EMORY UNIVERSITY NIH GRANT PROPELS PHYSICIANS TOWARDS TRANSPLANT BREAKTHROUGHS

The National Institutes of Health (NIH) has awarded physician-researchers in Emory University'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 those who receive donor organs from the toxic side effects of daily immunosuppressant medicines, but it 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, Emory transplant surgeons Christian P. Larsen, M.D., D.Phil., and Thomas C. Pearson, M.D., D.Phil., along with a team of Emory investigators, will extend their groundbreaking research, which already has led to a new strategy to stop rejection of transplanted organs.

Organ transplant patients are required to take daily regimens of immunosuppressant medicines for 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. They also are not effective past an average of eight years. About 30% of patients go through episodes of organ rejection, requiring hospitalization and extra doses of immunosuppresants to save their transplants.

Drs. Larsen and Pearson hope their newest strategy, combined with their 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 the T-cells in the immune system to reject invading microorganisms as well as transplanted tissues. Preventing the T-cells from getting these necessary "second-signals" is called a "costimulation blockade." In studies of laboratory mice, Drs. 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.

Researchers from the U.S. Naval Medical Research 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, Drs. 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, in which 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. They also believe it may allow them to eliminate the need for the immunosuppressant drug cyclosporine, which seems to interfere with the success of the costimulation blockade.

In addition to Drs. Larsen and Pearson, the new NIH grant includes Emory Assistant Professor of Medicine Fadi Lakkis, M.D., whose laboratory at the Atlanta Veterans Affairs Medical Center is studying why the costimulation blockade works or why it fails. Rafi Ahmed, Ph.D., director of Emory's Vaccine Center, along with Christine Biron from Brown University, is studying immune responses to viruses in transplant patients in relation to the new blocking strategy.

"When we turn off immune responses to the transplant," explains Dr. 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 NIH grant is built on a strong foundation of Emory transplantation research funded since 1995 by the Carlos and Marguerite Mason Trust as well as previous and ongoing NIH grants. The Mason Trust is a private foundation created by Mrs. Marguerite Fugazzi Mason that awards grants to Georgia non-profit organizations to improve the care of Georgians receiving organ transplants and to improve the process of organ transplantation. This year, the Mason Trust has awarded Emory transplant researchers almost $3.5 million to establish a transplant biology research center to develop strategies for greater tolerance of organ transplants.

"The Mason Trust money allowed us to build up the resources and expertise we needed to successfully compete for the NIH grant," says Dr. Pearson. "Other money from the Mason Trust will allow us to recruit additional investigators who will bring other perspectives and expertise to these issues."

Emory's program in organ transplantation is the most comprehensive clinical transplant program in the State of Georgia. Since 1986 the program has jumped from about 40 transplants a year to more than 220 a year. Emory surgeons including Drs. Larsen and Pearson have performed more than 1,500 kidney transplants and more than 110 kidney-pancreas transplants since the program's inception.

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," explains Dr. Larsen, "they need to achieve immune tolerance also, which is the goal of our project."

At the same time Drs. Larsen and Pearson are continuing their present studies in mice to refine the costimulation pathway, they also are carrying out preclinical studies in primates at Yerkes Primate Research Center combining bone marrow transplants with the costimulatory blockade. They expect the primate research to take five years, in order to evaluate long-term organ acceptance.

Already the researchers are using their new strategies in patients with autoimmune diseases like rheumatoid arthritis. The first clinical trials in human organ transplant patients will begin within a year, first to establish safety and efficacy and then to try and 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," Dr. Pearson points 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."

Eventually the new strategies may allow the researchers to substitute for drugs like cyclosporine. And some day in the not too distant future, the Emory researchers believe their work will lead to true tolerance - without any immunosuppressants -of donor organs.