Over the past ten years techniques for lung transplantation (LTx) have been refined, indications have been broadened, and the postoperative care has become less complicated. A number of lung transplant programs, including their own, have reported operative mortality rates of less than 10 percent. Despite this improvement in early survival, the longterm outlook for lung allograft recipients is bleak due to a syndrome of chronic lung allograft dysfunction termed bronchiolitis obliterans syndrome (BOS). Although much has been written on the possible etiologic factors involved in the pathogenesis of BOS, to date there are no definitive answers to explain the basic mechanisms leading to the development of BOS. However, it is widely presumed that this condition is due to chronic rejection. The findings of significant correlation between the development of anti-HLA antibodies (Abs) during the post-transplant period and development of BOS in lung transplant recipients support this hypothesis. Also, it has been proposed that cytomegalovirus (CMV) infection may predispose the transplant recipients to the development of BOS. This proposal will determine the role of donor specific anti-HLA and anti-endothelial Abs in the development of BOS after LTx. The kinetics of post-transplant development of Abs specific for donor HLA and endothelial antigens will be prospectively analyzed by cytotoxicity and immunofluorescence methods. In patients where antibody development is transient, the investigator will examine the development of anti-idiotypic Abs and their role in down-regulating the anti-HLA response. To test the hypothesis that the development of anti-HLA Abs is primarily due to indirect HLA antigen presentation of donor HLA peptides to recipient T cells, they will determine whether T cells specific for donor MHC antigens and their peptides are present in lavage fluid and blood samples obtained from lung transplant recipients. Finally, the presence and frequency of CMV activated T helper and cytotoxic cells in lavage fluid will be determined using limiting dilution analysis. The frequency of such cells will be correlated with the development of BOS after LTx. The investigator will also define the MHC restriction and peptide specificity of these CMV specific T cells. The longterm goal of this proposal is to understand the immunological mechanisms leading to the development of BOS after LTx in order to formulate new strategies for the prevention and/or cure of this major clinical problem facing LTx.
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