Objective
Type 1 diabetes (T1D) can be cured by pancreatic islet transplantation, which replaces the insulin-producing beta cells that are lost to autoimmunity. However, like any other organ transplant, patients must take long-term immunosuppression that affects the entire body, increasing the risk for infection or cancer. The goal of this project is to decrease or eliminate the need for this chronic systemic immunosuppression, which will make islet transplantation available to more patients with T1D. We will do this by developing innovative drug-releasing and cell-delivering biomaterial platforms that can be directly co-transplanted with islets. These approaches will then suppress and/or reprogram the immune system to protect the islets only in the local transplant site without causing negative side effects in the rest of the body. Importantly, our approaches will be compatible with other breakthroughs in beta cell replacement including stem cell-derived islets, which will solve our dependence on limited donor organs, and transplantation in alternative locations outside the liver. We will test islet transplantation with these immunomodulatory drug-releasing and cell-delivering platforms in preclinical animal models of T1D which have high applicability to human islet transplantation.
Background Rationale
Type 1 diabetes (T1D) is an autoimmune disease where a patient’s immune system attacks and destroys their own beta (β) cells within the pancreas, which normally supply our bodies with insulin and regulate our blood glucose. When β cells are lost, patients can no longer produce their own insulin and must manually manage their blood glucose with insulin injections. Since this is the first-line approach for treatment, T1D is currently managed, not cured. However, T1D can be cured by replacing the β cells in a patient’s body, which can then re-establish natural and automatic insulin secretion and blood glucose regulation.
One method to replace β cells is pancreatic islet transplantation. β cells are in a part of the pancreas known as the pancreatic “islets”, which are microscopic clusters or “islands” of cells scattered throughout the pancreas. Because of this anatomy, pancreatic islets can be easily separated from the rest of a donated pancreas (which does not contain β cells). Physicians then transplant the islets into the liver of a patient with T1D. This procedure leads to better blood glucose control, fewer long-term complications, and improved quality of life compared to standard insulin injections.
However, like any other organ transplant, transplanted islets are recognized as foreign tissue by the recipient’s immune system and are rejected. To prevent this, patients must take powerful immunosuppressing drugs to stop their immune system from rejecting the transplanted islets, and they must be taken permanently to continuously prevent rejection. When given by mouth or IV, these drugs also affect the entire body thus compromise normal immune protection from infections or cancer. For these reasons, islet transplantation is rarely performed.
Our goal is to protect transplanted islets from rejection without negatively affecting the entire body. The key innovation in this project is testing localized immunomodulatory therapy- we will co-transplant a sustained drug-releasing biomaterial or islet-supporting cells directly with islets. In this way, our therapies will be delivered only where they are needed (the islet transplant) without harming the rest of the body.
One approach we will test is delivering drugs that block activation of immune cells that would reject the transplanted islets. When drugs are taken by mouth or intravenously, they distribute evenly throughout the body and become diluted. Thus, to achieve the needed concentration of drug to protect the transplant site, higher doses of drug must be taken. To deliver drugs only locally with the transplanted islets, we will design and develop a sponge-like biomaterial that stores drug and releases it slowly over time. We will co-transplant this biomaterial alongside the islets so that the released drug can protect the islets without negatively affecting the rest of the body. Finally, some of the drugs we will test are already clinically approved and so this new method of delivery will reach patients faster.
Another approach we will test is delivering another type of cell found in our lymph nodes that has the potential to reprogram the immune system away from attacking the transplanted islets and towards healing. Like delivering drugs, we will deliver these cells only with the transplanted islets without having them spread throughout the whole body. To do this, we will co-transplant these cells directly alongside the islets and then study their mechanisms of action and islet-protecting effect. Although this approach is newer and less-studied, it is translatable to clinical practice as these supporting cells can be collected and grown from lymph node biopsies.
Description of Project
Type 1 diabetes (T1D) is an autoimmune disease where a patient’s immune system attacks and destroys their own beta (β) cells within the pancreas, which normally supply our bodies with insulin and regulate our blood glucose. When β cells are lost, patients can no longer produce their own insulin and must manually manage their blood glucose with insulin injections. Since this is the first-line approach for treatment, T1D is currently managed, not cured. However, T1D can be cured by replacing the β cells in a patient’s body, which can then re-establish natural and automatic insulin secretion and blood glucose regulation.
One method to replace β cells is pancreatic islet transplantation. β cells are in a part of the pancreas known as the pancreatic “islets”, which are microscopic clusters or “islands” of cells scattered throughout the pancreas. Because of this anatomy, pancreatic islets can be easily separated from the rest of a donated pancreas (which does not contain β cells). Physicians then transplant the islets into the liver of a patient with T1D. This procedure leads to better blood glucose control, fewer long-term complications, and improved quality of life compared to standard insulin injections.
However, like any other organ transplant, transplanted islets are recognized as foreign tissue by the recipient’s immune system and are rejected. To prevent this, patients must take powerful immunosuppressing drugs to stop their immune system from rejecting the transplanted islets. These drugs also affect the entire body and thus compromise normal immune protection from infections or cancer. Finally, patients must continuously prevent rejection by taking these drugs permanently. For these reasons, islet transplantation is rarely performed. This study will investigate methods to avoid these downsides by (1) testing two therapies that better target only the immune cells that attack transplanted islets and (2) co-transplanting these therapies alongside the islets so that they do not affect the whole body. If successful, curative islet transplantation will become safer and more accessible to patients with T1D.
In one approach, we will select drugs that block activation of the immune cells that would otherwise reject the transplant. Next, delivering drugs directly alongside the transplant is challenging- we can give the drugs only once (during the transplantation surgery), and one dose of drug would quickly wear off. Moreover, we seek to maintain these drugs at a high, effective concentration within the transplant for a prolonged time (>1 month) without spreading to the entire body. Our solution is to develop an innovative sponge-like biomaterial that can store drugs and release them slowly over time. This sustained drug-releasing biomaterial can be co-transplanted with the islets to protect them without causing systemic immunosuppression.
In another approach, we will test co-transplanting islets with immunomodulatory lymph node stromal cells. While our immune system is well-known for its ability to attack infection, it also plays an important role in wound healing, like after surgery. These stromal cells form our lymph nodes and can redirect, or modulate, our immune systems away from attacking transplanted islets and towards healing and acceptance of the islets. These immunomodulatory cells have been beneficial in pre-clinical heart transplant and are not yet explored in islet transplantation.
We will test these two approaches for localized islet transplant protection in animal models of T1D. Both approaches have high clinical translatability since the drugs we will test are clinically approved and the stromal cells can be isolated from patients with T1D through minimally invasive procedures. If successful, our approaches can eliminate the need for chronic systemic immunosuppression and can be used with upcoming cutting-edge approaches like transplantation of stem cell-derived β cells and extrahepatic islet transplantation.
Anticipated Outcome
In aim 1 of this proposal, we will develop, optimize, and test an innovative biomaterial platform for localized, sustained, and prolonged delivery of selected drugs to protect transplanted islets from rejection. These drugs are already clinically approved and have shown therapeutic efficacy in preventing islet rejection when delivered systemically, and we anticipate that our localized delivery approach will still achieve islet protection but without compromising the immune system in the rest of the body.
In aim 2 of this proposal, we will develop, optimize, and test an innovative immunomodulatory cell platform for suppressing immune cells that reject islets and promoting other immune cells that protect islets. Like aim 1, we will deliver these islet-supporting cells locally in the islet transplant site and anticipate that islet rejection and recurrence of autoimmunity will be prevented while sparing overall immunity in the rest of the body.
These studies will take place in preclinical animal models of type 1 diabetes, but both approaches have a clear path to translation to the clinic and patients. In aim 1, we will test drugs that are already clinically approved or have already shown efficacy in protecting islet transplants when given systemically. In aim 2, the immunomodulatory cells we are studying can be obtained and grown from patients through lymph node biopsies prior to the islet transplantation procedure.
In all, we anticipate that achieving local protection of islets only in the transplant site without affecting the rest of the body will solve the risks and of whole-body immunosuppressive regimens that currently limit the use of islet transplantation, ultimately making this curative procedure safer and more accessible to patients with type 1 diabetes.
Relevance to T1D
Patients with established type 1 diabetes can benefit from beta cell replacement through transplantation of islets obtained from organ donors or stem cell-derived islets. This procedure restores a patient’s ability to produce their own insulin, which eliminates the need for insulin injections, improves metabolic control and quality of life, and reduces long-term complications. However, the procedure is currently performed only in patients with severe type 1 diabetes due to the unavoidable side effects of the chronic systemic immunosuppression needed to prevent islet rejection and recurrence of autoimmunity. In this proposal, we will evaluate two innovative approaches for localized immunomodulation to prevent islet rejection and recurrence of autoimmunity while sparing patients’ overall immunity. In doing so, these localized immunomodulation approaches will increase the safety and accessibility of islet transplantation for patients with established type 1 diabetes. We will test these approaches in preclinical animal models of type 1 diabetes, and both have high clinical translatability since the drugs we will test are clinically approved and the stromal cells we will test can be isolated from patients with type 1 diabetes through minimally invasive procedures. If successful, our approach can address the remaining challenges of β cell replacement for patients with type 1 diabetes by eliminating the need for chronic systemic immunosuppression and can be used in combination with some of the most innovative approaches, including transplantation of stem cell derived β cells and extrahepatic islet transplantation.