Final Activity Report Summary - ROSAT (EST programme to study the regulation of organ survival after transplantation)
The ROSAT project was devised to provide four EST fellows with the skills required to investigate mechanisms of inflammatory tissue damage with particular reference to chronic organ failure after transplantation. The four EST fellows worked on separate but related projects which examined aspects of the rejection of transplanted human kidney, lung and liver. Together these projects identified a similar set of processes which can cause chronic failure of each of these organs.
The functional units of the lung, liver and kidney consist of ducts which are lined by epithelial cells. In the lung these ducts carry air, in the kidney they carry waste products to the urinary bladder, and in the liver they collect and carry bile to the gut. Three of the EST fellows demonstrated that ductular epithelial cells from each of these organs can be induced to transform into fibroblasts, resulting in function-damaging scar formation. This process is termed Epithelial to mesenchymal transition (EMT). Importantly, the fellows showed that components of the immune response which are active after transplantation can induce this EMT process. These include cytokines such as TGFbeta and TNFalpha, the presence of oxidative stress, and graft infiltrating immune cells.
Crucially, the individual fellows also showed how EMT-promoting cytokines are activated in graft tissues, how immunoregulatory T can contribute to this chronic pathology and how molecules which are expressed early in the EMT process can regulate fibrosis. Each of these observations has been described at conferences and has either been published already or will soon be submitted for publication.
The fourth fellow has examined molecular components of the excess extracellular material which is deposited during graft failure. Crucially, this work has shown how a key enzyme is regulated during this process. It is already clear that modulation of the activity of this enzyme can alter the activity of cytokines which promote graft inflammation and fibrosis.
By the conclusion of the project, one fellow has submitted her PhD thesis for examination and two will submit PhD theses within the next few months. The fourth fellow is completing further research in my group but also plans to submit her PhD in due course.
The functional units of the lung, liver and kidney consist of ducts which are lined by epithelial cells. In the lung these ducts carry air, in the kidney they carry waste products to the urinary bladder, and in the liver they collect and carry bile to the gut. Three of the EST fellows demonstrated that ductular epithelial cells from each of these organs can be induced to transform into fibroblasts, resulting in function-damaging scar formation. This process is termed Epithelial to mesenchymal transition (EMT). Importantly, the fellows showed that components of the immune response which are active after transplantation can induce this EMT process. These include cytokines such as TGFbeta and TNFalpha, the presence of oxidative stress, and graft infiltrating immune cells.
Crucially, the individual fellows also showed how EMT-promoting cytokines are activated in graft tissues, how immunoregulatory T can contribute to this chronic pathology and how molecules which are expressed early in the EMT process can regulate fibrosis. Each of these observations has been described at conferences and has either been published already or will soon be submitted for publication.
The fourth fellow has examined molecular components of the excess extracellular material which is deposited during graft failure. Crucially, this work has shown how a key enzyme is regulated during this process. It is already clear that modulation of the activity of this enzyme can alter the activity of cytokines which promote graft inflammation and fibrosis.
By the conclusion of the project, one fellow has submitted her PhD thesis for examination and two will submit PhD theses within the next few months. The fourth fellow is completing further research in my group but also plans to submit her PhD in due course.