Characterizing the Alloimmune Response to Human ES-derived Pancreatic Lineage Cells
Human embryonic stem cells hold promise for treating a variety of diseases because of their capacity to differentiate into any cell type in the body and replace damaged tissues. A major limitation of using embryonic stem cells for transplantation is that they express major histocompatibility antigens that have the potential to be recognized by the patient’s immune system as foreign and be rejected. At present, few studies have addressed if and how the immune system detects and rejects tissues derived from embryonic stem cells. It is necessary to understand the immunological responses that occur to foreign human embryonic stem cell-derived tissues to be able to monitor these parameters in future studies seeking to achieve immune tolerance to these grafts. A critical step before implementing stem cell therapies for treatment of human diseases is to establish their immunogenicity in relevant preclinical models. Study of the human immune system responses to the cells derived from embryonic stem cells has been limited by the lack of an appropriate preclinical animal model. For this reason, we developed a novel mouse model that shows long-term reconstitution with a complete range of human blood cells. Furthermore, these mice develop strong immune responses providing a powerful model system to study human immune function to embryonic stem cell derived transplanted tissues. We propose to study the immune response in humanized mice that receive human embryonic stem cell-derived pancreatic cell transplants. We have chosen to focus this research work on pancreatic lineage cells with the ultimate goal of developing novel therapeutic strategies for treatment of Type 1 diabetes. Type 1 diabetes is an autoimmune disease that strikes both children and adults. Diabetes is widely prevalent in the United States with over 23.6 million children and adults affected by this devastating disease (7.8% of the population). Approximately, 1.6 million new cases of diabetes are diagnosed each year and it is the seventh leading cause of death in the United States. Persons with type 1 diabetes are dependent upon giving themselves insulin injections daily to control their blood sugar levels. Unfortunately, insulin is not a cure for diabetes, nor does it prevent its severe complications, which include kidney failure, blindness, heart disease, stroke, and amputation. The knowledge gained through this research work would be an extremely important achievement toward improving not only islet transplantation for the treatment of diabetes, but can be applied to transplantation of other stem cell-derived tissues. Ultimately, in addition to developing new tools for improved imaging of human stem cell-derived transplants and the identification of immunological assays for clinical management of patients, this work will help to understand the mechanisms of tolerance and approaches for tolerance induction.
Development of methods for regenerative medicine using tissues derived from human embryonic stem cells will result in therapies that have the potential to improve the health and quality of life for millions of Californians and human populations world wide. Type I diabetes is the 7th leading cause of death in the United States and affects over 23.6 million children and adults representing 7.8% of the U.S. population. The cost for treatment of diabetes is estimated at $174 billion annually including $116 billion for direct medical costs and $58 billion for indirect costs related to disability, work loss and premature mortality. The research that we propose in this application will lead to an improved understanding of how the human immune system responds to islet cell transplants derived from human embryonic stem cells. This information is critical to enable the development of therapies to induce tolerance and prevent the rejection of islet cell transplants. Furthermore, through this research we will develop a battery of immune monitoring assays that can be used in the diagnostic setting to monitor graft acceptance or rejection and improve the clinical management of the patient and transplant outcome. This research will also benefit Californians by disseminating the scientific findings and tools developed in this work to researchers throughout California. If funded, this research work will create 2 new jobs that create tax revenue for the State of California