Alloimmunogenicity and Tolerogenic Acceptance of ESC-Derived Hepatopancreatic Cells
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.
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.