Transplantation is the treatment of choice for most causes of end stage renal disease (ESRD), and for brittle/complicated type 1 diabetes mellitus (T1DM). Unless the recipient's immune system is bridled however, allografts are destroyed through a process known as rejection. Thus, patients who receive an allograft do so with the understanding that they will have to take immunosuppressive drugs for life. Current therapies are designed to suppress T cell-mediated immune responses. A variety of regimens are used. The most common is a triple drug regimen combining steroids with a calcineurin inhibitor and an antiproliferative agent. About half of U.S. transplant centers add an anti-lymphocyte antibody preparation. These therapies are non-specific; they indiscriminately blunt the immune response both to the allograft and to pathogens. Thus, the regimens subject the patient to a lifelong risk of infection and malignancy greatly exceeding that of the general population. They also have many non-immune side effects that limit their tolerability. Accordingly, researchers and clinicians have long sought to define the minimal immunosuppression still capable of preventing rejection. Even better, to find a way to avoid chronic drugs completely. The latter defines a process termed transplant tolerance. Certain specific immune interventions can render an experimental animal tolerant to a transplanted organ. The success of these tolerance protocols in animals has reached a point where trials in humans are now feasible. If successful, tolerance protocols could greatly improve the transplant therapy success and dramatically reduce both morbidity and cost. The fundamental goal of this project is to transition promising experimental strategies for kidney allograft tolerance induction into the clinic. In addition, significant effort is being directed toward studies elucidating the basis of allograft rejection and tolerance. The goals of this project have being accomplished through the development of three types of protocols: 1) Infrastructure, 2) Mechanistic, and 3) Clinical Tolerance. As organ transplantation is a complex therapy that has never been performed at the Clinical Center until this past year, several protocols (99-DK-0107, 99-DK-0119, 99-DK-0120) have been approved to support the required infrastructure. In the past year, 38 cadaveric and living donor transplants have been performed to establish an NIH standard of care. Allograft survival has been 100% clearly demonstrating the Clinical Center as an exceptional environment for investigative organ transplantation. One of these protocols has been designed to also elucidate the fundamental immunological mechanisms underlying allograft rejection and tolerance (99-DK-0119). Individual patients vary greatly with regard to their need for immunosuppression. Some patients rapidly reject their graft even after years of normal graft function, while others can be completely withdrawn from immunosuppression without any adverse effect. It is currently impossible to prospectively determine where patients sit in this spectrum. Many trials have attempted to empirically wean immunosuppression. Most have reported success in removing one of the three drugs used in about half the cases. These studies suggest that approximately half of the transplant population is over-treated with immunosuppressive agents, but it is currently not possible to identify the good prognosis group from the rest. Many methods designed to detect donor specific hyporesponsiveness have been developed in animal models. Few have been applied clinically to reduce immunosuppressive therapy. These methods generally involve white blood cell assays or allograft biopsy tissue. In protocol 99-DK-0119, over 40 patients have been evaluated by serial biopsy supplemented by immunohistochemical analysis and transcriptional studies to correlate graft outcome with the cellular and molecular events occurring in the allograft. We have also utilized assays to evaluate recipient anti-donor T cell responses to find correlates between an in vitro test and true allograft tolerance. The goal of these studies are to find ways of selectively eliminating immunosuppressive drugs from patients that don't need them. Dramatic genetic analysis advances have been made in the past several years. These include methods such as gene array chips to screen thousands of transcripts or genetic polymorphisms. Individual responses to immune manipulations are very likely governed in part by genetic factors. Thus, protocol 99-DK-0119 is also used to screen for genetic polymorphisms and for unique transcriptional responses to immunosuppression. These associations are valuable not only for identifying tolerant individuals, but also for suggesting strategies for future immuno-pharmaceutical development. Three projects have been initiated with the sole goal of testing potentially toleragenic treatments in humans (99-DK-0109, DK-00-0013 and 00-DK-0196). Each of these studies has used a novel regimen for the first time in humans. Evidence suggests that separating the immune system from the actual transplant procedure by aggressively depleting immune cells at the time of the transplant may decrease subsequent rejection risk. It is believed that the events occurring at the time of surgical implantation play a critical role in determining the magnitude of the subsequent donor directed immune response. For instance, both surgical trauma and ischemia have been shown to increase cellular immune activity. Further, adhesion molecules, oxygen free-radicals, activated platelets, and the effects of physical endothelial damage are known to be potent stimulators of immunity. However, if immune cells are not present at the time of surgery, these short lived factors could be expected to dissipate and to therefore have no effect on the alloimmune response. We have therefore used depletional drugs like the anti-T cell antibody Campath-1H, or the polyclonal anti-T cell preparation Thymoglobulin, to profoundly, but transiently deplete mature immune cells at the time of transplantation. Our goal is to test whether by allowing the cells to return after the operation, the patient can regain immune function without rejecting the organ. In other studies, a monoclonal antibody directed against the costimulatory molecule CD154 has been shown to prevent allograft rejection in several clinically relevant animal models. This therapy has also been used in a limited pilot trial to test for its toleragenic properties. To date, 11 patients have been enrolled in tolerance induction trials. All patients have retained excellent renal function without ongoing rejection with greatly reduced requirements for immunosuppression. Though primarily focused on tolerance, we have also sought to test transplantation therapies for particularly vexing renal diseases (e.g. HIV nephropathy and Focal Segmental Glomerulonephritis). For these diseases, transplant success has been hampered by disease pathogenesis. In addition, this project has supported other Clinical Center groups with patients requiring transplantation therapy. For instance, in the upcoming year we plan to implement a protocol for the treatment of HIV associated renal disease, and a collaborative study with the NIDDK Liver Diseases Section to treat hepatitis C virus in dialysis patients prior to renal transplantation. Both of these studies address major health issues and for which there is no currently accepted therapy. Moreover, these diseases disproportionately afflict underserved patient populations. This project thus aims to improve the standard of care by way of its tolerance trials, while continuing to address the immediate health needs of the renal failure population.
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