- Dr. Su Metcalfe, Principal Investigator
- Miss Poorni Muthukumarana, Ph.D. Student
- University of Cambridge, Addenbrookes Hospital, Cambridge, UK
- Does Axotrophin Regulate Tolerance in Organ Grafts?
Cellular activity is regulated by on and off switches, ensuring that appropriate responses only occur when they are required. This control is vital in the context of the immune response, and a special type of regulatory T lymphocyte normally prevents auto-immune reactivity whilst permitting immune attack against pathogenic microbes. There is great scientific and medical interest in exactly how the regulatory lymphocyte succeeds in preserving this balance. The answer to the question "What regulates the regulator?" will advance exploitation of natural immunity for preventing rejection of organ transplants and for successful use of stem cell implants in regenerative medicine.
Axotrophin is a novel gene of unknown function that is found in mammalian stem cells. Using micro-array analyses we have discovered that axotrophin is associated with tolerance to heart grafts in mice. We also found that axotrophin has profound effects in T lymphocytes, effects that might be exploited in treatment of disease. Our aim is to identify how axotrophin functions in organ graft tolerance. To test our hypothesis that axotrophin plays a critical role in regulatory lymphocyte function we will use mice that lack the axotrophin gene. Here we anticipate that attempts to induce transplantation tolerance will fail. Other experiments will use cloned regulatory lymphocytes to ask if "knock down" of axotrophin destroys the regulatory phenotype. The knock down experiments use RNA interference, a highly specific technique that will also allow us to look for a relationship between axotrophin and Foxp3. Foxp3 is a molecular "master switch" in the regulatory T lymphocyte and we hypothesise that axotrophin and Foxp3 are somehow linked in function.
By understanding the regulatory role of axotrophin in lymphocytes, we may eventually develop means to produce donor-specific regulatory T lymphocytes in transplant recipients, so harnessing the power of immune regulation for graft tolerance whilst simultaneously preserving full immune competence to protect the patient from infection.