Mechanisms to protect hESC-derived cells from allogenic immune rejection
The potential of human embryonic stem cells (hESC) to differentiate into a tremendous range of biologically active cells/tissues is the basis for many novel therapeutic strategies. However, immune-mediated rejection of hESC-derived tissues by the patient remains a significant barrier to the promise of regenerative therapies. Therefore, it is key to develop strategies to induce immunological tolerance to hESC-derived tissues/cells, thereby inhibiting rejection and evading the risks of routinely used systemic immunosuppressants, including the cytotoxicity and increased risk of infection and cancer. To accomplish this objective, we have expressed proteins known to restrain lymphocyte activity in hESC-derived cells. Importantly, when transplanted into mouse models with functional human immune system, we find that transplanted cells derived from modified hESCs evade rejection and induce sustained immunological tolerance. This is the first time the immune responses to hESC-derived cells have been studied in an in vivo context. Here, we propose to explore the molecular pathways and immune cell types that mediate the induction of immune tolerance and pursue additional targets for further blunting rejection of tissue grafts derived from hESC. To achieve the full potential of hESC-based therapy, it is critical to develop effective approaches to promote long-term immune tolerance of hESC-derived cells, and our studies provide a novel strategy to this end.
Thousands of Californians receive life-saving tissue transplantation each year. However, the human and medical cost of long-term immunosuppression to promote survival of grafted cells and the limited availability of donor tissues/cells prevents the realization of the full benefits. The potential of human embryonic stem cells (hESC) to differentiate into a tremendous range of biologically active cells/tissues is the basis for many novel therapeutic strategies. However, immune-mediated rejection of hESC-derived tissues remains a significant barrier to the promise of regenerative therapies. Thus, it is key to develop strategies to induce immunological tolerance to hESC-derived tissues/cells, which will allow the clinic realization of the full range of benefits to the health of Californians. We propose a novel approach to promote long-term acceptance of hESC-derived tissues and to better understand the mechanisms of immune tolerance in the context of tissue transplantation. We will focus on the immune tolerance of hESC-derived lung epithelial cells that have been shown to rescue lung functions in animal models, as this cell therapy will save the life of patients with various lung diseases such as the chronic obstructive lung diseases that are major killers in California and pose tremendous burden on medical care in our state. Our research will thus lead to important progress in stem cell therapies to better meet the needs of Californians.
Human embryonic stem cells (hESCs) hold great promise for cell therapy as a source of diverse differentiated cell types. One key bottleneck to realizing such potential is allogenic immune rejection of hESC-derived cells by recipients. We established hESCs that constitutively express immunosuppressive signals. We then demonstrated that allogenic can be protected from immune destruction. These findings are instrumental for developing a strategy to protect hESC-derived cells from allogenic immune responses without requiring systemic immune suppression.
Human embryonic stem cells (hESCs) can undergo unlimited self-renewal and retain the ability to differentiate into all cell types in the body. Therefore, as a renewable source of numerous cell types, stem cells hold great promise for human cell replacement therapy. Significant progress has been made in establishing the conditions to differentiate hESCs into several lineages of biologically active cells. For example, recent studies in animal models have shown that myocytes differentiated from hESCs improve cardiac function after myocardial infarction, and oligodendroglial progenitors could rescue spinal cord injury. hESC-derived lung epithelium has been shown to repair and improve the lung function after acute lung injury1. In addition, pancreatic β cells derived from hESCs are functional in animal models. These recent encouraging reports suggest that hESC-based cell replacement therapies can be achieved in the near future.Despite the promising progress in generating hESC-derived tissues, several major obstacles must be addressed prior to successful application of hESC-based cell replacement therapies in patients. One major complication is the immune-mediated rejection of hESC-derived cells by the recipient due to expression of allo-antigens and specific alterations in gene expression. We are working to "turn off" the cells of the immune system responsible for graft rejection but only in the response to grafted tissues derived from stem cells. This strategy is a significant improvement over total immune suppression which is typically used to promote graft acceptance. This year we have made significant progress in that we have generated stem cells that are accepted as grafts and begun to dissect the molecular pathways responsible for graft acceptance.