is established therapy for the treatment of end-stage heart failure. However, chronic rejection in the form of accelerated arteriosclerosis remains the primary cause of late death after heart transplantation. Despite the development of several new drugs to combat rejection, the incidence of this form of chronic rejection has not changed. We have hypothesized that endothelial cells, which line coronary arteries, are capable of directly activating CD8+ T cells, which may play an important role in the development of graft vascular disease. We have established both in vitro and in vivo mouse models to study this process. The broad objective of this grant proposal is to define the differences in the ability of murine endothelium to activate CD4+ and CD8+ T cells in vitro and then to use analogous in vivo models to define the allorecognition pathways and effector mechanisms responsible for graft vascular disease. To achieve this goal, we will: 1. Test the hypothesis that endothelium activates both unprimed and primed CD8t T cells preferentially due to a less stringent requirement for costimulation. 2. Test the hypothesis that endothelium is a suitable target for CD8+ T cell cytotoxicity predominantly via the Fas/FasL pathway. 3. Test the hypothesis that graft vascular disease is a CDK about-dependent process. In summary, this proposal will determine whether endothelium has the capacity to stimulate CD8F T cells and the ability to act as targets for CD8+ cytotoxic T cells, which is sufficient to induce graft vasculopathy in a mouse model. Insights from this study will undoubtedly provide information that will lead to rational strategies to help prevent this lethal complication of human heart transplantation.

描述（逐字从申请人的摘要中）：心脏移植 已建立治疗终末期心力衰竭的疗法。然而， 以加速动脉硬化形式的慢性排斥仍然是 心脏移植后晚期死亡的主要原因。尽管有 开发几种新药来应对拒绝，这是这种情况 慢性排斥的形式没有改变。我们假设 内皮细胞（冠状动脉冠状动脉）能够直接 激活CD8+ T细胞，这可能在开发中起重要作用 移植血管疾病。我们已经建立了体外和体内小鼠 研究此过程的模型。该赠款提案的广泛目标是 定义鼠内皮激活CD4+的能力的差异 和CD8+ T细胞体外，然后使用类似的体内模型来定义 负责移植物的同种认识途径和效应器机制 血管疾病。为了实现这一目标，我们将：1。检验以下假设： 内皮优先激活未进行的CD8T T细胞 对共生的要求不太严格。 2。检验假设 内皮是CD8+ T细胞细胞毒性的合适靶标 FAS/FASL路径。 3。检验以下假设：移植血管疾病是一种 CDK关于依赖性过程。总而言之，该提议将确定是否 内皮具有刺激CD8F T细胞的能力和作用的能力 作为CD8+细胞毒性T细胞的靶标，足以诱导移植物 鼠标模型中的血管病。这项研究的见解无疑将 提供将导致理性策略的信息，以帮助防止这一点 人心脏移植的致命并发症。