Pathogenesis and Therapy of Chronic Lung Rejection

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.