Objective
This study objectives are to 1) characterize the immune cells that are involved in recurrence of T1D in transplanted patients; 2) determine the dependence of these immune cells on glucose to produce energy to support their function and ability to proliferate; 3) determine the impact of treatment to suppress glucose metabolism (using a GLUT-1 inhibitor) in immune cells on their function, ability to proliferate, as a novel way of controlling autoimmunity, in vitro; 3) determine the therapeutic efficacy and safety of suppressing glucose metabolism in immune cells (using a GLUT-1 inhibitor) in two preclinical experimental models, of beta cell transplantation and diabetes reversal after diagnosis.
Background Rationale
There is a clear need to replace the lost insulin-producing beta cells in patients with type 1 diabetes (T1D). Many advances have been made over the years through whole pancreas and islet transplantation, and more recently with stem cell derived beta cells. However, transplantation of the whole pancreas organ, isolated or stem cell derived pancreatic islet beta cells requires controlling immunological rejection and the potential that the autoimmune process that caused T1D in the first place may be reactivated and destroy the transplanted beta cells. We have previously demonstrated recurrence of T1D in patients with simultaneous pancreas-kidney (SPK) transplants; this occurred despite chronic immunosuppression that prevents rejection. The relapse of autoimmunity usually occurs years after transplantation, it proceeds slowly, and yet it is difficult to control with standard immunosuppression. Approximately 5% of SPK recipients in our cohort have developed T1D recurrence, at a similar frequency at which chronic rejection is observed. Attempts to halt recurrent autoimmunity and save the transplanted beta cells have been made in some patients by adding short course treatments with several immunosuppressive drugs, but these therapies have very modest impact. Thus, there is a critical need to better understand the mechanisms of recurrent T1D, and to identify novel, effective and safe therapies that can prevent/suppress recurrence of T1D. With advancements in the development of stem cell-derived beta cells for transplantation, it is critical to identify therapies that promote their survival.
Description of Project
There is a clear need to replace the lost insulin-producing beta cells in patients with type 1 diabetes (T1D). Many advances have been made over the years through whole pancreas and islet transplantation, and more recently with stem cell derived beta cells. However, transplantation of the whole pancreas organ, isolated or stem cell derived pancreatic islet beta cells requires controlling immunological rejection and the potential that the autoimmune process that caused T1D in the first place may be reactivated and destroy the transplanted beta cells. We have previously demonstrated recurrence of T1D in patients with simultaneous pancreas-kidney (SPK) transplants; this occurred despite chronic immunosuppression that prevents rejection. The relapse of autoimmunity usually occurs years after transplantation, it proceeds slowly, and yet it is difficult to control with standard immunosuppression. Approximately 5% of SPK recipients in our cohort have developed T1D recurrence, at a similar frequency at which chronic rejection is observed. Attempts to halt recurrent autoimmunity and save the transplanted beta cells have been made in some patients by adding short course treatments with several immunosuppressive drugs, but these therapies have very modest impact. This study is focused on better characterizing the immune cells that are
involved in recurrence of T1D; we have data supporting the concept that immune cells associated with the development of T1D in non-transplanted patients need to burn glucose to produce energy to support their function and ability to proliferate, and we will determine whether this feature is shared with patients with recurrence of T1D.
To this end, we will characterize blood samples already collected from SPK patients categorized in different groups based on the presence/absence of autoimmunity and recurrence of T1D. We also have data that treating these immune cells with an inhibitor of glucose metabolism (by blocking the entry of glucose into the cells mediated by glucose transporter-1, GLUT-1) impairs their ability to proliferate and may render them dysfunctional and incapable to sustain immune responses. We will investigate this further, and better determine the changes that are induced in these cells by this treatment (GLUT-1 inhibitor), and the durability of this effect. Moreover, we will use two
experimental preclinical models. In a first model, we will investigate whether treatment to suppress glucose metabolism in immune cells can promote survival of transplanted beta cells, which were derived from human pluripotent stem cells, in mice that have been “humanized” with immune cells from patients with T1D. This model recapitulates the clinical context of transplantation. In a second model we will investigate whether treatment to suppress glucose metabolism in immune cells can reverse diabetes in mice who spontaneously develop disease, representing the clinical setting of patients with newly diagnosed T1D. In this case, we will also explore this treatment in combination with therapy with anti-CD3 antibody, which has already shown efficacy in clinical trials. In summary, this study aims at investigating a novel approach to control the immune system, which does not rely on conventional immunosuppression and may have better safety. The proposed study involves a combination of investigations in patients and experimental mice, with a highly translational scope. This effort represents a collaboration from investigators at the Diabetes Research Institute, University of Miami, the San Raffaele Institute (Milan, Italy), and the City of Hope.
Anticipated Outcome
We anticipate learning about: 1) key features of immune cells associated with recurrence of T1D in transplanted patients; 2) the dependence of those immune cells on glucose metabolism, and whether suppressing glucose metabolism using a GLUT-1 inhibitor induces functional changes in immune cells that can be helpful to control autoimmunity; 3) the efficacy and safety of a GLUT-1 inhibitor in promoting survival of transplanted beta cells and in reversing diabetes at diagnosis in two highly translational preclinical models. Overall, the findings would provide novel insight into the function of immune cells associated with T1D and inform about the potential therapeutic value of GLUT-1 inhibition. The demonstration of a positive impact would support further investigations, including clinical trials to test this novel therapy in patients. Of note, there are a number of potential drugs that are being developed in the field, and the concept of GLUT-1 inhibition has also relevance to cancer research.
Relevance to T1D
This research is relevant to developing new, efficacious and safer means to control autoimmunity. Intervention with GLUT-1 inhibitors to control autoimmunity is applicable to disease prevention, intervention at diagnosis, and after transplantation to support the success of beta cell replacement therapies.