PITTSBURGH, Oct. 15 -- A study by researchers at the University of Pittsburgh Medical Center may lead to the use of gene therapy for the prevention of chronic organ rejection, a major cause of patient death following transplantation.
The study, in the October issue of The Journal of Clinical Investigation, found that transplant arteriosclerosis, a potentially fatal complication of transplantation, can be prevented by the gene iNOS (inducible nitric oxide synthase) in animals receiving aortic grafts.
iNOS is an enzyme that triggers production of nitric oxide (NO), a potent chemical that suppresses transplant arteriosclerosis, which occurs over several months after transplantation.
"Our study suggests that iNOS expression partially protects aortic transplants from the development of arteriosclerosis and that iNOS gene transfer strategies may prove useful in preventing the development of this otherwise untreatable disease process," said Si Pham, M.D., assistant professor of surgery and principal investigator in the study.
The investigators developed the iNOS gene therapy following their discovery that cyclosporine, which is given to transplant patients to prevent acute organ rejection, inhibits the natural production of iNOS in rats. By inhibiting the production of natural iNOS, these drugs actually accelerate chronic rejection, as evidenced by arteriosclerosis.
"By controlling acute transplant rejection with cyclosporine, we are defeating the body's own ability to counter chronic rejection with iNOS," said Dr. Pham.
Transplant arteriosclerosis is the buildup of smooth muscle cells within blood vessels which blocks the flow of blood inside the arteries of transplanted organs, leading to chronic organ rejection. It has been detected in some six to 18 percent of heart transplant recipients at one year following transplant and in as many as 50 percent of patients after five years.
"Chronic rejection has proven to be the major obstacle to long-term organ function," said Dr. Pham. "In heart transplant patients, the development of accelerated coronary arteriosclerosis has become the principle cause of organ dysfunction and late death."
To test their iNOS gene therapy against transplant arteriosclerosis, the investigators performed aortic transplants between genetically unrelated rats. Tissues transferred from one genetic strain of rat to another genetic strain, called allografts, are typically rejected because they are genetically "mismatched." Some of the rats received aortic grafts that had been treated with the iNOS gene. Another group of rats received the untreated aortic grafts.
Twenty-eight days after transplantation, the researchers removed and examined the allografts. Aortic grafts that had not been treated with the iNOS gene prior to transplantation showed severe arteriosclerosis. Grafts that received the iNOS gene prior to transplantation had no signs of this disease process.
"Patients who are at greatest risk for the development of organ injury and the development of arteriosclerosis also receive the highest doses of drugs that block iNOS expression. The end result is an accelerated development of chronic rejection," Dr. Pham said. "With these patients, it is conceivable that gene therapy may allow iNOS expression to continue even in the face of high levels of cyclosporine and steroids."
Others in the research team include: Larry L. Shears II, M.D., Nobushi Kawaharada, M.D., Edith Tzeng, M.D., and Timothy Billiar, M.D., from the department of surgery; Simon Watkins, Ph.D., from the University of Pittsburgh Center for Biologic Imaging; and Imre Kovesdi, Ph.D. and Alena Lizonova, Ph.D., from GenVec Corporation in Rockville, MD.
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Journal
Journal of Clinical Investigation