Lung transplant (LTx) is a viable treatment option for a variety of end-stage pulmonary parenchymal and vascular diseases. Advancements in surgery, immunosuppression and recipient selection have significantly improved perioperative survival following LTx. However, the long term survival of the transplanted lungs is limited by the development of bronchiolitis obliterans syndrome (BOS), an irreversible and often fatal condition that is unresponsive to therapy. During the previous award period we demonstrated: 1) The development of anti-HLA antibodies (Abs) to mismatched donor antigens precede and increases the risk of BOS, 2) a role for indirect antigen presentation of mismatched HLA in the development of BOS 3) A role for airway epithelial damage caused by the anti- MHC Abs in the innate immune activation, up regulation of inflammatory mediators and recruitment of immune cells into the lung, and 4) induction of de novo autoimmunity to K-?1 tubulin and collagen V following anti-MHC Ab development or viral infection. Therefore, the overall goal is to test the hypothesis that chronic rejection following human LTx (BOS) is the net result of epithelial cell (EC) damage caused either by allo- or anti-viral immunity leading to immune responses to self-antigens including K-?1 tubulin and collagen V. Hence, treatment regimens, which will prevent the development of autoimmunity by early intervention of alloimmune or anti-viral responses, will have a beneficial effect in preventing BOS. Towards this using lung transplant recipients from 2 centers we will;1) define the autoimmune process and its kinetics induced by allo- immune response to mismatched donor-HLA by determining the cellular reactivity to donor HLA and self antigens K-?1 tubulin and collagen V by ELISPOT and Ab development by luminex and ELISA, 2) define the mechanism by which viral infection leads to down regulation of regulatory T cells resulting in augmentation of allo-immunity as well as autoimmunity by enumerating T reg using FACS and analyzing the role for Fas and FasL in apoptosis, and 3) define the signaling mechanisms by which anti-MHC and auto-Abs to K-?1 tubulin result in EC proliferation, fibrosis and occlusion by analyzing the signaling intermediates, TLR2 and 4 by PCR and role for 1 and 2 defensins in inducing signals. Results from these studies will provide a basis to institute new therapeutic strategies to prevent BOS, the predominant factor that limits long-term survival following LTx.
Project Narrative/Relevance The overall goal is to test the hypothesis that chronic rejection following human LTx (BOS) is the net result of epithelial cell damage caused either by allo- or anti-viral immunity leading to immune responses to self-antigens including K-?1 tubulin and collagen V.
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