Objective
The objective of this proposal is to understand and benchmark a unique immunoprotective formulation that trains the recipient’s immune system to accept, instead of reject, the transplanted islets in a process called “tolerance”. If successful, only a short two week treatment will required instead of lifelong immunosuppression. We will gain a better understanding of how this formulation works as well as validate the new regimen in a clinically relevant animal model.
Background Rationale
We have already demonstrated that our novel formulation can “tolerize” transplanted islets and prevent their immune rejection in diabetic mice. While our preliminary data provides some insight into how this occurs, further investigation is required to better understand which immune cells are involved and how the process works. Based on this need to better understand the process as well as our success in a mouse model, we will pursue validation of the method in a clinically relevant large animal model.
Description of Project
Type 1 diabetes (T1D) is an endocrine disorder that leads to pancreatic β cell destruction and is managed by lifelong exogenous insulin therapy. Islet transplantation is a promising alternative treatment for T1D, which eliminates the need for exogenous insulin, but is currently limited by the side effects and low efficacy of immunosuppressive regimen that are currently employed to maintain islet survival. In this process, replacement islet cells are transplanted into the patient, which can then respond to changes in systemic glucose levels without the need for regular insulin administration. Unfortunately, these cells are quickly rejected by the recipient’s immune system, resulting in failure of the procedure. In this proposal, we present a new method to prevent rejection of transplanted islets, presenting a novel alternative to life-long immunosuppression. If successful, islet transplantation may become a standard treatment for T1D, essentially eliminating the need for routine insulin administration.
Anticipated Outcome
The proposed work has potential to generate a new drug candidate that will allow transplanted islets to survive within patients without the need for immunosuppressive therapy. We anticipate gaining an understanding of how this therapy works as well as validating the therapy in a large animal model, which would generate clinically relevant data.
Relevance to T1D
Type 1 diabetes (T1D) is commonly recognized as an endocrine disorder that leads to the destruction of pancreatic β cells. Once at culmination, it must be managed by life-time exogenous insulin therapy. Since 2008, approximately 18,000 new cases of T1D have been diagnosed annually among people below the age of 20 across the United States. Islet transplantation is a promising treatment for T1D, which eliminates the need for exogenous insulin therapy. However, the need for immunosuppressive therapy, which can cause islet toxicity and systemic side effects, prevents islet transplantation from becoming a clinical standard of care for all T1D patients. If successful, this proposal will provide a novel replacement for immunosuppressive therapy, maintaining normoglycemia following only a short two week regimen that will train the patient’s immune system to accept the transplanted islet cells.