Final Report Summary - RISET (Reprogramming the immune System for the Establishment of Tolerance)
The ultimate goal of RISET was to develop safe and efficient diagnostic tools and therapies to enable drug minimisation in transplanted patients. To this end, the development and validation of reliable tests to predict tolerance are mandatory steps for the implementation of large-scale clinical trials. These tests are based on immunological measurements as well as genomic or proteomic assays. They are needed to lower as much as possible the risk of rejection during immunosuppression minimisation or after withdrawal.
The RISET consortium has successfully developed new tests and defined molecular signatures of transplantation tolerance and rejection. The critical next step is the validation of the tests and signatures to enable them to be introduced as immune monitoring tools in clinical trials and to make them acceptable as surrogate markers of graft acceptance by regulatory agencies.
The results obtained in this study are very important and highlight the risk of using 'tolerogenic' allogeneic DCs for clinical therapy to induce tolerance. KCL has data in the rat, mouse and human to demonstrate that drug-treated DCs have a tolerogenic phenotype and function in vitro. However, once injected in vivo while in the rat they can induce tolerance to a kidney allograft, in the mouse they are very quickly reprocessed and represented in a stimulatory manner by endogeous APC. The prediction is that recipient DCs pulsed with alloantigens injected i.v. or locally can induce tolerance.
It was anticipated that approval for the production of human T regs for treatment of solid organ transplant patients was to be given by Spring 2011. At this time, we will be ready to proceed with the proposed study of T regs as a tolerancepromoting therapy in liver transplant recipients. This work holds enormous promise for transplant recipients as it may, for the first time, allow for a reliable tolerance induction without the toxic conditioning regimens necessitated by alternative protocols.