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 through a process called “tolerance.” If successful, only a short two-week treatment will be 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 model that recapitulates the human immune system.
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 ensure that our results in mice translate to humans. Advances in genetic engineering and immunology allow scientists to remove the immune system from a mouse, rendering the mouse immunodeficient, and then use human immune cells to engraft the mouse with a “human-like” immune system. We will use these humanized mice to assess our novel formulation for islet transplantation tolerance.
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 humanized mouse model, which would generate clinically relevant data.
Relevance to T1D
Type 1 diabetes (T1D) is an endocrine disorder characterized by the autoimmune-mediated destruction of insulin-producing pancreatic beta islet cells. The prevalence of T1D is on the rise, especially among youth. By 2050, 5 million people in the United States will have T1D. The only treatment for T1D is a lifetime prescription for exogenous insulin. Insulin therapy is extremely costly in the United States, having increased in price by over 1000% in the last ~20 years. However, even with adequate insulin and clinical management, side effects are commonplace. Complications of T1D include cardiovascular disease, neuropathy, eye damage, resulting in blindness, and foot damage, resulting in amputation. Thus, there is a great need for a curative treatment. Islet transplantation has the potential to provide transformative benefits therapy to patients living with T1D by eliminating the need to inject expensive exogenous insulin, providing normoglycemic control, and preventing devasting side effects. However, islet transplantation requires patients to take daily immunosuppressive drugs. Currently, immunosuppressive protocols are plagued with side effects, reducing a patient’s quality of life, predisposing them to infection, and often resulting in noncompliance (and subsequent graft failure). Instead of systemically suppressing the immune system, we have developed a nanodrug to train the immune system to accept transplanted islets. Our nanodrug is only taken over a two-week period and has a minimal side effect profile. If successful, this therapy could lead to a T1D-free future.