Kidney transplant recipients currently face a lifetime of immune-suppressing drugs that raise their risk of deadly infections, cancer, and heart disease. This project investigates whether infusing patients with their own regulatory T cells—a type of immune cell that naturally calms immune responses—can replace those drugs. The problem is that no one knows how well these infused Tregs actually work inside the body, or exactly how they prevent the immune system from attacking the donated kidney. The researcher will analyse blood and biopsy samples from transplant recipients, including those in an ongoing Oxford clinical trial, using high-resolution techniques to track whether the Tregs multiply, target the kidney specifically, and dampen inflammation without weakening the body’s ability to fight infections. If the mechanisms are clarified, the findings could improve the Treg “product” for future trials—making it more potent and safer—and ultimately reduce or eliminate the need for lifelong immunosuppression. That would transform long-term outcomes, especially for people transplanted at a young age who face decades of drug side effects.
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Kidney transplantation has been one of the major medical success stories of the twentieth century and significantly improves the survival of patients with end stage renal failure (ESRF)1. However, whilst the short-term outcomes are excellent after kidney transplantation, the longer term challenges of preventing a recipient’s immune system attacking the donated kidney, a term called ‘rejection’, remain. At present, lifelong immune-suppression medications are needed to prevent rejection. Continuous use of immunosuppressive drugs increases the risk of serious infections, cancer and heart disease, which are all amongst the leading causes of death in kidney transplant recipients2. This is a particular problem in people who receive a transplant at a young age and therefore have a higher lifetime exposure to these medications. Therefore, alternative methods of preventing kidney transplant rejection are urgently needed. Regulatory T cells (Tregs) are naturally occurring immune cells in the body that are known to play a critical role in preventing overactivity of the immune system and helping maintain immune equilibrium. Therefore, there has been much interest in using Tregs to control the harmful immune response to a transplanted kidney and has led to the development of several clinical trials to study the effectiveness of Tregs as a ‘living drug’ including the Transplantation Without Over-Immunosuppression (TWO) Study currently ongoing within the University of Oxford. Whilst Tregs may represent an encouraging alternative to immunosuppression, the degree to which infused Tregs can dampen the immune response to transplantation is not known. Furthermore, the mechanism of how Tregs can help prevent rejection are not fully understood. My proposal with the Transplantation Research and Immunology Group (TRIG) at the University of Oxford, focuses on better understanding the mechanisms in which infused Treg therapy can regulate the immune system after transplantation. I will use blood and biopsy samples from transplant recipients, including those within the TWO study, to answer these questions. In particular, I aim to study the biological features of infused Tregs using state-of-the art high-resolution techniques, including their ability to replicate, interact with other immune cells and specifically target the donated kidney. I also aim to investigate how Tregs contribute to overall immune function after transplantation compared to standard immunosuppression medication and in particular if they lead to a specific reduction in inflammatory cells against the kidney, without affecting the immune system’s ability to respond to infections. Gaining a better understanding of how Tregs exert their suppressive functions after transplantation will be important for a number of reasons. Firstly, it will provide valuable insights into the mechanism of immune regulation after transplant and perhaps highlight ways in which the immune system can be exploited in the future to prevent rejection. Secondly, it will provide valuable information to improve the Treg ‘product’ for future clinical trials, with the aim of developing therapy with enhanced function without unwanted side effects. These are exciting prospects that would impact the whole transplantation field.
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