TRANSGENIC MOUSE MODEL OF BRONCHIOLITIS OBLITERANS

本申请寻求为斯图尔特·C·斯威特博士提供资金，斯图尔特·C·斯威特目前是一名研究员 在圣路易斯华盛顿大学的儿科肺科，寻求 细胞免疫学方面的额外培训。斯威特博士的长期任期 兴趣涉及了解慢性移植物的细胞机制。 肺移植受者的功能障碍。该项目的目标是 本申请概述的是开发一种小鼠模型系统，该系统 模仿慢性肺移植最重要的形式 功能障碍，闭塞性支气管炎(BO)，发生在25%到 50%的肺移植受者，是晚期死亡的主要原因。 尽管BO的病因尚不清楚，但目前的证据表明 两种潜在的重要机制：慢性免疫介导的上皮细胞 血小板衍生生长因子(PCGF)的损伤和过度表达。我们 建议使用转基因小鼠来测试这两种可能性。 为了测试同种异体免疫反应是否导致了BO， 将产生表达小鼠I类抗原的转基因小鼠， L(D)在Clara细胞分泌蛋白(CCSP)启动子的控制下。 CCSP启动子将基因的表达导向Clara细胞 由交界区75%的细支气管上皮细胞组成 在传导细支气管和呼吸性细支气管之间。细支气管炎。这个 细支气管壁是BO的主要损害部位。 L(D)反应性过继转会致细支气管炎 淋巴细胞；这些动物的肺将进行组织学检查 与BO类似的变化。 为了确定过度表达是否在BO的发生发展中起重要作用， 将产生转基因小鼠，其中PDGF-B在 多西环素可诱导细支气管上皮细胞的形成。 如上所述，将检查这些动物的lng的组织学变化。 类似于BO。这两种潜在机制都存在的动物 Active也将被评估。 确定同种异体免疫反应是否足以诱导 BO的发展将尤为重要，因为在这个时候 加强免疫抑制是BO患者的主要治疗方法。 如果PDGF过度表达在BO的病因中起重要作用，那么它 将表明针对生长因子的治疗可能是 善意的。然后，这些动物将提供一个模型系统，在其中新的 治疗的形式可能会受到测试。 斯威特医生预计将加入儿科教员 1996年7月，并将在支助期间由 遗传学系的泰德·汉森教授。该公司提供的资金 这一奖项将促进Swets博士发展成为一名独立的 科学家。

This application seeks funding for Dr. Stuart C. Sweet, currently a fellow in Pediatric Pulmonary at Washington University, St. Louis, to seek additional training in cellular immunology. Dr. Sweet's long term interests involve understanding the cellular mechanisms of chronic graft dysfunction in lung transplant recipients. the goal of the project outlined in this application is to develop a murine model system which mimics the most important form of chronic lung transplant graft dysfunction, broncholitis obliterans (BO), which occurs in between 25% and 50% of lung transplant recipients and is th major cuase of late mortality. Although the etiology of BO remains unclear, current evidence implicates two potentially important mechanisms: chronic immune-mediated epithelial injury and over expression of platelet derived growth factor (PCGF). We propose to use transgenic mice to test both of these possiblities. To test whehter an allogeneic immune response is responsible for BO, transgenic mice will be generated which express the mouse class I antigen, L(d) under the control of the Clara cell secretory protein (CCSP) promoter. The CCSP promoter directs expression of genes to the Clara cells which comprise 75% of the bronchiolar epithelial cells in the junctional region between the conducting and respitory bronchioles. The bronchioles. The bronchiolar epitehlium is the primary site where damage is observed in BO. Brocchiolar injury will be induced by adoptive transfer of L(d) reactive lymphocytes; lungs from these animals will be examined for histologic changes similar to BO. To determine whether over-expression is important in the development of BO, trangenic mice will be generated in which PDGF-B expression in the bronchiolar epithelium can be induced by the administration of doxycycline. As above, lngs from these animals will be examined for histologic changes similar to BO. Animals in which both of the potential mechanisms are active will also be evaluated. Determining whether an allogeneic immune response is sufficient to induce the development of BO will be particularly important because at this time enhanced immunosuppression is the predominant therapy for patients with BO. If PDGF over-expression plays an important rolw in the etiology of BO, it will suggest that therapy directed against growth factors may be benfeficial. These animals would then provide a model system in which new forms of therapy may be tested. Dr. Sweet anticipates joining the faculty of the Department of Pediatrics in July 1996, and will be supervised during the period of support by Professor Ted Hansen in the Department of Genetics. The funds provided by this award will facilitate Dr. Sweets's development into an independent scientist.