Objective
The main goal of this proposal is to get rid of the need for lifelong medication to prevent the body from rejecting transplanted islets. We plan to do this by creating an ideal environment for the islets that takes advantage of the liver’s special immune cells to help the body accept the new islets.
Background Rationale
Allogeneic islet transplantation improves glycemic control and quality of life for people with Type 1 diabetes (T1D). However, this procedure requires lifelong medication to prevent the body from rejecting the transplanted islets. To make islet transplantation more accessible and successful for the approximately 1.6 million people with T1D in the US, it is crucial to develop new methods for immune system regulation and ensure a steady supply of islets. This is important because T1D costs over $16 billion in annual healthcare.
Typically, islet transplants are done by placing the islets directly into the portal vein where the reside in the vessels of the liver, which has a high success rate. However, this method has limitations, such as the risk of immediate inflammatory reactions, potential loss or dysfunction of the islets, and the need for long-term immunosuppressive medication, which can have serious side effects.
New approaches focus on transplanting islets to sites outside of the portal circulation. This method reduces certain risks, like the immediate inflammatory response, and depending on the site can allow for easier manipulation of the transplant environment and the possibility of containing and retrieving higher-risk cells. However, alternative sites face different challenges such as insufficient oxygen, altered insulin kinetics, and site effects on the body’s immune response which have resulted in lower success rates compared to intraportal transplantation. Similarly, many current treatments are designed specifically for the liver environment and may not work as well in other sites.
Our primary goal is to achieve immunological tolerance by engineering the peri-hepatic surface site using injectable SA-PD-L1-delivering microgels loaded with islets under the cover of transient sirolimus monotherapy to reverse diabetes in the clinically relevant diabetic NHP model. We hypothesize that the engineered microgels will offer enhanced distribution and support for islets, creating a robust tolerogenic environment that improves engraftment and long-term functional survival. This approach aims to accelerate the use of a novel, clinically relevant implantation site, eliminating the need for chronic immunosuppression.
Description of Project
Our approach utilizes innovative biomaterial particles to deliver an immunomodulatory protein (SA-PD-L1) using a minimally invasive approach to transplant islets at the surface of the liver. This protein, which tumors use to hide from the immune system, will help eliminate the need for lifelong medication to prevent rejection of the islets. The biomaterial particles are designed to improve how well the islets engraft and function by properly arranging them, providing necessary support, and influencing the local immune response. SA-PD-L1 will work with the special immune cells in the liver to help reduce the body's immune reaction to prevent rejection of the islets.
By combining these two advanced technologies in a rigorous study using a translational model, we aim to make islet transplants safer and more successful. This transplant strategy will reduce risks associated with next-generation cell therapies that offer the advantage of using an unlimited supply of islets, including those from animal or stem cell sources.
Anticipated Outcome
Microgels create a supportive environment by promoting blood vessel growth and arranging the islets to ensure they get enough oxygen and nutrients, to effectively make insulin for optimal blood glucose control. SA-PD-L1 is designed to work with the liver’s unique immune system to silence local immune cells that might attack the new islets. This approach should be safer and more effective than traditional medications that weaken the whole immune system.
Relevance to T1D
For people with Type 1 diabetes, taking islet transplants usually requires ongoing medication to prevent the body from rejecting the new islets. However, these medications can have serious side effects, including damage to cells, increased risk of cancer, and infections. Because of these risks, not everyone with Type 1 diabetes can safely undergo islet transplantation.