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Reprogramming the immune System for the Establishment of Tolerance

Final Report Summary - RISET (Reprogramming the immune System for the Establishment of Tolerance)

Transplantation dramatically improves the survival of patients with established organ failure. The transplant is literally a life saver and the short-term prospects of most transplant patients are very good. However, in the longer term many of these patients face serious health issues. A significant number of problems are caused by the cocktail of immunosuppressive drugs that transplant patients take to prevent their immune system from attacking the donor organ. These drugs are efficient in preventing or controlling early acute rejection episodes or graft versus host disease and allow for the excellent results of organ transplantation in the short term. Yet the side effects of these drugs include cancers, infections, kidney problems, cardiovascular diseases, diabetes and bone diseases, to name just a few. Currently, some patients receive more immunosuppression than required, whereas other patients develop chronic transplant damage because of insufficient immunosuppression. Tailoring immunosuppression according to the immune reactivity of each transplant recipient would therefore represent a significant advance in transplantation medicine.

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.

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