January 19, 1999
Volume 51, No. 16
Grant may propel researchers toward transplant tolerance
The National Institutes of Health (NIH) has awarded physician-researchers in Emory's Center for Transplantation a five-year grant they hope will allow them to establish true immune tolerance in patients receiving organ transplants. That accomplishment not only would free organ recipients from the toxic side effects of daily immunosuppressant medicines but also could lead to the "golden ring" of transplantation medicine--permanent, long-term acceptance of donor organs.
Using the interdisciplinary $7.5 million NIH program project grant are Emory transplant surgeons Christian Larsen and Thomas Pearson, along with a team of Emory investigators, who will extend their ground-breaking research that already has led to a new strategy to stop rejection of transplanted organs.
Organ transplant patients are required to take daily immunosuppressant medicines as long as they live. Unfortunately, these same medicines leave patients highly susceptible to viral and bacterial infections as well as cancer, kidney failure, diabetes and osteoporosis. Moreover, the drugs prove ineffective after about eight years. About 30 percent of patients go through episodes of organ rejection, requiring hospitalization and extra doses of immunosuppresants to save their transplants.
Larsen and Pearson hope their newest strategy, and previous discoveries, will hold the key to transplant acceptance. Several years ago the researchers developed the ability to simultaneously block two molecular pathways, CD40 and CD28, required by T-cells in the immune system to reject invading microorganisms as well as transplanted tissues. Preventing T-cells from getting these necessary "second-signals" is called a "costimulation blockade." In studies of laboratory mice, Larsen and Pearson found that by blocking these two signaling pathways at the time of transplant, they could maintain grafts of transplanted tissue for long periods of time without using any other immunosuppressants.
U.S. Navy medical researchers have used the double-blocking therapy successfully in kidney transplants in rhesus monkeys, some of whom maintained their transplants for a year or more without immunosuppressants.
In a new strategy Larsen and Pearson plan to combine the costimulation blockade with donation of the organ donor's bone marrow at the time of transplant, thus introducing "chimerism," where tissues or cells of one organism co-exist with those of another. The researchers believe chimerism may overcome their difficulties in getting the costimulation blockade to last over the long term. It also may allow them to eliminate the need for the immunosuppressant cyclosporine, which seems to interfere with the success of the costimulation blockade.
In addition to Larsen and Pearson, the new NIH grant includes Assistant Professor of Medicine Fadi Lakkis, whose laboratory at the V. A. Medical Center is studying why the costimulation blockade works or fails. Rafi Ahmed, director of the Emory Vaccine Center, is studying immune responses to viruses in transplant patients in relation to the new blocking strategy with Christine Biron of Brown University.
"When we turn off immune responses to the transplant," said Larsen, "we run into a potential problem of turning off the immune response to viruses or infectious agents. We need to be able to induce tolerance to the transplant while preserving protective immunity in the long term to viruses. Our experience shows that while introducing a new virus at the time of transplant could have bad consequences, once the costimulation blockade has worn off and the transplant is accepted, animals are able to recover their immunity to environmental pathogens."
The Emory transplant research program also is a core partner with a new Engineering Research Center at the Georgia Institute of Technology funded by the National Science Foundation. Georgia Tech researchers Robert Nerem and David Ku are using tissue engineering to develop new products to treat disease, including vascular substitutes, skin substitutes and islet cells to treat diabetes. "Because those living tissues will probably elicit an immune response," explained Larsen, "they need to achieve immune tolerance also, which is the goal of our project."
At the same time Larsen and Pearson are continuing their present studies in mice to refine the costimulation pathway, they also are carrying out pre-clinical studies combining bone marrow transplants with the costimulatory blockade in primates at Yerkes. They expect the primate research to take five years in order to evaluate long-term organ acceptance.
The researchers already are using their new strategies in patients with autoimmune diseases such as rheumatoid arthritis. Initial clinical trials in human organ transplant patients will begin within a year, first to establish safety and efficacy and then to reduce the rejection rate for donor organs.
"It works out well that our strategies in organ transplantation have an impact on autoimmune diseases as well," Pearson pointed out. "Likewise, Dr. Ahmed's work with vaccines is just the flip side of what we do in trying to inhibit the immune response. All these fields are very complementary."