Transplantation Overview Since the first successful kidney transplant between identical twins in 1954, organ and tissue transplantation has offered the hope of life to tens of thousands suffering from a wide range of conditions. Today, doctors routinely transplant more than 25 different organs and tissues as a treatment for kidney failure, Type 1 diabetes, leukemia, end-stage pulmonary disease, liver disorders, and cardiovascular disease, among others. The hope and promise of transplantation has been tempered with disappointment. Despite tremendous progress, two major barriers still remain to the overall success of transplantation: transplant rejection and a shortage of donor organs and tissues. Although one-year survival after organ transplantation has improved markedly over the last 25 years the long-term survival of grafts and patients continue to improve relatively little. Nationwide, the demand for organ transplants far outstrips the supply. Unfortunately, many candidates die while awaiting a suitable organ. Through its sponsorship of world-class research and the development of research infrastructure, the National Institute of Allergy and Infectious Diseases works to extend survival for transplant recipients, to improve their quality of life, and to make the promise of organ and tissue transplantation a reality. History of Transplantation Humans have long realized the possibilities unleashed by transplantation of organs and tissue. As early as the 6th Century BC, the Indian surgeon Sushruta described how to reconstruct disfiguring facial wounds by transplanting skin and cartilage from one place on the body to the other. Below is a list of significant events in the development of transplantation as a viable clinical procedure that occurred over the past century. New Hope for Kidney Transplant Patients Since the first successful kidney transplant between identical twins in 1954, organ and tissue transplantation has offered hope to tens of thousands of individuals suffering from a wide range of conditions. Today, doctors routinely transplant more than 25 different organs and tissues as a treatment for kidney failure, Type 1 diabetes, leukemia, end-stage pulmonary disease, liver disorders, and cardiovascular disease, among other diseases. The Challenge The hope that transplantation has given to many people facing a debilitating and often fatal illness, however, has sometimes been tempered with disappointment. Except in the rare case in which a donor is an identical twin to the recipient, transplants involve immunologic mismatches. As a result, the graft may be rejected or not function properly, or cells from the graft may attack the patient’s healthy cells. All these problems remain potential barriers to a transplant recipient resuming a normal life. In addition, transplant recipients generally must take anti-rejection drugs daily for the rest of their lives, and the drugs can themselves cause organ damage and increase susceptibility to disease, infection, and cancer. Though the one-year survival rate after organ transplantation has improved markedly over the last 25 years, the long-term graft and patient survival rates have improved relatively little. Immune Tolerance The Holy Grail of transplantation has always been immune tolerance: inducing the recipient’s body to accept the transplanted tissue while maintaining immunologic responsiveness to infectious agents of disease. Through the efforts of researchers affiliated with the NIAID Immune Tolerance Network (ITN), researchers are beginning to make small successes in this area. Recently, David Sachs, M.D., a surgeon at Massachusetts General Hospital in Boston, led an experimental study that transitioned four of five kidney transplant patients from a traditional regimen of anti-rejection drugs to living without the drugs. The fifth patient rejected the organ. This outcome was especially noteworthy because the kidneys were very close, but not perfect, immunologic matches for the recipients. In the study, Dr. Sachs’s team used a regimen of drugs and radiation to severely weaken the immune system of the transplant patient prior to receiving the donated organ. During surgery, the patient then received not only the organ but also an infusion of bone marrow from the donor. This was followed by a course of anti-rejection drugs that were gradually reduced, depending on the patient’s condition, over the course of 9 to 14 months. Though the immune system that renewed itself after the bone marrow transplant was initially a hybrid from both the donor and the recipient, or chimeric, over several weeks the immune system reverted to the original characteristics of the recipient while continuing to tolerate the transplanted organ. According to their report published in January 2008, the patients in this study had lived without anti-rejection drugs for between 2 and 5.3 years. Study Limitations While the findings are encouraging, this study was small-scale. In addition, although the donor organs were not a perfect immunologic match, they were mismatched by only a single HLA haplotype, the set of genetic information that determines if transplanted tissue is compatible with the recipient’s immune system. Moreover, the organs were donated by living family members. Most organs come from cadavers. In such cases, the pre-transplant procedure that culminated in a bone marrow transplant is not feasible. Despite its limitations, the study validates the concept of gradually weaning transplant patients from powerful anti-rejection drugs and allowing them to fulfill the promise of transplant surgery by leading full and healthy lives. “We are very encouraged by our initial success in inducing tolerance across the HLA barrier, something that has been a major goal of transplant immunology for years,” notes Dr. Sachs in a Massachusetts General Hospital news release that announced the study findings. “While we need to study this approach in a larger group of patients before it is ready for broad clinical use, this is the first time that tolerance to a series of mismatched transplants has been intentionally and successfully induced.” Induction of Immune Tolerance The drug regimens that suppress a patient’s immune system usually can prevent graft rejection, but they also cause serious side effects such as infections and malignancies. NIAID is working to develop treatments that can both reduce these risks and improve graft survival. One promising alternative is to selectively modify the immune response to establish tolerance to the graft while leaving protective immune responses intact. Prevention of Immune-Mediated Graft Rejection The major goals of NIAID’s transplantation research program are to understand the pathways whereby the immune system recognizes transplanted organs, tissues, and cells; characterize the cellular and molecular components of acute rejection and chronic graft failure; evaluate novel therapies for treating rejection and prolonging graft survival in preclinical models; develop and implement strategies for immune tolerance induction; and conduct clinical trials of new therapies to improve graft survival, while minimizing the toxic side effects of immunosuppressive drugs. Shortage of Human Donor Organs The number of organ transplants performed in the United States continues to increase but these numbers would be even higher if more donor organs were available; the waiting list for transplants has quadrupled since 1988. NIAID is working to address this problem by supporting efforts to improve donor registries that identify potential donors and by developing educational initiatives to increase public understanding of organ donation, especially among minority populations. The use of nonhuman organs, tissues, or cells in human transplantation, called xenotransplantation, is another strategy The potential of xenotransplantation, however, is severely limited by the violent response of the human immune system to nonhuman tissues; concerns have also been expressed that infectious agents might inadvertently be introduced from animal donors into humans. NIAID-supported xenotransplantation research focuses on increasing our understanding of the human immune response to antigens present on cells from nonhuman species, and on the development of methods for rapid identification and treatment of any infectious diseases that might be caused by organisms present in animal donor tissue.
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