Objective
Many reports indicate that invisible stem cell lines and their derivatives (ie islet-like cells) might not be able to hide indefinitely from the immune system. To achieve complete and long-lasting invisibility, we reason that the stem cell-derived islets should actively regulate the immune system. The objective of this proposal is to generate islet-like cells that evade the immune-system AND control it to promote long lasting survival of the graft.
Background Rationale
Organ rejection is well-documented phenomenon, leading to prompt disfunction and destruction of transplanted organs unless immunosuppression is administered. These immunosuppressive medications are associated with considerable toxicity, including an increased risk for infections and cancer. Following breakthroughs by several groups, it is now possible to generate pancreatic islet-like cells in vitro from human pluripotent stem cells, which are available in nearly limitless quantities. This overcomes the major limitation of islet and pancreas transplant of organ scarcity, and this greatly increases availability of organ replacement therapy for patients with Type I diabetes. However, in the absence of immunosuppressant medications, these stem cell-derived islets would be just as susceptible to immune rejection as cadaveric islets.
Decades of research have identified specific proteins called HLA, as the primary cause of rejection, and recent studies have suggested that elimination of HLA expression on transplanted organs and tissues may prevent rejection. However, we hypothesize that to fully prevent rejection, loss of HLA would need to be coupled with the local immune control. In this proposal we aim to provide stem cell-derived islets with this type of control.
Description of Project
Type 1 diabetes (T1D) is an autoimmune disease characterized by the loss of insulin-producing pancreatic beta cells. Due to this loss, people living with T1D are dependent on exogenous insulin administration to control sugar levels in the blood. While insulin administration modalities are improving, the constant burden still dramatically affect the quality of life of people living with T1D and their families. Whole pancreas or islet transplantation can, in some cases, eliminate the need for insulin injections, as they can replenish the lost beta cells. However, the shortage of suitable donors and the requirement for chronic immunosuppression limit the use of transplantation to few individuals.
We and others have developed different methods to generate islet-like cells containing insulin producing cells from human stem cells, which could eliminate the problems associated with donor shortages. However, these stem cell-derived islets are still susceptible to being destroyed by the immune system if transplanted without immunosuppression. The elimination of immunosuppression would revolutionize this treatment by expanding the number of patients eligible for transplantation. We have generated data supporting the use of cell lines that have been modified to elude the immune system, but for them to be transplanted without immunosuppressants, additional modifications, that would make these cells fully resistant to any immune attack, are still required. In this proposal, we plan to test the functionality and longevity of novel cell products, with the goal of generating one cell source amenable for transplantation without immunosuppressants for all people living with T1D.
Anticipated Outcome
Based on an extensive body of research implicating HLA molecules as key drivers of immune rejection, we believe that eliminating the expression of HLA proteins may prevent the rejection of transplanted cells. To this end, we have obtained stem cells that have been modified to lack HLA molecules. We have successfully generated islet-like cells from these stem cells and have confirmed that they lack HLA expression and avoid destruction from a specific group of immune cells (T cells). We anticipate that additional modifications will equip the cells with regulatory tools that will offer additional protection from ALL immune cells, not just T cells, and allow the islet-like cells to survive for many months in animal models.
Relevance to T1D
This proposal will establish whether the use or regulatory cytokines can be employed to control the immune system and aid in the prevention of graft rejection of immune-evasive cells. We believe that islet-like cells generated from these universal donor cell lines can be used as surrogates for islet or pancreas transplant, and will not only overcome the major problem of organ scarcity, but will also be resistant to immune rejection. This would allow patients to benefit from the glucose-lowering effects of islet transplantation without having to suffer the adverse effects of systemic immunosuppression.