Objective
We propose to use ‘human immune system’ mouse translational models to accomplish two objectives. The first aim is to analyze immune cells infiltrating autologous (self) and allogeneic (non-self) stem cell-derived beta cell grafts, particularly in the context of immune systems produced from T1D donors, using cutting edge techniques. This study will help us understand the interplay between different immune populations and how they contribute to graft infiltration and rejection. The second aim is to evaluate Soluble Antigen Arrays, a novel immunotherapy platform that can directly target some of the disease-causing T cells and help turn them into regulatory T cells capable of suppressing other disease-causing immune cells. Using HIS mice with immune systems from T1D donor and/or enriched for disease-causing T cells, we will determine the effect of this treatment on these T cells and on overall graft infiltration by human immune cells.
Background Rationale
The isolation of insulin one hundred years ago has been a lifesaving and life changing discovery for people suffering from Type 1 diabetes (T1D). While great strides have been made in better controlling the delivery of insulin (e.g., with the help of pumps), the process of daily insulin administration is tedious, particularly with children, and glycemic control is not optimal, such that complications may continue to develop in the long term. Restoring endogenous production of insulin by glucose-responsive beta cells remains the best approach to achieve tight glycemic control without the need for exogenous insulin. Whether one wants to spare residual beta cells in individuals with recent onset diabetes or restore insulin production by islet transplantation in individual with insufficient residual islet cell mass, the autoimmune response must be stopped. Moreover, acceptance of grafted beta cells originating from a donor other than self requires immunosuppression, which comes with its own set of challenges and risks. Immunotherapies that can target specific immune cell populations, particularly those directly involved in the autoimmune response, would be preferable. Many such therapeutic approaches have been evaluated in animal models, but translation to patients has been hindered by an inability to test these therapies in vivo on actual human immune systems. Animal models are genetically and immunologically homogeneous, while patients are very diverse. This leads to high variability in responsiveness to therapies, which end up not meeting their objective in patients. In recent years, mice harboring human immune systems (HIS) have been developed, with unique cohorts reflecting the variability of the human population and recapitulating immune abnormalities that can contribute to disease. This immune system is produced from stem cells from the donor and can be modified to generate more disease-causing immune cells, making it easier to assess the effect of targeting these cells. We have determined conditions in which functional stem cell-derived beta cells can be successfully transplanted in HIS mice and become infiltrated over time.
Description of Project
The isolation of insulin one hundred years ago has been a lifesaving and life changing discovery for people suffering from Type 1 diabetes (T1D). While great strides have been made in better controlling the delivery of insulin (e.g., with the help of pumps), the process of daily insulin administration is tedious, particularly with children, and glycemic control is not optimal, such that complications may continue to develop in the long term. Restoring endogenous production of insulin by glucose-responsive beta cells remains the best approach to achieve tight glycemic control without the need for exogenous insulin. Whether one wants to spare residual beta cells in individuals with recent onset diabetes or restore insulin production by islet transplantation in individual with insufficient residual islet cell mass, the autoimmune response must be stopped. Moreover, acceptance of grafted beta cells originating from a donor other than self requires immunosuppression, which comes with its own set of challenges and risks. Immunotherapies that can target specific immune cell populations, particularly those directly involved in the autoimmune response, would be preferable. Many such therapeutic approaches have been evaluated in animal models, but translation to patients has been hindered by an inability to test these therapies in vivo on actual human immune systems. Animal models are genetically and immunologically homogeneous, while patients are very diverse. This leads to high variability in responsiveness to therapies, which end up not meeting their objective in patients. In recent years, mice harboring human immune systems (HIS) have been developed, with unique cohorts reflecting the variability of the human population and recapitulating immune abnormalities that can contribute to disease. This immune system is produced from stem cells from the donor and can be modified to generate more disease-causing immune cells, making it easier to assess the effect of targeting these cells. We have determined conditions in which functional stem cell-derived beta cells can be successfully transplanted in HIS mice and become infiltrated over time.
We propose to use HIS mouse translational models for two objectives. The first aim is to analyze immune cells infiltrating autologous (self) and allogeneic (non-self) beta cell grafts, particularly in the context of the immune system produced from a T1D donor, using cutting edge techniques. This study will help us understand the interplay between different immune populations and how they contribute to graft infiltration and rejection. The second aim is to evaluate Soluble Antigen Arrays, a novel immunotherapy platform that can directly target some of the disease-causing T cells and help turn them into regulatory T cells capable of suppressing other disease-causing immune cells. Using HIS mice with immune systems from T1D donors and/or enriched for disease-causing T cells, we will determine the effect of this treatment on these T cells and on overall graft infiltration.
These in vivo studies will be key to understanding immune cell interactions during graft infiltration and will test for the first time the effect of targeted immunotherapy on actual human immune systems as an important step to clinical development.
Anticipated Outcome
We expect that analysis of immune cell infiltrates around beta cell grafts, and the effect of experimental depletion of some of these immune cell populations, will inform on the conditions that govern beta cell graft rejection and autoimmune destruction in T1D patients. We expect that autoreactive T cells engaged by antigens carried by Soluble Antigen Arrays will change their functional characteristics to become more regulatory and less pathogenic ultimately limiting graft infiltration and rejection.
These in vivo studies will be key to understanding immune cell interactions during beta cell graft infiltration and will test for the first time the effect of targeted immunotherapy on actual human immune systems. These are important steps to clinical development.
Relevance to T1D
This work is directly and highly relevant to T1D, central to the overarching objective of achieving operational tolerance and blocking autoreactive immune cells that contribute to beta cell graft infiltration and rejection. It is particularly relevant due to the use of human immune systems, focusing on T1D immune systems and/or systems enriched with T1D-causing immune cells.