Innate and Adaptive Immunity to Stem Cell Allografts: Pathways to Tolerance Induction
Although stem cell-based therapies offer tremendous hope for treatment of a variety of human diseases, the full potential of this approach will not be reached unless we can achieve stem cell graft acceptance. The main barrier to reaching this goal is that we do not fully understand how the immune system of graft recipients causes the transplanted cells to be rejected. If we could understand this process, it would be possible to develop new approaches to prevent, or circumvent, graft rejection. Our previous work in organ transplantation has identified certain cells and molecules in the immune response that are critically involved in graft rejection. We have also identified methods that promote long-term organ graft survival in donor-recipient transplant combinations that would ordinarily result in graft rejection. Here we plan to determine what the specific cells and molecules are that cause an immune response and rejection of transplanted stem cell grafts. We will analyze this process using three different types of stem cell grafts to understand how the graft itself, and where it is placed, contributes to the outcome of transplantation. On the basis of these findings we will develop new methodologies to help the recipient immune system accept the transplanted stem cell grafts as if they were not foreign, but instead were “self”. Finally, the efficacy of our strategies will be tested in a model of liver disease to determine if we can achieve long-term survival of foreign stem cell transplants that ultimately restore liver function. These studies have the potential to improve the outcome of stem cell transplantation in general, as well as to expand treatment options for people with liver disease or liver failure.
Liver diseases are a significant cause of morbidity and mortality in the United States and are disproportionately evident in California. A recent study by the Institute of Medicine estimates that one in fifty Americans has viral hepatitis, a major cause of liver cancer and the leading cause of liver transplants nationwide. Twenty percent of all Americans on waiting lists for liver transplantation reside in California yet there is a dramatic shortage of transplantable organs to treat these patients. Stem cell therapies have the potential to overcome the shortage of available donor livers, and ultimately to provide treatment and disease cures that could save the lives of California children and adults with liver disease.
The liver is one of the least immunogenic organs however, paradoxically, isolated allogeneic hepatocytes are readily rejected by the immune system. Our studies will define the immune response to stem cell-derived allografts that could promote hepatic regeneration for Californians with liver disease. We will use this information to develop strategies to achieve long term survival of stem cell transplants.
Over the next twenty years, annual medical costs for people with liver disease are projected to increase dramatically, thus it is essential that effective therapies be developed soon. Our proposed studies will help to preserve California’s leadership role in research in stem cell biology, liver disease, and transplantation and stimulate growth of the California biotechnology and pharmaceutical industries. Successful completion of our work will lead to therapies to improve the health of Californians with liver disease and will have broad applicability in realizing the goal of applying stem cell-based therapies to regenerative medicine.