Objective
The key objective of this research is to develop a new strategy to protect transplanted beta cells from immune destruction. Beta cell replacement treatment holds high promise in the treatment of type I diabetes. The main challenge for this treatment is the protection of transplanted beta cells from immune detection and destruction. Current efforts have focused on the development of materials and devices that can shield the beta cells from immune system. However, these technologies still need to overcome foreign body reaction as well as other biological processes. Our proposed research aims to develop an alternative strategy. We plan to chemically engineer beta cells with high levels of immune checkpoint molecules (don't attack me signals to prevent autoimmune reactions). We hypothesize that these engineered beta cells can suppress immune reaction and induce immune tolerance. This will facilitate the clinical translation of beta cell replacement treatment.
Background Rationale
Type 1 (T1D) diabetes is an autoimmune disease in which one’s own immune system attacks the insulin-producing beta cells in the pancreas, resulting in insulin deficiency. T1D diagnosis is most common in children, and more than 18,000 children are diagnosed annually. The incidence is also increasing by 2% each year. Despite advances in insulin replacement therapies and care, individuals with T1D still develop complications and have a higher premature death rate compared to the general population. Complications often arise because insulin replacement cannot recapitulate the body’s rapid production of insulin from beta cells.
While there is intense interest in the development of beta cell replacement strategies, challenges remain. Most approaches have been focused on the development of materials and/or devices that can shield the transplanted beta cells from the immune system. However, normal physiology such as foreign body reaction is difficult to overcome. Recently, our group has developed a novel strategy to biologically induce immune tolerance. As a physician-scientist and oncologist, my research program has focused on applying advances in engineering to improve treatment of cancer. Through my research in improving cancer immunotherapy, I recognized that lessons learned from tumor cells can be applied to the treatment of autoimmune diseases, such as T1D. Tumor cells have many mutations and are recognized by the immune system as foreign. However, many tumors use immune checkpoint molecules, markers of “self”, to prevent and exhaust immune cells’ attack, which lead to tolerance/acceptance. Blocking these immune checkpoint molecules has led to dramatic improvement in cancer treatment, but side effects often mimic autoimmune disease, including T1D. These observations establish that cancer and autoimmune diseases can be viewed as two sides of the same “coin”. Thus, we theorized that immune checkpoint molecules can be used to protect normal cells and cure autoimmune diseases, including T1D.
High levels of immune checkpoint molecules can be engineered onto normal cells through either biological manipulation or chemical reactions. Biological manipulation is riskier, as it can lead to cancers, so I chose to engineer cells through chemistry. With the goal of curing T1D, we engineered beta cells with high levels and multiple types of immune checkpoint molecules using chemistry and nanotechnology. We have shown that the engineered beta cells can deplete autoimmune cells and lead the immune system to tolerate rather than attack the beta cells. Our preliminary data showed that this approach was highly successful in reversing T1D in mouse models of early onset T1D. In this application, we aim to apply this novel approach to beta cell transplantation/replacement.
Description of Project
Type 1 (T1D) diabetes is an autoimmune disease in which one’s own immune system attacks the insulin-producing beta cells in the pancreas, resulting in insulin deficiency. T1D diagnosis is most common in children, and more than 18,000 children are diagnosed annually. The incidence is also increasing by 2% each year. Despite advances in insulin replacement therapies and care, individuals with T1D still develop complications and have a higher premature death rate compared to the general population. Complications often arise because insulin replacement cannot recapitulate the body’s rapid production of insulin from beta cells.
While there is intense interest in the development of beta cell replacement strategies, challenges remain. Most approaches have been focused on the development of materials and/or devices that can shield the transplanted beta cells from the immune system. However, normal physiology such as foreign body reaction is difficult to overcome. Recently, our group has developed a novel strategy to biologically induce immune tolerance. As a physician-scientist and oncologist, my research program has focused on applying advances in engineering to improve treatment of cancer. Through my research in improving cancer immunotherapy, I recognized that lessons learned from tumor cells can be applied to the treatment of autoimmune diseases, such as T1D. Tumor cells have many mutations and are recognized by the immune system as foreign. However, many tumors use immune checkpoint molecules, markers of “self”, to prevent and exhaust immune cells’ attack, which lead to tolerance/acceptance. Blocking these immune checkpoint molecules has led to dramatic improvement in cancer treatment, but side effects often mimic autoimmune disease, including T1D. These observations establish that cancer and autoimmune diseases can be viewed as two sides of the same “coin”. Thus, we theorized that immune checkpoint molecules can be used to protect normal cells and cure autoimmune diseases, including T1D.
High levels of immune checkpoint molecules can be engineered onto normal cells through either biological manipulation or chemical reactions. Biological manipulation is riskier, as it can lead to cancers, so I chose to engineer cells through chemistry. With the goal of curing T1D, we engineered beta cells with high levels and multiple types of immune checkpoint molecules using chemistry and nanotechnology. We have shown that the engineered beta cells can deplete autoimmune cells and lead the immune system to tolerate rather than attack the beta cells. Our preliminary data showed that this approach was highly successful in reversing T1D in mouse models of early onset T1D. In this application, we aim to apply this novel approach to beta cell transplantation/replacement. We aim to identify the most effective immune checkpoint molecules for immune tolerance. We will also examine the feasibility of engineering human islet cells with immune checkpoints and the use of such engineered cells as beta cell replacement in mouse models of T1D. Successful completion of this study will lead to new strategies for T1D treatment. The proposed therapeutics can be rapidly translated clinically. Ultimately, my efforts can lead to the first curative treatment for T1D. If successful, it will significantly improve the quality of life and life expectancy of many children.
Anticipated Outcome
We expect to identify the most effective formulation for engineered beta cells in suppressing immune destruction. We believe these engineered cells can induce long term tolerance from the immune system, thus allowing the transplanted beta cells to provide physiologic insulin for long periods of time. We aim to demonstrate this in mouse models of type I diabetes. We also aim to demonstrate this using both mouse and human beta cells. In the short-term, we expect our work to generate new patent applications and industry interest in further development of this technology. Long term, we expect our technology to be translated clinically and facilitate the development for a cure for type I diabetes.
Relevance to T1D
Our work aims to develop a new technology to protect transplanted beta cells for beta cell replacement therapy. It directly addresses one of the key technical challenges for beta cell replacement treatment. If successful, our work will enable clinical success of beta cell replacement and enable curative treatment for type I diabetes.