Stem cells can give rise to many different types of cells and tissues in our body. Therefore, stem cell transplantation has been considered as a promising alternative to current therapeutic approaches in treating cancer and autoimmune diseases. The premise upon which stem cell treatment is based is that replenishment of diseased or destroyed tissues with cells derived from transplanted stem cells would prevent the progression of or potentially cure disease. However, similar to what occurs in organ transplantation, most if not all available sources for stem cells are from individuals of distinct genetic background. Consequently, the patient receiving stem cell transplantation typically develops a harmful immune response that attacks and destroys the transplanted stem cells or their derivatives. The development of novel methods to overcome such harmful immune responses becomes necessary before a successful stem cell based therapy for diseases, such as cancer or autoimmune diseases, can be applied clinically. Recent developments in research suggest that development of cancer or autoimmune diseases could be due to an imbalance in the immune system. As such, (re)establishing the balance in the immune system may hold great promise for prevention, intervention and cure of disease. Important findings in immunology in the past few years showed that a specialized population of immune cells, called regulatory T cells, functions by regulating other immune cells and, in turn, the body’s immune response. We hypothesize that these cells can potentially be used to modulate both immunity and autoimmunity, and consequently the direction of the body’s immune responses. We and others have shown that regulatory T cells may inhibit autoimmune diseases such as type 1 diabetes and participate in the regulation of tumor development. The purpose of our proposed studies is to determine whether regulatory T cells can also be used to overcome the immunological barriers imposed by patients receiving treatment, and re-balance the immune system in order to provide an environment that is much more suitable for stem cell grafts. It is expected that, for cell replacement therapy, regulatory T cells can induce immune tolerance to promote acceptance of stem cells allowing their growth and replacement of damaged cells in patients and leading to disease cure.
Statement of Benefit to California:
More than 1 million Californians have a history of cancer, and an estimated nearly 150,000 new cases will be diagnosed in 2010. In addition, autoimmune diseases such as type 1 diabetes and multiple sclerosis, also affect hundreds of thousands of Californians every year. These life-threatening diseases result in deteriorating health conditions and have devastating effects in terms of patient quality of life. While the heavy emotional, physical and financial impact of these diseases is felt by patients and their families, a significant economic burden is also felt by the State, as treatment and care of these patients costs California billions of dollars every year. Additional losses are incurred by the private and public sectors resulting from reduced worker productivity, absence from work and loss of future earnings. The rising cost of medical care is an additional factor underscoring the critical need to develop novel therapies to prevent and treat patients with on-going autoimmune disease. Stem cell transplantation is a promising alternative to current therapeutic approaches in treating cancer and autoimmune disease patients, due to the potential for stem cells to develop into many different types of cells and tissues in the body. Although promising, engraftment of stem cells, as well as cells or tissues derived from stem cells, still suffer from immune or autoimmune attacks and subsequent destruction from the patient’s own immune system, resulting in potential treatment failure or the need for extended patient care. Recent developments in research have suggested that development of cancer or autoimmune diseases could be due to an imbalance in the immune system. It is likely that (re)establishing the balance of the immune system may hold great promise in both prevention and intervention of the diseases. The proposed studies using T cells with potent regulatory function are expected to achieve this goal by inducing active immune tolerance in patients. Should our proposed studies be successful, our results will provide a solid base to facilitate rapid translation of our findings from laboratory to clinics, overcoming the immunological barriers imposed by host patients, with significant medical and economic benefits to Californians in terms of effective treatment of cancer and autoimmune diseases.
The objective of this proposal is to investigate whether regulatory T cells (Tregs) can be used to reprogram the host immune system to improve engraftment of an allogeneic cell therapy. This approach will be tested using two donor cell types, hematopoietic stem cells (HSCs) and embryonic stem cell (ESC)-derived insulin-producing cells, in both allogeneic and in humanized murine models. The proposal is based on the hypothesis that establishment of immune tolerance in recipients using Tregs will not only facilitate engraftment of stem cells and their derivatives following transplantation, but will also suppress auto- and allo-immunity that damages cell grafts. Three specific aims are proposed. Aim 1 is to examine the effect of Tregs in promoting allogeneic HSC engraftment efficiency in a mouse model. Aim 2 is to use a humanized mouse model to determine whether human Tregs will induce tolerance and facilitate engraftment of human HSC. Aim 3 is to investigate whether Tregs of either mouse or human origin will induce tolerance and promote engraftment of ESC-derived insulin-producing cells of the same species in allogeneic and humanized murine models of disease, respectively. The reviewers agreed that the proposal has the potential for significant impact. They commented that if successful, and if human Tregs prove to facilitate engraftment and enable the survival of human stem cells (HSC and ESC -derived insulin-producing cells) in the humanized mouse model, this would represent a significant finding and would advance the clinical applicability of stem cells. Reviewers also stated that the proposal, although it lacked novelty overall, contained elements of innovation and creativity, particularly in regard to the experiments proposed in Aim 3. The reviewers considered the proposal’s hypothesis to be well-supported by previous work, however aspects of the rationale and general lack of clarity in the experimental plan raised serious concerns that severely dampened the reviewers’ enthusiasm for this proposal. For example, the reviewers were unclear as to whether the applicants wanted to reduce graft rejection or Graft-versus-Host Disease (GVHD) in the model of allogeneic HSC transplantation. Modulation of these two processes requires Tregs with different antigenic specificities. Furthermore, reviewers questioned the use of Tregs specific for a pancreatic autoantigen to improve the outcome of HSC transplantation. Although these antigen specific-Tregs have been shown to be more effective than polyclonal Tregs in inducing tolerance to islet transplants, it is unclear why the same effect of pancreatic auto-antigen specific-Tregs is expected for HSC transplants. They also criticized the applicants proposal to test modulation of GVHD or rejection development in the auto/allo transplant models as superficial and often unclear and would have like to see more emphasis on acquisition of function, especially of T cells. Another criticism was the absence of a plan to compare the immunomodulatory effects of Tregs with those of immunosuppressive drugs in the preclinical models. The reviewers praised the qualifications of the Principal Investigator and the co-Investigator, commenting that they are experts in the field of Tregs, mouse models, and ESCs and have the necessary complementary skills to carry out this project. In summary, the goal of this proposal centers on increasing stem cell graft acceptance by co-injecting Treg cells to potentially modulate the host immune system. Despite containing some innovative concepts, the reviewers had serious concerns about the experimental design, the absence of important experimental details, and the general lack of clarity that undermined their confidence in the applicant’s ability to successfully carry out the proposed research.