- Prof. Andrew George, Principal Investigator
- Dr. Giovanna Lombardi, Co-Investigator
- Mr. Frank Larkin, Co-Investigator
- Prof. Robert Lechler, Collaborator
- Imperial College London, Hammersmith Campus, London, UK
- Modification of Dendritic Cells and DNA Vaccination for the Induction of Tolerance
The major challenge in transplantation is to find ways of stopping the immune system from destroying the graft. This is normally done by blanket immunosuppression, in which drugs are used to prevent the immune system from working properly. This has disadvantages, for example it leaves the patients prone to infection. It would be much more desirable to develop methods of inducing specific tolerance to the graft, so that the immune system does not recognise the graft but otherwise functions normally.
We have recently developed a method that we think will achieve this by genetically modifying a cell called the dendritic cell. A dendritic cell can be thought of as the sentinel of the immune system, spotting foreign material and then presenting it to the T cells, that then respond to the invaders – for example by killing them. The dendritic cell uses a number of molecules to communicate with the T cells, and we have shown that it is possible to remove two of these molecules (called CD80 and CD86) using a new strategy involving genetic modification of the dendritic cell. The gene that we introduce into the cell encodes for a protein that binds to CD80 and CD86 and prevents them getting to the cell surface. When this happens the dendritic cell is no longer able to activate the T cell.
We now want to see whether we can induce tolerance to grafts in animals. We will genetically modify the dendritic cells and introduce them into animals. We will then see if this can lead to the survival of heart and corneal grafts in the animals. We expect that this approach will allow specific tolerance to the grafts. We then plan to develop a method of administering the gene using vaccination, which would be simpler to use in the clinic.