Basic Biology V
$1 191 000
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.
A major unsolved problem in the field of stem cell research is how to introduce foreign “non-self” stem cells or cells derived from them into human or animal hosts without these cells being rejected by the host’s immune system. The goal of this Fundamental Mechanisms Award proposal is to determine the potential to induce tolerance using human embryonic stem cell (hESC)-derived thymic cells. It is in the thymus that immune cells are educated (become tolerant) so that they will not attack cells identified as “self”. The applicant will assess if thymic cells differentiated from human pluripotent stem cells (hPSCs) can induce immune tolerance to other differentiated stem cell derivatives (pancreatic cells) from the same stem cell line. The applicant will also determine the cellular mechanisms involved in the induction of immune tolerance by these derived thymic cells through the use of a model antigen system. The research provides a potential method for induction of tolerance to specific antigens in the context of stem cell therapies. Significance and Innovation - Reviewers considered the proposed research innovative and cutting edge, as the proposed studies have been made possible only with recent advances in the field. - The proposal is also highly significant. If the goals of the research are realized, it would represent a major step forward in enabling transplantation without toxic immunosuppressive drugs and would be an important step toward the development of a transplantable thymus. The project may benefit transplantation of many different cell types and therapies for a variety of diseases. Feasibility and Experimental Design - The experimental design is well constructed and presented. Given the expertise and experience of the research team, the proposed studies are feasible. Experiments for each aim were well presented and designed to meet the objective of the proposal. - Reviewers differed in their opinions regarding the strength of the preliminary data. Some viewed the preliminary data as strong and in support the hypothesis and research plan, whereas some were not convinced that the data were sufficient to suggest a high probability that the project would be successful. In particular, the complete functionality of the derived thymic cells in generating sufficient numbers of immune cells was questioned. For example, expression of some genes critical for tolerance generation was not demonstrated. Additionally, there was some concern regarding the feasibility of generating the cell lines needed for the project. - There was also concern regarding whether the experimental models proposed were adequate and clinically relevant for the overall goal of the work. Some of the reviewers expressed reservations that the differentiation protocol needed further optimization. - Although the PI acknowledged some of the potential pitfalls, the alternatives proposed were not always satisfactory and not all potential pitfalls were acknowledged by the PI. Principal Investigator (PI) and Research Team - The PI is an outstanding and respected scientist with expertise in immune tolerance and in understanding the immunological processes in Type 1 diabetes. - The co-investigator is an outstanding developmental biologist, with whom the PI previously collaborated. Their collaboration has been productive and successful. Both are productive, innovative scientists with the expertise to conduct the project. - To some the budget requested appeared high for the research proposed. Responsiveness to the RFA - This proposal is considered to be very responsive to the RFA. It proposes to utilize human stem cell-derived thymic cells and pancreatic progenitors to test a question of significance for the use of stem cells in treating disease—how to induce tolerance to, and avoid rejection of, transplanted stem cell-derived tissue.
- Brian Harfe