June 8, 1999 In clinical trials planned for this year, researchers from the National Naval Medical Center, the Walter Reed Army Medical Center, and the National Institutes of Health seek to test new methods to prevent the rejection of transplanted and health-restoring organs and tissues. The goal of the program is to develop methods that permit transplantation without the need for chronic immunosuppression or with a greatly reduced need for immunosuppression. Studies will also explore ways of identifying patients who may need far less immunosuppression than is currently prescribed. The investigators are particularly interested in agents that modulate the cell-signaling pathway that triggers immune activation and the eventual rejection of transplanted tissue.
The first clinical study applying immune modulation therapy will be in patients receiving a kidney transplant for end-stage renal disease. Later this year, the researchers plan to transplant islet cells in patients with diabetes caused by a pancreatectomy or clearly documented (by genetic testing) maturity onset diabetes of youth (MODY). Islets will be isolated by an expert team from the University of Miami together with NIH Department of Transfusion Medicine. The islets will then be infused via a tube inserted through the skin into the liver's portal vein. If this trial shows that immune modulation methods can prevent the immune system from rejecting transplanted islets, the study will be expanded to determine whether people with type 1 diabetes can also benefit.
Past islet transplant experience has shown that at least two hurdles must be overcome before islet transplantation can be developed into a viable curative therapy for type 1 diabetes. One hurdle is the immune response all patients generate against transplanted organs or tissues. Another is that people with type 1 diabetes have the disease because their immune system has already destroyed their islet cells. Research suggests that if islets are transplanted into patients with type 1 diabetes, not only are those islets subjected to the usual immune response, but the autoimmune response is also re-activated. Therefore, the NIH protocol will first test whether new techniques can overcome the first hurdle by excluding patients with beta cell autoimmunity.
The trials will be conducted at the NIH Organ/Tissue Transplant Research Center, which opened in May 1999. Located in the NIH Clinical Center in Bethesda, MD, the Center is a collaborative project of the NIH, the Walter Reed Army Medical Center, the Naval Medical Research Center, and the Diabetes Research Institute at the University of Miami. The site includes a state-of-the-art clinical transplant ward, operating facility, and outpatient clinic designed for the study of new drugs or techniques that may improve the success of organ and tissue transplants.
Enrollment is now beginning for clinical trials involving patients with renal failure who need a kidney or kidney pancreas transplant, or patients with diabetes in need of a pancreatic islet transplant. Trials involving patients who already have been transplanted are planned as well. If you are interested in enrolling in one of these clinical studies, please call the NIH Clinical Center's Patient Recruitment and Public Liaison Office at 1-800-411-1222.
Immune Modulation Research
In the past 10 years, scientists have made enormous progress in understanding the complex workings of the immune system. Current research in immune modulation builds on a growing body of knowledge gained from painstaking research on the molecular signals that govern immune cell communication. These new insights have exciting implications for preventing transplant rejection and treating diseases of the immune system, such as autoimmunity and immunodeficiency. T Cell Recognition is First Step in Activation
In a healthy adult, about 100,000,000,000 to 1,000,000,000,000 T cells are circulating in the body's tissues and blood stream. Each T cell is constantly on the lookout for the one and only one target it is designed to recognize. The sensor that allows the T cell to recognize that target is called the T cell receptor, or TCR, and the target recognized by an individual TCR is highly specific. T cells routinely recognize and take steps to kill a cancerous or infected cell while leaving intact a benign neighboring cell. While each T cell can recognize only one target, we have so many T cells that a large number (approximately 1,000,000,000) of targets can be recognized. The range of targets an individual's T cells can recognize is known as the T cell repertoire.
Stimulation of Two Receptors Needed to Activate T Cells
Immunologists used to believe that when a T cell found its target, the recognition alone would trigger the T cell to become activated. The activated T cell would make more copies of itself, secrete hormone-like factors called cytokines or interleukins, "mature" in other ways, and destroy the encountered target. About 20 years ago, however, scientists began making observations that called into question simple recognition-induced T-cell activation. They proposed a new theory, the "two-signal" model for T-cell activation. According to this model, to be activated the T cell must not only encounter the one target it was designed to specifically recognize, but it must also simultaneously have another kind of T cell sensor triggered. The second sensor, called the costimulatory receptor, was thought to send the "second signal" to the T cell to activate it.
This costimulatory receptor was not specific for any one target but could be thought of as an "on-off" switch for the T cell. According to the two-signal model, each of the two classes of T-cell sensors serves two different but vitally important functions. The TCR has the difficult job of accurately identifying a potential target, and the costimulatory receptor turns on the T cell once target recognition has occurred.
Most of the time the immune system does what it is designed to do with amazing accuracy: cancer cells are destroyed, infections are thwarted, and normal tissues are left alone. Some illnesses, however, are caused when the immune system begins attacking normal cells. People with type 1 diabetes require insulin therapy because, for unknown reasons, their T cells have killed the insulin-producing cells of the pancreas. Individuals who have received a life-saving organ or tissue transplant, only to have that transplant later rejected by the immune system, know how immune system responses can be counter-adaptive.
All the medicines currently used to prevent these counter-adaptive immune responses act by impairing all T cells indiscriminately. Thus, the steroids and cyclosporine A, which prevent T cells from recognizing a transplanted organ and block graft rejection, will also impair T cells from recognizing, for example, a cell infected by cytomegalovirus.
About 5 years ago, agents were developed that interfered with the function of the T cell's costimulatory receptor. The beauty of these agents is that they allow for the overall functioning of the immune response while affecting only those T cells encountering their target and making the critical decision (dependent on costimulatory receptor function) whether to become activated. A corollary of the two-signal model of T-cell activation is that if a T cell encounters its target but does NOT receive the costimulatory signal needed to activate it, the T cell either dies or is "re-educated." The T cell has learned that it should not become activated even if it encounters the same target at a later date. Since a T cell can live for years, the immune re-education can be long lasting.
Immune Modulation Prevents Transplant Rejection in Monkeys
Since 1992, studies by researchers at the NIH; the University of Chicago; University of Massachusetts; University of Michigan; University of Pennsylvania; University of California, Berkeley; Emory University; Harvard University; and within the U.S. Navy demonstrated that immune modulation reagents would prevent the rejection of transplanted organs and tissues in rodents. New therapies that work well in rodents, however, often fail when tested in more complex species. Therefore, Navy researchers Drs. David Harlan, Allan Kirk, and Tom Davis, and collaborators Drs. Stuart Knechtle and John Fechner at the University of Wisconsin, decided to test whether administering "second signal" blocking agents could prevent the rejection of a transplanted organ in a primate model. The team found that rhesus monkeys given a mismatched kidney transplant and "second signal" blocking agents for the month after surgery (and none later) tolerated the medicines without any apparent toxicity and showed no signs of graft rejection for at least 6 months after the transplant. They also found that the immune system did not appear to be generally impaired by the therapy. This study was reported in the Proceedings of the National Academy of Sciencesin 1997 (vol. 94, pp. 8789-8794). Scientists at the Diabetes Research Institute of the University of Miami recently made similar observations in a rhesus monkey islet transplant model.
"These studies need to be repeated and extended in additional animal studies, and the therapy needs to be studied in carefully designed clinical trials," says Dr. David Harlan, now head of the Transplant Research and Autoimmunity Branch of the National Institute of Diabetes and Digestive and Kidney Diseases at the NIH.
New agents that act through mechanisms other than the T cell costimulatory receptor also appear to improve the long-term survival of transplanted tissues and organs. If preliminary results hold, whether costimulatory modifying reagents are used alone or in combination with other techniques under development, a new era in transplantation medicine may be on the horizon.
"The new transplant initiative is not wed to any one theory but to the proposition that graft acceptance can be achieved without long-term immunosuppression. For the time being, though, all patients currently under the care of a transplant physician or transplant surgeon are most strongly encouraged to take their medicines as prescribed with the hope that a better future is coming," said Harlan.
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