Type I diabetes is caused by an immune-mediated process that involves the destruction of one’s own pancreatic insulin producing tissue. The mechanisms that are responsible for this self-destruction remain unclear but are thought to involve a component of the immune system known as the cytotoxic arm. A number of general immunosuppressive medications have been shown to slow down or prevent the onset and/or progression of this autoimmune destruction. However, this therapeutic option is at the expense of serious drug-induced side effects. This has led to a need for an immunosuppressive therapy with minimal side effects. Recently, a type of stem cells, known as mesenchymal stem cells, has been shown to possess immunosuppressive effects. Human clinical trials showed these cells could be used to suppress graft-versus-host-disease in patients undergoing bone marrow transplantation. This cell-based therapy was in replacement of traditional immunosuppressive medications such as cyclosporine. Although very promising, the immunosuppressive effect was only observed for two weeks, suggesting a transient nature. Our group has recently discovered a rare subpopulation of mesenchymal stem cells in the fat tissue of humans with persistent immunosuppressive effects. Further studies to characterize the underlying mechanism of immunosuppression revealed these cells block the cytotoxic arm of the immune system, providing a significant relevance for use as a therapeutic for type I diabetes. The advantages of a cell-based immunosuppressive lie in their ability to achieve these effects in the absence of end-organ damage thereby providing increased safety for patients. In addition, our preliminary experiments involved transplantation of human cells into mice with a normal immune system. In this model, human cells were not rejected, suggesting the possibility that this rare stem cell population may be used similar to drugs, in an off-the-shelf fashion, without concern for special tissue matching procedures that continue to limit commercialization of stem cells. Another limitation, however, is in the ability of stem cells to be mass produced for commercial scale use. Through the use of genetic engineering, our group has designed a tool that allows for large scale cell expansion in the tissue culture dish. This mechanism can only be turned on in the presence of a special drug that would otherwise not be present in the human body, thereby allowing for complete control of the induction mechanism. We believe that engineering of this inducible mechanism into the stem cell population with immunosuppressive effects will solve the two major hurdles currently limiting stem cell commercialization while creating a stable safe and efficacious therapeutic for type I diabetes. A mesenchymal stem cell with persistent immunosuppressive effects that can be mass produced similar to a drug will represent a major breakthrough in the field, allowing for treatment of other autoimmune diseases.
Statement of Benefit to California:
California is home to over 100,000 people afflicted with type I diabetes with current demographic trends suggesting this number will steadily increase for the next two decades. Since the onset of type I diabetes is often in childhood, the cumulative impact over a patient's lifetime is significant at a number of levels including quality of life, emotional stability, as well as the currently unavoidable late-stage sequela such as blindness, kidney damage, and cardiovascular disease. The costs associated with providing vigilant monitoring and care for patients with diabetes are high and will continue to increase barring a paradigm shift in the therapeutic approach. Much attention has been paid to the treatment of type II diabetes using regenerative medicine approaches such as islet cell transplantation using embryonic stem cells. However, unlike type II diabetes, type I diabetes is caused by an autoimmune reaction against one's own islet cells. Thus, islet cell replacement is unlikely to significantly impact the quality of life of type I diabetics in the absence of preventing the continued autoimmune destruction process. The proposed research aims to develop an innovative therapeutic stem cell approach that differs from those currently in development. Instead of utilizing stem cells to replace the destroyed islet cells, our laboratory believes we can exploit recent evidence that a particular adult-derived stem cell population possesses immunosuppressive effects. The work conducted in this project will allow for the development of a stem cell based therapeutic approach that addresses the underlying pathophysiology of type I diabetes by preventing the autoimmune destruction of insulin-producing islet cells. This approach offers the State of California and its citizens a significant advance in the therapeutic approach to type I diabetes, allowing patient's to preserve their insulin producing cells thereby preventing the significant short- and long-term problems associated with this devastating disease. If successful, this approach may be applied more broadly to all autoimmune diseases providing the State of California with the first therapeutic capable of preventing autoimmune disease safely and efficaciously, leading to a tremendous reduction in the California health care burden and improvement in the overall health and productivity of its citizens.