PATHOPHYSIOLOGIC MECHANISMS OF LUNG INJURY AFTER BMT

描述（改编自申请人的摘要） 同种异体骨髓移植后发生的肺炎是非感染性的， 被称为特发性肺炎综合征（IPS）。 虽然时间 IPS和移植物抗宿主病（GVHD）之间的关联已经被 据报道，两者之间的机械关系还不清楚 定义了 候选人已经获得了初步数据， 这种形式的肺损伤可能代表移植物抗宿主的假设 针对肺部的反应。 这种反应被认为涉及级联反应 炎症细胞因子，可以被概念化为三种不同的 步 第一步，全身照射增强了宿主的能力， 同种异体抗原，以刺激供体T细胞在骨髓输注的时间。 在 第二步，活化的T细胞自我刺激增殖， 它们同时通过分泌 干扰素-γ（IFN γ）。 在第三步，启动的肺巨噬细胞接受 第二信号-内源性（肠源性内毒素）或外源性 （吸入/静脉注射毒素）-并被触发释放大量的 导致肺破坏的细胞毒性介质（TNF α、IL-1B、NO） 组织. 这个实验计划将更具体地研究肺 BMT后的损伤，因为它涉及到这个细胞因子级联反应的每一步。 使用 一个良好建立的小鼠骨髓移植模型，具体的目的是：1。 评价 内毒素作为第二信号在IPS发展中的作用， 确定负责这一过程的炎症介质， 特异性细胞因子抑制剂来消除肺损伤。 2. 分析 IFN γ在激发肺巨噬细胞释放促炎性因子中的作用 导致肺损伤的细胞因子。 3. 调查的作用 移植前全身照射（TBI）调节和程度 细胞因子失调传播中的供体/宿主组织不相容性 最终导致肺中毒 该提案将联合收割机与广泛的实验室经验相结合， 教学课程，旨在获得基本的技术， 细胞和分子生物学，并开发一种关键的方法， 移植免疫学 该计划将直接监督博士。 费拉拉的实验室致力于了解 GVHD的免疫病理生理机制。 一个高级调查小组 在DFCI将监测该项目的进展，并提供建设性的 为筹备和最终过渡到联合国咨商地位而提出的批评 独立首席调查员

DESCRIPTION (Adapted from the applicant's abstract) Almost half of the pneumonias occurring after allogeneic BMT are noninfectious in origin and are referred to as idiopathic pneumonia syndrome (IPS). Although a temporal association between IPS and graft versus host disease (GVHD) has been reported, a mechanistic relationship between the two has not been clearly defined. The candidate has obtained preliminary data that supports the hypothesis that this form of lung injury may represent a graft versus host reaction targeting the lung. This reaction is thought to involve a cascade of inflammatory cytokines that can be conceptualized as three distinct steps. In step one, total body irradiation enhances the ability of host alloantigens to stimulate donor T cells at the time of marrow infusion. In step two, activated T cells undergo self stimulation and proliferation while they simultaneously prime pulmonary macrophages by secreting Interferon-gamma (IFNy). During step three, primed lung macrophages receive a second signal - either endogenous (gut derived endotoxin) or exogenous (inhaled/intravenous toxin) - and are triggered to release large amounts of cytotoxic mediators (TNFa, IL-1B, NO) which lead to the destruction of lung tissue. This experimental plan will take a more specific look at lung damage after BMT as it relates to each step of this cytokine cascade. Using a well established murine BMT model, the specific aims are: 1. To evaluate the role of endotoxin as a second signal in the development of IPS and identify the inflammatory mediators responsible for this process by using specific cytokine inhibitors to abrogate lung injury. 2. To analyze the role of IFNy in priming pulmonary macrophages to release proinflammatory cytokines contributing to lung damage. 3. To investigate the role of pre-transplant total body irradiation (TBI) conditioning and degree of donor/host histoincompatibility in the propagation of cytokine dysregulation and eventual pulmonary toxicity. This proposal will combine an intensive laboratory experience with a broad didactic curriculum geared toward acquiring fundamental techniques in cellular and molecular biology and developing a critical approach to transplant immunology. The program will be directly supervised by Dr. Ferrara, whose laboratory is dedicated to understanding the immunopatho-physiologic mechanisms of GVHD. A panel of senior investigators at DFCI will monitor the progress of this project and offer constructive criticism to facilitate preparation for and eventual transition to status of an independent principal investigator.