Molecular Signatures of Tolerance
The Indices of Tolerance project and the Rescue Study
Indices of Tolerance
The Indices of Tolerance project, which centred on kidney transplantation, began in mid-2003 and ran for more than three years, finishing in 2007. The work took place in various clinical centres throughout Europe and was coordinated by King's College London.
The work of the project was to try to identify renal transplant patients who had stopped their immunosuppressive regimens, without then going on to reject their kidneys. Once those patients had been identified the next step was to try to identify those biological factors that led to transplant tolerance and apply this knowledge to future renal recipients, in the hope that it would enable patients to reduce or even stop completely the long-term medication they have to take.
This study was funded by the European Commission.
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The RESCUE Study
RESCUE (Recurrent Cutaneous Squamous Cell Carcinoma Under Rapamune) is a randomized prospective open label multi-centre study comparing the efficacy and safety of conversion to Sirolimus in stable renal transplant recipients with cutaneous squamous cell carcinoma.
Up to 30% of renal transplant patients will develop non melanoma skin cancer within 20 years of transplantation. One of the main reasons for this increased risk is the use of immunosuppressive agents to prevent graft rejection. Sirolimus is a new anti rejection drug that also has anti cancer effects.
Patients in this trial either stay on their current anti-rejection medications or convert to Sirolimus and low dose steroid. They are then followed up for two years to see if Sirolimus has reduced the chance of developing more skin cancers.
To monitor the changes in Regulatory T cell populations when people are converted to Sirolimus and whether high levels of Regulatory T cell are a risk factor for developing skin cancer.
Previous work arising from the RESCUE trial, undertaken by TRIG, found that increased regulatory T-cell (Treg) number in peripheral blood are associated with development of cutaneous squamous cell carcinoma (cSCC) in kidney transplant recipients and predict further cSCC development (Carroll et al 2010). This is associated with increased Treg numbers in the tumours themselves compared to patients with cSCC who haven’t had a kidney transplant. Further work is being undertaken to elucidate the mechanism of this.
Another population of regulatory cells, regulatory B-cells (Breg), are associated with the development of both tolerance and cancer in human and animal studies. A case-control study in transplant recipients is underway in collaboration with the Oxford Transplant Unit to establish whether Breg are also associated with cSCC and whether this associated with the development of molecular markers of tolerance.
*this work is in collaboration with Dr Paul Harden of the Oxford Kidney Unit