UF research reveals secrets of transplant antirejection drug developed from Easter Island bacterium

University of Florida researchers have solved a mystery with roots reaching back to Easter Island, but it involves organ transplants, not giant stone statues.

A UF study using human cell cultures revealed that the antibiotic rapamycin, produced from a bacterium discovered on the remote South Pacific island in the 1970s, activates a gene that produces a well-known protective enzyme, heme oxygenase-1. The results apparently explain — at least partially — how rapamycin prevents a form of scarring that causes many organ transplants to eventually fail.

The discovery could lead to new therapies to prolong survival of transplanted kidneys, hearts, livers and lungs, said Gary A. Visner, D.O., a UF associate professor of pediatrics who led the study.

Rapamycin has been used since 1999 to fight short-term rejection in kidney transplants, the most common form of organ transplant. In April, the U.S. Food and Drug Administration approved the drug for use in a new protocol to prevent chronic rejection in kidney transplants, and research on its potential for other transplant procedures continues.

“Chronic rejection is a major problem in solid organ transplants,” said Visner, also chief of pediatric pulmonology at UF’s College of Medicine. “It’s a fibroproliferative disorder, causing injured airways or blood vessels to develop an abnormal repair process leading to impaired organ function.”

If enough scar tissue accumulates it can stop organ function altogether, Visner said. Such scarring, called fibroproliferation, is the leading cause of long-term failure in kidney and lung transplants. More than 10,000 organ transplants have been performed in the United States this year, including more than 6,000 kidney transplants, according to the United Network for Organ Sharing. One recent survey of kidney transplant recipients showed that 88 percent to 94 percent of their new organs were functioning a year after surgery, but only 76 percent to 87 percent still functioned after three years.

Rapamycin apparently fights long-term rejection at least in part by signaling a gene to produce the enzyme heme oxygenase-1, or HO-1, said Anupam Agarwal, M.D., a UF associate professor of medicine and co-author of the study. Best known for its role in destroying old red blood cells, HO-1 has other protective functions scientists are just beginning to understand.

“Whenever you have an injury, the gene that controls HO-1 production gets turned on as a response to protect the cell,” said Agarwal, interim co-chief of UF’s division of nephrology, hypertension and renal transplantation. “So in organ transplants, if you turn the gene on, you don’t get long-term rejection.”

Rapamycin may fight long-term rejection through additional mechanisms, he said.

It’s unclear how HO-1 prevents fibroproliferation, Visner said. He plans to explore the roles this enzyme and rapamycin play in the process using rat lung transplant and mouse tracheal transplant models.

The UF study was reported in the February issue of the journal Circulation. A research team, funded by the American Lung Association of Florida and the state Department of Health, obtained sections of human pulmonary arteries and used them to culture two types of cells. Preliminary experiments showed that rapamycin induced the cells to produce HO-1, that HO-1 activity in cells increased along with enzyme production, and that another popular antirejection drug, cyclosporin A, does little to increase HO-1 production.

The most significant experiment showed that when HO-1 activity was inhibited, rapamycin had little effect on cell growth, meaning the drug only works when HO-1 activity is possible — an important piece of evidence suggesting rapamycin inhibits fibroproliferation by inducing HO-1 production.

Visner later gained more evidence for the theory that rapamycin causes HO-1 production by showing the drug has no effect on vascular cells from genetically altered mice that cannot produce HO-1.

The UF findings could encourage drug designers to develop compounds that increase expression of HO-1 but have fewer side effects than rapamycin, said Bruce Kaplan, M.D., medical director of renal and pancreas transplantion for Shands at UF medical center. Although rapamycin is nontoxic to kidneys, it can raise cholesterol levels and suppress bone marrow activity, and it may impair wound healing.

“The other important thing from this study is that it may indicate that there are people who genetically make more or less HO-1,” said Kaplan, also a UF professor of medicine and of pharmacology and therapeutics. “That may help us determine who will respond better to rapamycin and who won’t.”

Eventually, researchers may be able to induce HO-1 production using gene therapy to deliver a short DNA sequence to cells, bypassing the need for drugs altogether, Agarwal said. He and Visner are investigating which DNA sequences in the HO-1 gene rapamycin activates.