Transforming growth factor beta, allograft acceptance and chronic allograft rejection

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 beta (TGFbeta) has been strongly implicated in promoting fibrotic diseases and CR. However, TGFbeta 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 TGFbeta in cardiac transplant was performed.;In this study, the role of TGFbeta on graft-reactive cellular and humoral responses, T regulatory cell (Treg) function, allograft acceptance and the progression of CR are assessed. These studies identify TGFbeta dependent and independent pathways to allograft acceptance, and investigate the contribution of TGFbeta-induced IL-17 in the progression of CR. Since TGFbeta exhibits exacerbating or ameliorating characteristics depending on the site of action, TGFbeta neutralization within the allograft addresses local TGFbeta 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.