SPECIFIC AIMS: Obliterative bronchiolitis (OB) is the leading cause of late death after lung transplantation (LTx) and the principle unmet obstacle to improved long-term outcomes. Therefore, our long-term goal is to identify novel mechanisms of transplant injury so as to be able to develop therapeutic strategies to prolong Tx survival. Increasing evidence indicates a role for recipient autoimmunity in the pathogenesis of graft rejection. Autoreactive antibodies (Abs) directed against lung-restricted proteins, such as Collagen V (ColV) and /or K-α tubulin (KAT), produced post-Tx have been shown to promote rejection and OB. Emphysema, a principle indication for LTx, has been shown to express a wide-spectrum of extracellular matrix (ECM) autoreactive antibodies and T cells directed towards collagen, elastin, and decorin, the impact of which on post-Tx outcomes is unknown.
The scientific premise of these studies is to determine if pre-transplant pre-existing autoreactive immunity induced by emphysema, promotes early post-transplant injury that leads to worse ischemia reperfusion injury (IRI) and OB. Therefore, in these studies we will utilize mouse models of emphysema and orthotopic lung transplantation, to investigate lung transplant outcomes in a clinically relevant scenario. The project will use a series of immunological techniques to probe the mechanisms under investigations.