Human embryonic stem cells (hESCs) possess the ability to become specialized cells such as brain, cardiac, and pancreatic cells. However, despite the excitement surrounding ESC research, important issues surrounding immunogenicity have not been fully addressed and strategies to prevent the immune system from rejecting transplanted hESCs remain largely untested. A viable alternative to hESC therapies is the use of induced pluripotent stem (iPS) cells, which are non-pluripotent cells (i.e. skin, neural, adipose) “reprogrammed” to a hESC-like state. In theory, iPS cells would not face the same barriers such as immune response and rejection, because iPS cells can be derived from and transplanted back into the same person. However, no study has investigated whether iPS cells will indeed evade immune recognition if transplanted in such a manner. Therefore, it will be essential to investigate the immune properties of iPS cells, and our proposal aims to address three issues that are critical to understanding the immunogenicity of iPS cells and the development of strategies to promote long-term survival of transplanted cells.
Our first goal is to characterize the immunogenicity of iPS cells. We will measure the expression level of numerous genes and proteins which are recognized by the host immune system and can stimulate an immune response. To “reprogram” a cell into an iPS cell requires that either genes or proteins be inserted into the cell. This can be accomplished by viral, non-viral, or protein-based techniques. The immunogenicity of iPS cells may vary based on the technique employed. We will generate iPS cells by all three techniques and compare the immunogenic profile of cells generated from each technique in an attempt to identify the least immunogenic approach.
Our second goal is to study iPS cells in an environment which most closely resembles that found in a human. We will use a live animal model termed a “humanized” mouse model to study the immune response of human immune cells against human iPS cells. A “humanized” mouse is generated by transplanting human immune system progenitor cells into an immunodeficient mouse. Through this model, we will examine the same gene markers profiled in the first goal, while concurrently monitoring the immune response to iPS cells transplanted into a foreign immune environment.
Our third goal is to develop methods by which transplanted iPS cells may survive in the long term. To maximize the potential of success we will target both the transplanted cells and the host immune system. To make the transplanted iPS cells less offensive to the immune system, we will force the expression of molecules that inhibit and decrease the expression of molecules which activate the immune system. To blunt the response of the host immune system to the transplanted iPS cells, we will deliver an immunosuppressive regimen which prevents T-cell activation against foreign cells.
At present, the most urgent problem in transplantation is the chronic lack of suitable donor organs and tissues. As the population ages and life span increases, demands for organs and tissue therapies will only increase. One alternative to organ transplantation is cell therapy, which promises to replace, repair, or enhance the biological function of damaged tissue or diseased organs. Thus, a prerequisite for cell transplantation is to find a renewable source of cells that could be used in humans to regenerate damaged tissues and organs. In recent years, human embryonic stem (hESCs) have been heralded as the cell population best suited for this purpose. However, standard methods for hESC derivation requiring embryo destruction come under ethical and political controversies. In addition, the potential immunological rejection of allogeneic transplanted hESCs represents another major barrier precluding their therapeutic application. These concerns have stimulated an intense search for alternative sources of pluripotent stem cells. One alternative that can theoretically circumvent these concerns is induced pluripotent stem (iPS) cells. iPS cells are assumed to be non-immunogenic if they are therapeutically transplanted into the same patient from whom they were derived. However, they have never been studied in any immunocompetent animal model, and it remains unknown whether they will be immunologically rejected. Therefore, it is critical for scientists to further understand the immunogenic properties of iPS cells. Specifically, we must find out which molecules iPS cells possess that could stimulate an immune response so as to develop techniques to remove these molecules or avoid the immune response altogether.
We believe that answering these questions will lead to significant advances in iPS cell research and novel therapies. We have assembled a multidisciplinary team of experienced investigators to attack the challenges of this project. At the same time, we will train and mentor a new generation of bright students and junior scientists in the areas of technology development and iPS cell biology. This ensures that an essential knowledge base will be preserved and passed on into the foreseeable future.