Objective
Our goals are threefold. First, we will grow and modify regulatory T cells (Tregs) from both Type 1 diabetes (T1D) and healthy donors and study how well they survive, remain stable, and spread throughout the body when returned to personalized immune mice that replicate the immune system of the original patient or healthy donor. Some of these Tregs will be specially engineered to recognize diabetes-related targets. Second, we will further enhance these Tregs using advanced gene-editing techniques to make them longer-lasting and resistant to other immune treatments often used in diabetes trials. We will also equip some Tregs with built-in support signals to help them survive and function better. Third, we will test whether these optimized Tregs can prevent or even reverse immune attacks on insulin-producing cells grown from the donor’s own stem cells and transplanted into the mice.
Background Rationale
T1D is caused by the immune system mistakenly attacking and destroying the insulin-producing cells in the pancreas. Certain genes—especially those called HLA genes—greatly increase a person’s risk of developing T1D, but many other genes also play smaller roles. Because of this genetic complexity, no two people with T1D are exactly alike. Unfortunately, most animal models used to study T1D rely on a single strain of mouse with a fixed genetic background. While these mice share some features of human disease, they cannot reflect the wide diversity seen in people with T1D. This limits how well new treatments can be tested before moving to human trials. To address this problem, we developed a new “personalized immune” mouse model that more closely resembles the human immune system. In this model, mice are given blood-forming stem cells from either people with T1D or healthy volunteers. These stem cells grow into a full human immune system inside the mouse, producing human T cells, B cells, and other immune cells. To ensure proper immune development, the mice are also implanted with a small piece of human thymus tissue that shares key genetic risk factors with T1D donors. As a result, each mouse carries an immune system that reflects the genetics and immune behavior of a specific human donor. Using this model, we found major differences between mice created from T1D donors and those created from healthy individuals. Mice with T1D-derived immune systems showed problems in how harmful immune cells are normally eliminated during development, as well as abnormal numbers and types of immune cells in the body. Their B cells, which make antibodies, were also improperly regulated and showed signs of autoimmune activity. Most importantly, immune cells from T1D-derived mice spontaneously attacked insulin-producing cells grown from the same donor’s stem cells, closely mimicking what happens in people with T1D. This did not occur in mice with healthy donor immune systems. This unique model allows us to test immune-based treatments in a setting that closely mirrors human disease.
Description of Project
Type 1 diabetes (T1D) is caused by the immune system mistakenly attacking and destroying the insulin-producing cells in the pancreas. Certain genes—especially those called HLA genes—greatly increase a person’s risk of developing T1D, but many other genes also play smaller roles. Because of this genetic complexity, no two people with T1D are exactly alike. Unfortunately, most animal models used to study T1D rely on a single strain of mouse with a fixed genetic background. While these mice share some features of human disease, they cannot reflect the wide diversity seen in people with T1D. This limits how well new treatments can be tested before moving to human trials.
To address this problem, we developed a new “personalized immune” mouse model that more closely resembles the human immune system. In this model, mice are given blood-forming stem cells from either people with T1D or healthy volunteers. These stem cells grow into a full human immune system inside the mouse, producing human T cells, B cells, and other immune cells. To ensure proper immune development, the mice are also implanted with a small piece of human thymus tissue that shares key genetic risk factors with T1D donors. As a result, each mouse carries an immune system that reflects the genetics and immune behavior of a specific human donor.
Using this model, we found major differences between mice created from T1D donors and those created from healthy individuals. Mice with T1D-derived immune systems showed problems in how harmful immune cells are normally eliminated during development, as well as abnormal numbers and types of immune cells in the body. Their B cells, which make antibodies, were also improperly regulated and showed signs of autoimmune activity. Most importantly, immune cells from T1D-derived mice spontaneously attacked insulin-producing cells grown from the same donor’s stem cells, closely mimicking what happens in people with T1D. This did not occur in mice with healthy donor immune systems.
This unique model allows us to test immune-based treatments in a setting that closely mirrors human disease. Our research team brings together experts from Columbia University, UCSF, and the University of Florida to evaluate a promising therapy using regulatory T cells (Tregs). Tregs are a special type of immune cell that normally keep the immune system in check and prevent autoimmunity.
Our goals are threefold. First, we will grow and modify Tregs from both T1D and healthy donors and study how well they survive, remain stable, and spread throughout the body when returned to these personalized mice. Some of these Tregs will be specially engineered to recognize diabetes-related targets. Second, we will further enhance these Tregs using advanced gene-editing techniques to make them longer-lasting and resistant to other immune treatments often used in diabetes trials. We will also equip some Tregs with built-in support signals to help them survive and function better. Third, we will test whether these optimized Tregs can prevent or even reverse immune attacks on insulin-producing cells grown from the donor’s own stem cells and transplanted into the mice.
By using mice that carry a human immune system and show natural autoimmune behavior, this research fills a critical gap in diabetes research. The findings will help refine Treg-based therapies and combination treatments, bringing us closer to safer and more effective immune therapies for people with type 1 diabetes.
Anticipated Outcome
This unique model allows us to test immune-based treatments in a setting that closely mirrors human disease. Our research team brings together experts from Columbia University, UCSF, and the University of Florida to evaluate a promising therapy using regulatory T cells (Tregs). Our studies will allow us to compare the efficacy of Tregs with different genetic modifications and different properties of antigen recognition in a T1D immune systems with autoimmunity. By using mice that carry a human immune system and show natural autoimmune behavior, our research will help refine Treg-based therapies and combination treatments, bringing us closer to safer and more effective immune therapies for people with type 1 diabetes. The ultimate outcome of the work will be new clinical trials taking advantage of the most effective form of Treg therapy observed in our study.
Relevance to T1D
This unique model allows us to optimize Treg therapy in a setting that closely mirrors human Type 1 diabetes. The ultimate outcome of the work will be new clinical trials taking advantage of the most effective form of Treg therapy identified in our study, providing new hope for a cure.