Entwicklung eines Modells der chronischen Abstoßung von Lungentransplantaten in sensibilisierten, immunsupprimierten Empfängern in der Ratte
Final Report Abstract
Background: In spite of remarkable progress in prevention and treatment of acute pulmonary rejection (AR), modern immunosuppressive therapy has not substantially affected the course of chronic rejection (CR). Multiple etiologic factors, both immunologic and non-immunologic, are contributing to the development of CR. Within three years post-transplantation, in more than 60% of all lung allografts, fibro-obliterative remodeling of the small airways has been found on transbronchial biopsy, correlating with a progressive and most often irreversible decline in ventilatory function. The pathological hallmark of CR in pulmonary transplants is bronchiolitis obliterans (BO), triggered by lymphocytic infiltration of bronchiolar structures, which induces a fibroproliferative response, eventually leading to luminal obstruction of medium and small bronchioli. Once BO is emerging, modification of immunosuppressive therapy may only ameliorate its dynamics, but will not reverse the impeding deterioration of graft function. Working Hypothesis: In spite of the impact of chronic pulmonary rejection on patient morbidity and mortality, straightforward experimental models addressing CR do not exist. We propose a clinically relevant and reproducible model of CR with sensitized recipients receiving unilateral orthotopic lung transplants. Specific Aitns: Based on experience in establishing a cardiac CR model, and advancing our studies in pulmonary allograft transplantation in sensitized rats, we developed a reproducible experimental setup to study BO. In a first proof-of-concept approach, we have identified treatment regimen and timeframe to initiate BO-like changes in orthotopic pulmonary grafts in sensitized rat recipients. Experimental Design and Methods: LEW-rats, sensitized with BN-skin receive left lung transplants from LBNFp donors, seven days later. The development of CR is modulated by a sequential treatment pattern with rapamydn (RPM) and cyclosporine (CsA). Pulmonary function tests, intragraft m-RNA expression of T-bet and GATA-3, and immunohistochemical and immunofluorescent staining of Thl/Th2 cytokines are used to track and document the course of BO. Value of the Proposed Project: We proposed a relevant and reproducible approach for studying CR in lung transplantation. This model will allow for better understanding of the pathological changes at die level of small airways during the course of BO. Subsequently, it will serve as a standardized in vivo setup and workbench for testing the efficacy of novel therapeutic interventions and the impact of secondary injuries on the progress of this disease.
