Advances in organ transplantation have significantly improved allograft and patient survival. However, chronic immune rejection remains a significant basis for graft failure across organ types. For example, allograft failure due to immune-mediated rejection is the most common reason for kidney re-transplantation. In cardiac transplant, allograft vasculopathy, a hallmark of chronic rejection, is one of the most common causes of death in recipients beyond 3 years of transplantation and, similarly, chronic beyond therapies lung allograft dysfunction is the leading cause of death 1 year of lung transplantation. Therefore, there is an unmet need to develop effective to halt and reverse damage due to chronic rejection.A hallmark of chronic rejection is fibrosis which progressively replaces functional tissue ultimately leading to allograft failure. This proposal seeks to modify the natural history of progressive fibrosis in the allograft. Cancer associated fibroblasts (CAFs) promote fibrosis that shield the tumor from the immune system and therapies. One approach to deplete pathogenic fibrosis within the tumor microenvironment targets fibroblast activation protein (FAP), a cell surface proteolytic enzyme that is expressed by activated fibroblasts. Pre-clinical studies have shown anti-tumor efficacy of FAP-targeted immunotherapy and have spurred clinical trials aimed at eliminating FAP+ fibroblasts. One strategy employing FAP-specific chimeric antigen receptor (CAR) T cells has yielded impressive tumor regressions in murine models. Recently, FAP-CAR T cells have also been shown to reverse pathologic cardiac fibrosis that occurs following myocardial injury. In addition to paving the way for use of CAR T cells for restoration of organ function in common non- cancer conditions, this work also clearly implicates FAP+ fibroblasts as an important cell type in collagen deposition in the context of malignancy as well as non-malignant tissue fibrosis. Our preliminary data demonstrates FAP expression in lung, kidney, and cardiac allografts undergoing rejection with associated fibrosis. The presence of FAP across species and allograft types suggests FAP/FAP+ cells are an important participant in allograft fibrosis. Therefore, we hypothesize that chronic rejection leads to FAP+ fibroblast accumulation which promotes deposition of extracellular matrix leading to fibrosis and progressive allograft dysfunction. The proposed studies seek to define the expression of FAP in the context of allograft rejection, determine the contribution of FAP and FAP+ cells to allograft dysfunction, and test a CAR T approach to mitigating fibrosis.