Transforming Growth Factor

Abstract

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.