Lung transplantation (LTx) is a common treatment option in a variety of end-stage pulmonary Parenchymal and vas diseases. Improvements in recipient selection, surgical techniques, and immunosuppressive regimens have all increased survival following LTx. However, the long term survival of the lung allograft are limited by the development of bronchiolitis obliterans syndrome (BOS) an unexplained and irreversible condition unresponsive to therapy and in most cases fatal. Although much has been written on the possible etiological factors and pathogenesis of BOS, no definite answers exist to explain the basic mechanism by which BOS develops. A growing body of evidence suggests that BOS is caused by immunological-mediated injury directed against epithelial cells of the lung allograft. Using a unique murine model of heterotopic transplantation of HLA-A2 transgenic tracheal grafts into CD8 T cell-knockout (KO) as well as CD4 T cell-KO C57BL/6 mice, we have obtained compelling evidence for a seminal role for indirect antigen presentation of the mismatched HLA-A2 molecule in the pathogenesis of obliterative airway disease (OAD). Specific goals of this project are: 1) To define the role of CD4 T cells, CD8 T cells, and NK cells in the development of OAD in this model where there is only a single MHC difference between donor and recipient. This will be accomplished by HLA-A2 tracheal transplantation into CD4-KO or CD8-KO animals as well as administration of anti-CD4 or anti-CD8 antibodies to abrogate the pathology. In addition, the role of interleukin-2 in the immunopathogenesis of OAD will be investigated. 2) To determine the mechanism of OAD development following HLA-A2 tracheal transplantation into syngeneic CD8-KO recipients. We will test the ability of spleen cells from animals with OAD to respond to HLA-A2 and their peptides. Requirement for processing of HLA-A2 molecules as well as production of antibodies specific for HLA-A2 will be investigated. 3) To determine the dominant HLA-A2 epitopes to which immune response takes place leading to OAD. Towards this, proliferation assays at different time points following transplantation will be done using peptides covering the alpha1, 2 and 3 domains of HLA-A2 molecule. 4) To determine the role of CD4 TH1 and TH2 cells against the HLA-A2 peptides in the development of OAD. Passive transfer of in vitro generated HLA-A2 specific CD4 TH1 or TH2 cells and its consequences on OAD will be investigated, and 5) To define the role of antibodies specific for HLA-A2 in the development and/or perpetuation of OAD in the HLA-A2 tracheal grafts. This will b accomplished by using Immunoglobulin-KO recipients and by passive administration of HLA-A2 antibodies following transplantation. Production of growth factors by epithelial cells and their effect on fibroblasts and smooth muscle cells will also be investigated to define the mechanism of OAD development. The overall goal of this proposal is to employ this unique murine preclinical model of OAD in order to define the cellular and molecular mechanism leading to BOS following clinical lung transplantation.
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