PATHOGENESIS OF CHRONIC REJECTION IN LUNG TRANSPLANT

Washington University, Saint Louis MO

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Abstract

[unreadable] DESCRIPTION (provided by the applicant): The long term survival and function of transplanted lungs are limited by the development of bronciolitis obliterans syndrome (BOS), an unexplained often nonreversible condition unresponsive to therapy and in most cases fatal. Over the past two years, compelling evidence has been obtained that the development of anti-HLA antibodies against mismatched donor antigens and the detection of in vivo priming against mismatched donor HLA class I antigens defined by indirect antigen presentation assays have significant correlation with the development of BOS. The first specific aim of this proposal is to demonstrate increased frequencies of donor reactive T cells prior to the appearance of anti-HLA antibodies in lung transplant recipients. This will be done by testing recipient peripheral blood leukocytes with donor mismatched HLA class I and II peptides in the presence of autologous antigen presenting cells in a proliferation assay. Therefore, in vitro methods to detect in vivo priming against mismatched donor HLA class land II antigens may serve as a good measure of successful intervention by changes in immunotherapeutic protocols. The second specific aim of this proposal is to define the biology and biochemistry of this newly identified airway epithelial antigen and to correlate the development of antigen specific antibodies with the development of BOS. A panel of airway epithelial cells (AECs) and the AEC specific silo antibodies developed post transplant will be used to define the polymorphism of this antigenic system. Using internal labeling of AEC and immunoprecipitation analysis using alloantibodies specific for AEC antigen, the biochemistry of this antigen will also be defined. The overall goals of this proposal are to continue to define the cellular and molecular mechanisms contributing to the development of BOS subsequent to lung transplantation and to allow the institution of new therapeutic strategies which will prevent the development and consequences of BOS, a major limiting factor for the continued function of the transplanted organ.