USE OF LOW-DOSE IL-2 TO EXPAND ENDOGENOUS REGULATORY T CELLS AND ACHIEVE TRANSPLANTATION TOLERANCE

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A population of immune cells, called regulatory T cells or Tregs, have been shown in experimental animal models to regulate the immune system and to play a central role in preventing organ rejection and in controlling autoimmune and inflammatory diseases. In animal models of transplantation, Tregs are key to induce immunological tolerance, a situation in which the transplanted organ is indefinitely accepted in the absence of anti-rejection medication. The use of IL-2 at low doses has been shown to selectively and safely increase the number of Tregs in humans, but whether this can be used to induce tolerance in transplanted patients has never been investigated. Liver transplantation is an optimal clinical setting to do so, given that there are evidences indicating that transplantation tolerance can spontaneously occur in these patients (albeit only many years after transplantation), and that liver transplantation is the only solid organ transplantation setting in which it is safe to investigate the development of tolerance by intentionally discontinuing all anti-rejection medications. Our hypothesis is that administration of a short course of low-dose IL-2 will transiently expand the number of Tregs and allow for the permanent discontinuation of anti-rejection medication. In the current project we propose to conduct a clinical study in which liver transplant recipients who have a very low probability of achieving tolerance spontaneously will receive daily injections of IL-2 during the period of time when their anti-rejection medication is gradually withdrawn. Patients will be carefully studied to investigate the following:1) Whether IL-2 is efficacious in expanding the number of Tregs in liver transplant patients. 2) Whether the expansion of Tregs in the circulation and/or the liver facilitates the successful discontinuation of anti-rejection medication.3) What are the effects of an increased number of Tregs in the immune system of a transplanted patient. Ultimately, the project will serve to clarify whether donor-specific Tregs are essential to establish transplantation tolerance, and the extent to which low-dose IL-2 is an effective strategy to promote this phenomenon. This will have implications for a number of other inflammatory diseases, and will open the door to future clinical trials in which low-dose IL-2 could used in combination with other tolerance-promoting medications.