Objective
The main objectives of this proposal are: 1) to investigate whether hPSC-derived immune regulatory cells can promote neovascularization and support survival of hPSC-derived islet-like cells after transplantation 2) to test the immune-protective effect of hPSC-derived immune regulatory cells against autoimmunity and allorejection.
Background Rationale
Currently, cell replacement therapy is limited by the less-than-optimal immunosuppressive treatments which lower the body’s ability to reject non-autologous cells. The need for lifelong immunosuppressive medication represents a major burden to the patients, as well as a major challenge to the widespread use of cell replacement therapies. In this proposal, we will investigate the potential beneficial role of using cell-based immunotherapies to mitigate/eliminate the need for chronic immunosuppression accompanying non autologous islet transplantation.
Description of Project
Type 1 Diabetes (T1D) is an autoimmune disorder that destroys insulin-producing pancreatic beta cells, resulting in insulin deficiency and chronic elevated blood sugar levels. As a result, people living with T1D are dependent and burdened from the need of life-long exogenous insulin administration, while suffering from severe complications. Whole pancreas or islet transplantation can, in some cases, eliminate the need for insulin injections, and drastically improve their quality of life. However, the shortage of suitable donors and the requirement for chronic immunosuppression both present challenges for this therapy's widespread use. Multiple research groups have developed different methods to generate islet-like cells containing insulin producing cells from human pluripotent stem cells (hPSC), which could eliminate the problems associated with donor shortages. However, these hPSC-derived islets are still susceptible to being destroyed by the immune system if transplanted without immune suppression medications. To eliminate or reduce the burden of immunosuppression, we propose to study the effect of a hPSC based cell therapy involving the use of immune regulatory cells in conjunction with islet-like cells. In this proposal, we will use hPSC to generate clusters of immune regulatory and islet-like cells to test whether the immune cells can offer protection against immune attack and support engraftment and long-term survival in vivo.
Anticipated Outcome
Overall, the project described in this proposal will deliver new insights into immune modulatory properties of hPSC-derived immune regulatory cells, supporting human islet survival and functionality, and ultimately providing a new approach for clinical applications.
Relevance to T1D
T cells are responsible for the destruction of beta cells in T1D and are also responsible for graft rejection after allogeneic islet or pancreas transplantation. The T cell specific killing is fostered by the inflammatory state of accessory immune cells, which are usually not targeted by immunotherapies. In this proposal, we aim to harness the immuno-regulatory properties of accessory immune cells to reduce inflammation and prevent T cell-mediated killing. Our approach is designed to provide an innovative method to temper the need for systemic immunosuppression and promote long term engraftment of transplanted hPSC-derived islet cells for T1D treatment.