APCs in Chronic Heart Rejection

描述(逐字摘自申请人摘要)：心脏移植 是治疗终末期心力衰竭的公认疗法。然而， 以加速动脉硬化为形式的慢性排斥反应仍然是 心脏移植后晚期死亡的主要原因。尽管 几种对抗排斥反应的新药的开发，这种情况的发生率 慢性排斥的形式没有改变。我们假设过 排列在冠状动脉内的内皮细胞能够直接 激活CD8+T细胞，可能在慢性粒细胞白血病的发生发展中起重要作用 移植物血管疾病。我们已经在体外和体内建立了小鼠 模型来研究这一过程。这项拨款提案的广泛目标是 确定小鼠内皮细胞激活CD4+能力的差异 和CD8+T细胞在体外，然后用类似的体内模型来确定 移植物的同种异体识别途径和效应机制 血管疾病。为了实现这一目标，我们将：1.检验假设 内皮细胞优先激活未激活和激活的CD8T T细胞 对协同刺激的要求不那么严格。2.检验假设 内皮细胞是CD8+T细胞杀伤的合适靶点，主要通过 Fas/FasL途径。3.检验移植物血管疾病是一种 CDK大约依赖的过程。总之，这项提案将决定是否 内皮细胞具有刺激CD8f T细胞的能力和作用于 作为CD8+细胞毒性T细胞的靶点，这足以诱导移植物 小鼠模型中的血管病变。这项研究的洞察力无疑将 提供有助于制定合理策略的信息，以帮助防止这种情况 人类心脏移植的致命并发症。

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.