Research Group

  • Prof. John Kirby, Principal Investigator
  • Prof. Alastair Burt, Co-Investigator
  • Dr. Helen Robertson, Research Associate

Location

  • University of Newcastle, Newcastle upon Tyne, UK

Title

  • Therapeutic Elimination of Intraepithelial T Cells: A Strategy to Reduce Epithelial-Mesenchymal Transdifferentiation and Chronic Allograft Dysfunction

Kidney transplantation remains the preferred treatment for end-stage renal failure but long-term graft survival is disappointing, with 35% failing within five years. A major feature of the chronically failing graft is the development of fibrosis, especially in the interstitium around the kidney tubules. Grafts that suffer the most severe acute rejection problems during the early period after transplantation tend to be those that subsequently develop fibrosis and fail. The link between these two processes is not understood and there is no effective treatment for chronic graft failure.
We have shown that recipient T cells accumulate within the kidney tubules during acute rejection and some of these T cells persist for long periods. In this project we will test the hypothesis that long-lived T cells generate a chronic stimulus, causing local tubular epithelial cells to change into fibroblasts. These fibroblasts then multiply around the tubules and produce extracellular matrix, which, over time, takes the place of functional tissue, causing graft dysfunction and eventually graft failure.
Loss of airway epithelium and fibrosis are also major features in obliterative bronchiolitis causing chronic lung graft failure, and vanishing bile duct syndrome occurs in late failure of around 10% of liver transplants. Therefore, there is the potential for similar processes to those described above to occur after transplantation, leading to dysfunction of lung and liver allografts. This will also be investigated.
An important consequence of our hypothesis is that elimination of intraepithelial T cells should prevent progression to chronic graft failure after initial acute rejection.