MECHANISMS OF EXTRACORPOREAL PHOTOPHERESIS IN THE TREATMENT OF LUNG ALLOGRAFT REJECTION



 DESCRIPTION (provided by applicant): Median graft survival for recipients of lung transplants remains approximately 5 years, the worst of all solid organ transplants. The major cause of death after the first year post-transplantation is chronic rejection, manifest primarily as bronchiolitis obliterans syndrome (BOS). Therefore, there is a critical unmet need for new treatment strategies that prevent or limit the progression of BOS and will thereby effectively prolong graft survival. Extracorporeal photopheresis has shown promise in the treatment of BOS, however it is typically used as a salvage therapy, instituted only after conventional approaches have failed. Initially developed for the treatment of cutaneous T cell lymphoma, ECP has also been successfully used to treat a number of diseases, including cardiac allograft rejection and chronic graft versus host disease following allogeneic stem cell transplantation. However, our ability optimally utilize this treatment is severely hampered by a lack of mechanistic understanding. The major goals of this proposal are to develop a murine model of ECP in lung transplantation, and to determine the mechanism by which ECP modulates the immune response. To accomplish this, we have developed in vitro and in vivo model systems which recapitulate the key effects of ECP, as well as the essential features of bronchiolitis obliterans. In specific aim 1, we will use an established murine orthotopic lung transplant model, pioneered by Washington University researchers, to determine the effectiveness of ECP to prevent the development of obliterative airways disease. This system will be the first, animal model to investigate ECP in lung transplantation. In specific aim 2, we will use both in vitro and in vivo approaches to dissect the mechanism by which ECP modulates effector T cell function. If successful, we will have established the first in vivo murine model system of the treatment of chronic lung allograft rejection with ECP, allowing us to explore mechanism, and most importantly, to determine how best to use ECP in the prevention and treatment of BOS in lung transplant recipients. The data obtained from this pilot project will provide essential information that will guide future studies in both mice and humans, and may provide critical supportive evidence for the early use of ECP to prevent bronchiolitis obliterans.