Pathogenesis of Post-Transplant Bronchiolitis Obliterans

Washington University, Saint Louis MO

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Abstract

Lung transplantation (LTx) is a treatment option for end-stage pulmonary parenchymal and vascular diseases. However, long-term survival of the lung allograft is limited by the development of bronchiolitis obliterans syndrome (BOS), a condition unresponsive to therapy and in most cases fatal. Using unique murine models of orthotopic and heterotopic transplantation we have obtained evidence regarding the seminal role for alloantibodies and TLR mediated activation of innate immune responses in the pathogenesis of obliterative airway disease (OAD). Further, using a sendai virus infection model of orthotopically transplanted trachea, we have demonstrated an important role for post transplant viral infection in augmenting epithelial destruction and fibroproliferation which paralles clinical BOS following respiratory viral infections in lung transplant recipients. Goals of this project are to : 1) define the mechanism by which viral infection augments the immuno pathogenesis of chronic rejection using a murine orthotopic tracheal transplantation and viral infection. Towards this, we will determine: a) Kinetics of epithelial cell repopulation , characteristics of the cellular infiltration and lesions following Sendai viral infection, b) lesions in Matrix Metalloproteinase -7 deficient mice incapable of re-epithelialization and c) presence of T cells specific for viral and alloantigens and evaluate their cross reactivity 2) Determine the mechanism of OAD development following the administration of monoclonal antibody specific for MHC class I into RAG-/-KO mice transplanted with trachea from HLA-A2 as well as H-2MHC class I mismatched donors. Towards this, we will determine the role of; a) FC receptor (FcR) in epithelial damage, b) T cells and their subpopulations in the development of OAD by cell transfer, c) stress proteins and TLR 2, 4 in the development of OAD. 3) Determine the role of TLRs and innate immunity in the destruction of epithelium and fibrosis in an OAD model of orthotopic tracheal transplantation across MHC mismatch. Towards this, we will determine: a) the kinetics of innate immune activation through TLRs, b) intra-cellular signaling events subsequent to TLR activation, and c) identify the endogenous ligands for TLR. The overall goal of this proposal is to employ unique preclinical murine models of OAD and post transplant viral infections in order to define the cellular and molecular mechanisms leading to.BOS following clinical lung transplantation.