Chronic allograft rejection (CR) is the main barrier to long-term transplant survival. CR is a progressive disease defined by interstitial fibrosis, vascular neointimal development, and graft dysfunction. The underlying mechanisms responsible for CR remain poorly defined, although transforming growth factor β (TGFβ) has been strongly implicated in promoting fibrotic diseases and CR. However, TGFβ is a suppressive cytokine, which may be beneficial in the transplant setting. Hence, an in depth assessment of the fibrotic and anti-inflammatory activities of TGFβ in cardiac transplant was performed. In this study, the role of TGFβ on graft-reactive cellular and humoral responses, T regulatory cell (Treg) function, allograft acceptance and the progression of CR are assessed. These studies identify TGFβ dependent and independent pathways to allograft acceptance, and investigate the contribution of TGFβ-induced IL-17 in the progression of CR. Since TGFβ exhibits exacerbating or ameliorating characteristics depending on the site of action, TGFβ neutralization within the allograft addresses local TGFβ inhibition on fibrosis and graft-reactive T and B cell responses. Studies in this dissertation provide insight into the underlying causes of CR and identify therapeutic targets for treatment of this disease
To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.