IMMUNE TOLERANCE TO STEM CELLS IN LIVER TRANSPLANT REGENERATION AND SURVIVAL
Liver transplantation is currently definitive therapy for patients with end-stage liver disease. However, the full potential for liver transplants is severely compromised due to shortages in the number of suitable donor livers. Today, partial liver transplants in which a piece of the liver (known as a split-liver graft) is used, has become a popular strategy to solve the problem of organ shortage. However, several problems and risks still exist. One such problem is the size of the grafts with many grafts too small to adequate liver function (i.e. “small-for-size” grafts). Another problem is the decreasing quality of donor grafts, primarily due to the aging of general population. Therefore, enhancing the quality and function of the liver grafts for transplantation is of major importance for the overall success of this life-saving therapy.
Poor quality liver grafts are particularly susceptible to injuries that are sustained when the graft is harvested and then transplanted into the host. These injuries, known as a damage due to ischemia and reperfusion, or IRI, represent one of the most understudied yet critical problems in liver transplantation. Our Laboratory has been at the forefront of liver IRI research for the last 20 years and our studies have suggested that IRI may be the result of the recipient’s immune system. Since the immune system can dictate the transplant outcome, the logical question arises as to how can we modify the host’s immune system to improve the quality and function of these liver grafts following their transplantation.
Over the years, striking advances in modifying the immune system’s response to transplanted organs has occurred. There is a general consensus that real progress in one of the most challenging areas of transplantation, i.e., the acquisition of tolerance to the donated tissue is now within reach. This proposal is aimed at applying state-of-the-art immunosuppression concepts with the burgeoning field of stem cells in order to improve the outcome of liver transplants. Specifically this, application proposes that liver grafts transplanted together with stem cells and combined with directed suppression of the host’s immune system may promote the ability of these stem cells to regenerate liver tissue and improve the quality of the transplanted graft. Based on the findings of this proposal the ultimate goal is to proceed to clinical trials and translate our data from the bench to bedside in liver transplant patients.
While liver transplantation has been established as the definitive therapy for patients with end-stage liver disease, its full potential is far from being realized due to the increasing numbers of recipients who vie for a limited donor supply. Indeed, in the last decade the number of liver transplants has grown by 2.5-fold, whereas the number of patients on waiting list has increased by 15-fold. As patients wait for their transplant, the cost of patient care increases exponentially. As some of these costs are too great for the patient to pay, the decreasing availability of suitable livers for transplantation, places a large burden on the state’s health care system. Although advances in surgical technique have allowed the use split donor livers from cadavers, this practice is not suited for the majority of cases. Partial liver transplantation using liver grafts from live donors is a valuable strategy to solve the problem of organ shortage. However, the quality and the size of the graft remain problems. Importantly, these “sub-optimal” livers not only contribute to the shortage of organs available for transplantation, but also experience higher incidence of both early acute and late chronic dysfunction once transplanted. Hence, enhancing the quality of the donated organ is of major importance, as it should improve the outcome of liver transplantation, decreasing the need and cost of post-surgical care. This application combines state-of-the-art immunosuppression techniques with the burgeoning field of stem cells in order to improve the outcome of liver transplants. Specifically, this application proposes that liver grafts transplanted together with stem cells and combined with directed suppression of the host’s immune system may promote the ability of these stem cells to regenerate liver tissue and improve the quality of the transplanted graft. Based on the findings of this proposal, the goal is to proceed to clinical trials and translate our data from the bench to bedside where it could potentially solve the growing problem of inadequate organ liver supply in the State of California.