Mechanisms of IL-2 induced Transplantation Tolerance

Organ transplantation is the treatment of choice and the only curative option for end-stage organ diseases. Over the last decades, major advances in pharmacological suppression of the immune system as well as improved surgical techniques and medical management allowed for excellent short-time survival rates in patients receiving kidney, heart, liver or lung transplants. Nevertheless, chronic graft dysfunction and subsequent late graft loss are still common clinical problems. Beyond that, patients suffer from side effects caused by chronic immunosuppressive therapy, leading to restricted quality of life and increased morbidity and mortality. Induction of (donor-specific) immunologicaltolerance wouldpreventchronic rejection andwouldrenderchronic immunosuppressive treatment unnecessary. One of the most promising tolerance approaches is the utilization of regulatory T cells (Tregs), which play a critical role in the maintenance of self-tolerance and have also been shown to be extremely potent in suppressing alloresponses. Therapeutic cellular Treg therapy has shown huge potency in pre-clinical trials and first clinical trials have already started. Nevertheless, several questions concerning source, isolation strategy, dosage, timing of infusion, best immunosuppressive regimen, and cell fate post-infusion remain unanswered. It has been shown that IL-2 cytokine/ab complexes (IL-2 cplx) are a potential pharmacological alternative to Treg cell therapy. They can be used as a tool to control and regulate immune responses by their pleiotropic effect on different cell types. By using this technique the benefits of Treg therapy can be utilized without the challenges and risks of cell-based therapy. In our previous project we could show that administration of IL-2 cplx lead to a potent and selective stimulation of Tregs, allowing allograft survival in the absence of chronic immune suppression. We demonstrated that Treg expansion via IL2-cplx synergizes with low-dose rapamycin and anti-inflammatory treatment with anti-IL-6, leading to significantly prolonged skin allograft survival and prevention of acute rejection even in the absence of ongoing treatment. In the proposed project we aim to find an optimal dosing regimen leading to indefinite survival of skin and heart allografts in a clinically relevant model. Specifically, we will address the role of Tregs in the suppression of acute and chronic allograft rejection and the interaction of Tregs and effector cells in direct and indirect allorecognition. We think the proposed experiments will provide insight into underlying tolerance mechanisms in this model and moreover have impact on the mechanisms of long-term graft survival in clinical transplantation.

Organ transplantation has become the treatment of choice and the only curative option for chronic organ failure. During the last decades, major advances in pharmacologic immunosuppression as well as surgical techniques have resulted in excellent short-term survival rates in kidney, heart, liver, and lung transplant recipients. Nevertheless, chronic rejection, leading to deterioration of organ function with subsequent organ loss is a common problem in the clinic with currently no effective treatment option. Furthermore, the side effects of immunosuppressive drugs lead to a reduction in quality of life as well as increased morbidity and mortality. Induction of immunological (donor-specific) tolerance would not only prevent (chronic) rejection but also reduce or even eliminate the need for life-long immunosuppressive therapy. A very promising approach for tolerance induction is the use of so-called regulatory T cells, which play a critical role in maintaining self-tolerance and are very potent in preventing rejection. Cell therapy with these cells has already shown great potential in animal models and initial clinical trials have been initiated, yet many questions remain regarding dosage, origin of cells and combination therapy with immunosuppressive regimens. It could be shown that specific cytokine/antibody complexes (IL-2 complexes) can be used to modulate different cell types in vivo and thus maximize the benefit of regulatory T cells - without the risks of cell therapy. In the previous project, we have already shown that selective proliferation of regulatory T cells is achieved by administration of these IL-2 complexes, which in temporary combination with the immunosuppressive drug rapamycin and short-term anti-inflammatory anti-IL-6 therapy, leads to prolonged graft survival without chronic immunosuppression. In this study, we demonstrated that this novel therapy not only impedes acute rejection, but also prevents the formation of donor-specific antibodies. These donor-specific antibodies are mainly responsible for chronic rejection and graft loss in clinical practice and there is currently no effective therapy available. We have been able to elucidate the mechanisms behind this phenomenon and have thus gained a better understanding of the mechanisms responsible for chronic rejection. We think that the results of this project are an important advancement in this field of research to enable efficient long-term survival of organ transplant patients in the clinic. Furthermore, by combining this novel therapy with personalized and reduced immunosuppressive treatments, we also hope to improve the quality of life of transplant patients.