Our Future Research
1. Tipping the balance towards tolerance- infusion of recipients tolerizing T cells
A population of human T cells that are tolerizing (i.e. counteracting the rejecting cells) has been defined recently. They express the product Foxp3 which is a transcription factor for activating the tolerance gene profile, secrete transforming growth factorβ and have mTOR inhibition. These cells can be proliferated in the laboratory in sufficient numbers to be infused into transplant recipients. But do they work in this context, how many cells need to be infused and are there adverse effects? These questions are currently being addressed in a multicentre study coordinated from Regensburg in Germany for countries in the European Union. We will assess their results before recommending undertaking our study. But the proposal of a tolerizing T cell infusion combined with reduced immunosuppression has the appeal of reducing the morbidity from immunosuppression. To carry this out our laboratory would need to have PC2 capability.
2. Tolerance induction by infusion of donor adult stem cells before transplantation
This proposal has a similar appeal. Here adult stem cells from the prospective renal donor are cultured in the laboratory and infused into the prospective transplant recipient before transplantation. These stem cells are thought to activate the tolerizing cells in the recipient before establishing the vascularized graft which later contributes to the tolerant state. This work is currently being done in the USA and we will assess the results in depth before studying it ourselves. To carry this out our laboratory would need to have PC2 capability.
3. Detecting tolerizing donor specific antibodies in recipients
The proposal that we wish to address is that a change in the type of donor specific antibody which disables it from binding complement plays a role in inducing tolerance towards the transplant. We have some evidence to support this in a remarkably complex recipient who appears to have developed non responsiveness towards the transplant. This finding is important but requires further analysis combined with functional assays to fully understand it. It will involve monitoring types of donor specific antibodies after transplantation in relationship to the function of the transplant and its renal histopathology.