Pathogenesis and Therapy of Chronic Lung Rejection

描述（申请人提供）：超过10，000个肺和心肺 移植手术已经在世界范围内进行。这些程序已被证明是 对许多接受者非常有效;然而， 肺受体显著低于在肾，心脏， 和肝脏接受者。这在很大程度上是由于 慢性肺排斥反应，组织学表现为OB，临床表现为 闭塞性细支气管炎综合征（BOS）。本提案的目的是 提高对免疫发病机制、分子诊断和 肺移植术后CR的治疗。为了实现这一目标，我们必须 组建了一个由经验丰富的调查人员组成的多学科小组， 世界？美国最有经验和最受尊敬的肺移植中心。拟议 该计划包括四个研究项目，应用创新的实验 的方法和最新技术，以解决 知识：首先，虽然同种免疫反应通常被认为是 CR发病机制的核心是， 反应的发生仍然模糊不清。项目1和项目2涉及 使用T细胞受体Tg小鼠CR的免疫发病机制， 可以鉴定移植物特异性T细胞的活性。第二个主要问题 一直无法确定一个特定的群体在风险接受者， 增强免疫抑制或新治疗剂的潜在候选物。 项目3通过使用大规模基因表达来解决这个问题 微阵列（> 10，000个基因）技术，用于识别敏感和特异性基因 与CR相关的表达模式。最后，目前的治疗 主要基于增强免疫抑制治疗的方法， 在大多数受影响的患者中， 个体项目4旨在探索一个新的治疗方向： 基因转染诱导气道成纤维细胞凋亡 构建体，其使它们对HMG-CoA还原酶抑制剂敏感。的项目 在本提案中，将由两个核心支持：1）行政核心 将协调行政、教育和生物统计职能， 该计划;和2）小鼠气管移植核心将集中 专业知识有关的执行，收获和处理异位 在项目1、2和4中使用的小鼠气管移植。

DESCRIPTION (provided by applicant): More than 10,000 lung and heart-lung transplants have been performed worldwide. These procedures have proven to be highly effective for many recipients; however, long-term survival rates for lung recipients are considerably lower than those observed in kidney, heart, and liver recipients. This is due, in large part, to the development of chronic lung rejection, manifested histologically as OB, and clinically as bronchiolitis obliterans syndrome (BOS). The goal of this proposal is to improve understanding of the immunopathogenesis, molecular diagnosis, and therapy of CR after lung transplantation. To accomplish this, we have assembled a multidisciplinary team of experienced investigators at one of the world?s most experienced and respected lung transplant centers. The proposed Program consists of four research projects which apply innovative experimental approaches and state-of the-art technologies to address three major gaps in knowledge: First, while an alloimmune reaction is generally accepted to be central to the pathogenesis of CR, the molecular mechanisms by which this reaction occurs remain obscure. Projects 1 and 2 address the immunopathogenesis of CR use T-cell receptor Tg mice in which the location and activity of graft-specific T-cells can be identified. A second major problem has been the inability to identify a specific group of at-risk recipients as potential candidates for augmented immune suppression or novel therapeutics. Project 3 addresses this problem by using large-scale gene expression microarray (>10,000 genes) technology to identify sensitive and specific gene expression patterns associated with CR. Finally, current therapeutic approaches, based primarily on augmenting immune suppressive therapy, are ineffective in reversing the course of chronic lung rejection in most affected individuals. Project 4 seeks to explore a novel therapeutic direction: triggering apoptosis in airway fibroblasts by transfection with gene constructs, which sensitize them to HMG-CoA reductase inhibitors. The projects in this proposal will be supported by two cores: 1) An Administrative Core will coordinate administrative, educational, and biostatistical functions of the Program; and 2) a Murine Tracheal Transplant Core will concentrate expertise related to performing, harvesting, and processing the heterotopic mouse tracheal transplants used in Projects 1, 2, and 4.