TRANSGENIC MOUSE MODEL OF BRONCHIOLITIS OBLITERANS

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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.