Grant Award Details
Generation of a functional thymus to induce immune tolerance to stem cell derivatives
To generate TEPs from human pluripotent stem cells and demonstrate their potential to establish and maintain specific immune tolerance to other stem-cell-derived tissue in a humanized mouse model. They will also identify the cellular mechanisms involved in the induction of tolerance, using a model antigen system to assess antigen-specific immune responses.
We continue to make progress with our efforts to generate functional thymic epithelial cells that are derived from stem cell sources. Over the last year we have been able to improve our ability to differentiate thymic epithelial progenitors by using a 3-Dimenstional culture system. This system has improved our efficiency and we are currently further refining it for use in our differentiation method. In future years, this will help accelerate our progress in TEP generation. A second area that we have made progress in is the generation of a reporter stem cell line for a key transcription factor called FOXN1. These cells express a key marker that help tell us how well our protocol is working. Through the use of this new cell line we again have made substantial progress in our differentiation efficiency. In looking forward to the next years of funding, we are well positioned for our more elaborate experiments for looking at immune tolerance that is induced by our cells.
Over the last year we continue to make substantial progress in our project on differentiating pluripotent stem cells into thymic epithelial progenitors (TEP's). We have now developed a robust differentiation protocol that improves expression of the key TEP transcription factor Foxn1. In addition, we have also made progress in generating more fully humanized immune system mice by grafting in our TEP's with hematopoetic stem cells. Preliminary results from these in vivo experiments indicate that our TEP's are capable of inducing T cell development. We are now further refining our technique to improve this efficiency and also other methods to induce Foxn1 expression in TEP's. Taken together, these results will provide the platform for potentially bringing this approach to the clinic.
<p>Although stem cell-based therapies can potentially be used to treat numerous prevalent diseases, their successful clinical translation requires overcoming the problem of immune rejection. Given that self-identity is encoded by thymic epithelial cells (TECs), an appealing approach to manipulating immune tolerance in the context of stem cell therapies would be to reprogram the immune system through the generation of stem cell-derived TECs. To address this hypothesis, we have developed a method to generate in vitro differentiated stem cell-derived thymic epithelial progenitors (TEPs) that are transplanted into mice reconstituted with human immune cells. We also established a robust protocol to produce functional pancreatic beta cells using a genetically matched hESC line. Co-transplantation of matched TEPs and beta cells as well as genetically distinct cells will allow us to test the ability of stem cell-derived TECs to induce immune tolerance to genetically matched stem cell derivatives. In addition, these humanized mice will be used to study if expression of specific proteins by TECs can influence immune responses against this antigen. Taken together, our work provides unique tools to study stem cell derivatives immunogenicity following transplantation in humanized mice. These studies will also help demonstrate if hESC-derived TEPs can be used as a method for the induction of long lasting immune tolerance to specific antigens and to stem cell derivatives.</p>
Grant Application Details
- Generation of a functional thymus to induce immune tolerance to stem cell derivatives
Stem cell research offers the promise of replacing missing or damaged tissues in the treatment of disease. Stem-cell-derived transplants still face problems with rejection as in traditional organ transplants. Several drugs can prevent rejection but also suppress the immune system, leaving patients vulnerable to infections and cancer. To avoid rejection without using drugs requires re-educating the immune system to “tolerate” the transplant and not see it as foreign. Because of its role in educating developing immune cells, the thymus is a critical organ in establishing what the immune system recognizes as “self” and not foreign, in a process known as immune tolerance. By growing a new thymus from stem cells matched to transplanted tissues, we can condition the immune system to be tolerant to the transplant and avoid chronic immunosuppression. We have developed a method to grow stem cells into thymic cells that become normal thymus tissue when grafted into mouse models. Notably, the new thymus can promote normal development of immune cells, indicating the potential for generating new, tolerant immune cells. We propose to induce immune tolerance to other stem-cell derived tissues using stem-cell-derived thymus tissue to engineer tolerance. We will optimize our methods of growing thymus tissue, which will be used to condition mice to accept stem-cell-derived pancreas grafts, testing their ability both to prevent rejection and to cure diabetes in a transplant model.
Statement of Benefit to California:
The proposed work aims to improve the effectiveness of stem cell treatments by preventing immunological rejection of transplanted tissue derived from stem cells. An important barrier to the clinical use of stem-cell-derived organs and tissues is the potential of the immune system to reject or damage this regenerated tissue. Improved approaches to address immune rejection are needed since stem cell therapies are underway in treating diseases that have a wide impact on the health of Californians, including diabetes, Parkinson’s disease, Alzheimer’s disease, retinal eye diseases, and musculoskeletal diseases.
The proposed studies will improve treatment for these diseases by providing a novel method to halt immunologic rejection or destruction of tissues that are derived from stem cells. We have successfully developed methods to grow thymus tissue, which controls the ability of the immune system to be “tolerant” of transplanted tissue. Here we will improve methods to generate thymus from stem cells and show that it can promote survival of transplanted tissue derived from the same cells. By using the thymus to condition the immune system towards tolerance, we hope to avoid immune rejection without the use of immunosuppressive drugs. Induction of a tolerant immune system in this way would represent a significant advance in improving stem cell therapies. Thus, this work could have a broad impact on a large number of the disease treatments that involve stem cells.
Source URL: https://www.cirm.ca.gov/our-progress/awards/generation-functional-thymus-induce-immune-tolerance-stem-cell-derivatives