$1 508 652
The liver is an "immune privilege” organ. Food proteins as well as toxins introduced into liver cells via the liver blood flow (portal vein) are tolerated. Notably, liver transplantation could result in systemic non-rejection. This hepatic tolerance scenario could extend to sittings of into the liver stem cell transplantation if CIRM, together with our scientific community, have the determination and commitment to define the underlining immunologic mechanisms of rejection, and establish clinically applicable into the liver tolerance strategies. The main goal of this research is to establish a tolerance induction strategy applicable to patients receiving stem cell grafts (such as liver cells or insulin-secreting cells) delivered into the liver. The project will pursue three Specific Aims in which studies are designed to (1) determine expression profiles of transplant antigens by stem cell grafts at designated stages of liver cell development; (2) determine the mechanism(s) responsible for tolerance acceptance of stem cell grafts; and (3) tolerance conditioning of cell therapy recipients with stem cell derived antigen presenting cells. The proposed research will ultimately fulfill our resolution to develop tolerance methods for the clinical application of stem cell transplants to cure patients dying of liver diseases, as well as to treat diabetes with stem cell derived islet grafts.
Statement of Benefit to California:
Currently over 3,500 patients suffering from end-stage liver diseases such as cirrhosis are awaiting liver transplantation in California (One legacy 2009). Due to donor organ shortage, only 700 cases of liver transplantations are performed annually in all 15 Liver Transplant Centers combined in the Golden State. For this very reason, stem cell derived liver graft transplantation will be a life saving procedure for liver failure patients. The potential benefits of the proposed research will also extend to 2.7 million diabetes patients in California (California Diabetes Program, DIRC). Specifically, patients with type 1 diabetes require insulin injections to maintain normal blood sugar levels and the prevention of fatal complications. Alternatively, stem cell derived islet transplantation could provide a cure for these patients. The tolerance induction strategies to be developed in the research will greatly facilitate acceptance by patients of stem cell derived islets as well as conventional pancreatic islet grafts. Therapeutic benefits will potentially cover >135,000 insulin-dependent diabetes patients in California alone. The tolerance mechanisms determined by this proposed research will ultimately contribute to a better understanding of stem cell transplant immunology. Knowledge gained from the research will form the scientific basis for designing and administering tolerance induction regimens to achieve rejection-free stem cell transplantation. In addition, the savings to health care for anti-rejection treatments could amount to billions of dollars for Californians.
The overall goal of this proposal is to develop a strategy for inducing tolerance to embryonic stem cell (ESC) – derived grafts delivered into the liver through use of a specific class of antigen presenting cells (APCs) that are derived from the same ESCs. To achieve these ends, the applicant has proposed a series of three Aims. First, the expression of transplant antigens of ESC- derived cells will be investigated at three key stages in the hepatic lineage. Next, the cellular mechanisms by which intrahepatically engrafted ESC-derived APCs induce donor-specific tolerance will be explored. For the third Aim, the applicant seeks to establish a tolerogenic conditioning strategy that is applicable to ESC-derived cell transplantation. The resulting methodology will be optimized and tested for effectiveness in a model of pancreatic endoderm engraftment. Reviewers agreed that developing a strategy for achieving donor-specific tolerance in a robust fashion could significantly advance the applicability of stem cell derived therapies. The idea of using tolerogenic APCs or the hepatic route of transplantation for tolerance induction is not new but, if successful, could afford a feasible protocol for engraftment of ESC-derived hepatic or pancreatic cells. Reviewers lacked confidence, however, in the underlying premise that allogeneic cells can escape rejection when delivered intrahepatically. As a result, their enthusiasm for the potential impact of this work was substantially diminished. Reviewers discussed a number of weaknesses in the project rationale that led them to doubt the feasibility of this effort. Importantly, they noted that there are limited published data to support the hypothesis that allogeneic ESC-derived APCS transplanted with allogeneic ESC- derived hepatic precursors (HP) could engraft and develop significantly in the liver of recipient mice. Although a compelling study from five years ago suggested this possibility, there have been no follow-up studies with appropriate statistics to bolster the notion. Furthermore, there were no preliminary data to support the applicant’s assertion that engraftment in this model could be established as late as one-year post transplant. These concerns, combined with the acknowledgement that increased expression of Major Histocompatibility Complex class I (MHC) on differentiating hepatic cells could lead to greater immunogenicity, led reviewers to conclude that the assumption of tolerance in this system is premature. As a result, the rationale for mechanistically pursuing the role of APCs in inducing this hypothetical tolerance lost its impetus. While reviewers appreciated the creative use stage-specific reporter genes to characterize MHC expression as ESCs differentiate towards the hepatic lineage, they were uncertain how this information would contribute to subsequent aims and to the project goal of inducing tolerance to differentiated grafts. They were also concerned at the apparent superficial consideration of ESC-derived APC generation, which can result in APCs that more or less tolerogenic depending on maturity or state of activation. Finally, while the individual experiments appeared soundly designed, reviewers believed that the overall research plan was based on poorly supported hypotheses rather than a balanced consideration of alternatives that might reasonably be investigated. The principal investigator (PI) is a distinguished transplant immunologist with experience in several aspects of transplant rejection and adult stem cell biology, including donor microchimerism and allograft non-responsiveness. There is no clear evidence of deep expertise with the proposed APC population or regulatory T cells, however, which was reflected in the application. The co-PI is a transplant surgeon with research interests in stem cells. Reviewers felt that this was a team of qualified investigators that lacked tolerogenic expertise. Overall, the rationale for this proposal was considered weak, and the preliminary data presented were not strong enough to suggest that the project is feasible.