The proposed research will attempt to resolve the major problems that presently prevent lung transplantation from being a practical therapeutic modality. To resolve the shortage of good donor lungs we will develop simple flush-cooling methods of lung preservation which are effective up to 72 hours. Such methods, which must also permit transportation, will also provide time for specific recipient treatment prior to transplantation. To prevent bronchial anastomotic complications we will study the pathogenesis of these problems so that the important causes may be eliminated. To this end microsurgical techniques will be used to restore bronchial artery continuity more simply and specific immunosuppression that does not rely on massive doses of corticosteroids will be developed. To determine the optimal unit of lung tissue to transplant in emphysema we will develop an experimental model of emphysema which has vascular changes comparable to human emphysema. Animals with this experimental emphysema in one lung will undergo functional testing before and after transplantation of their other lung. To prevent allograft rejection more safely and dependably methods for specific immunosuppression will be developed in mice and applied to dogs. These methods will involve recipient pretreatment with irradiation and antilymphocyte serum to produce an immunologically primitive state followed by reconstitution with bone marrow in which thymic dependent lymphocytes are decreased by treatment with specific antiserum. Survival and lung allograft function in animals so treated will be evaluated and compared with that obtainable with standard nonspecific immunosuppression. To evaluate mechanisms of lung allograft rejection and develop methods for identifying it earlier and more accurately we will perform serial studies of alveolar lavagates from transplanted lungs. Cellular morphology and function together with analysis of macromolecule chemistry and behavior (mediators) will be evaluated. To determine the long-term consequences of single lung transplantation in the absence of rejection, animals surviving after autotransplantation of the left lung and ligation of the right pulmonary artery will undergo serial evaluations of pulmonary morphology, function and hemodynamics at rest and after various stresses.
|Norin, A J (1988) The immunobiology of experimental lung transplantation with cyclosporine immunosuppression: cytolytic T lymphocytes and delayed type hypersensitivity in rejecting and tolerant recipients. Transplant Proc 20:125-30|
|Norin, A J; Kamholz, S L; Pinsker, K L et al. (1987) Cyclosporine-induced tolerance in experimental organ transplantation. Evidence of diminished donor-specific cytotoxicity relative to donor-specific proliferative response. J Immunol 139:332-7|