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Stanford Report, May 8, 2002

Old drug dusted off; anti-rejection properties found


Thirty years ago, researchers scooped some dirt on Easter Island and discovered bacteria that led to a potential anti-fungal drug. Little did they know that the drug -- which languished on shelves after proving ineffective in early trials -- would become popular in 1999 as a way to prevent rejection of transplanted organs.

Now, new studies from the medical center have found that the drug can also protect blood vessels of transplanted hearts, preventing the leading cause of heart transplant failure.

Randall Morris, MD, research professor and director of transplantation immunology in the Department of Cardiothoracic Surgery, elevated the drug -- called sirolimus -- from the brink of obscurity to its current role in transplantation. Morris presented results from his recent studies last month at the American Transplant Congress.

Acute transplant rejection occurs when cells of the immune system recognize the transplanted organ as foreign and attack it as a potential threat. Powerful immune-suppressing drugs -- including sirolimus -- keep the immune system under wraps, preventing this immediate rejection.

Immune cells passing through blood vessels in the transplanted heart, however, inflict a consistent, low-level attack on cells lining the vessel walls. In response, these smooth-muscle cells build up scar tissue that may eventually block the vessel and starve the heart of oxygen. This process, called chronic rejection, is the most common cause of heart transplant failure. "To prevent chronic rejection, you want to stop proliferation of smooth-muscle cells," Morris said. His research shows that's exactly what sirolimus does.

Laying the groundwork

In studies during the late 1980s, Morris transplanted hearts in rats using sirolimus to prevent rejection. Not only did the rats avoid rejection problems, but the hearts that received sirolimus had much cleaner blood vessels than those that received a different anti-rejection drug. "We thought maybe sirolimus did more than just suppress the recipient immune system," Morris said. "Maybe it also acted on donor blood vessels."

These results inspired Morris and postdoctoral fellow Camille Dambrin, MD, to test sirolimus on transplanted aortas -- the major artery leaving the heart. In their initial trials on rats and primates, delayed treatment with sirolimus stopped the progression of chronic rejection once it had started. In the latest work, the researchers tested whether sirolimus could prevent chronic rejection altogether if the drug was started at the time of transplant.

They transplanted aortas in 12 primates: six received sirolimus throughout the trial while six received a placebo. They monitored the internal diameter of the transplanted vessels with ultrasound for 105 days. The animals that received sirolimus had arteries that were nearly normal compared with the significantly clogged arteries in animals that had received the placebo.

Morris said early results from this work led to the use of sirolimus to prevent chronic rejection in human heart transplants. The federal Food and Drug Administration approved the drug for use by transplant recipients in 1999. He added that worldwide trials in human heart transplant recipients using sirolimus or a chemically modified version show these drugs significantly prevent artery narrowing.

Another notable application

While preventing chronic rejection would be a major improvement for heart transplant patients, the most significant use of sirolimus may address a different problem. Cardiologists often use balloons to open clogged arteries in a process called angioplasty. They then insert coiled wires called stents to hold the artery open. Scar tissue can eventually build up around the stent, blocking blood flow.

In recent trials, cardiologists implanted stents coated with sirolimus to prevent this renewed division of the blood vessel wall. Two years later, those vessels were still clear. "This is probably where our discovery of this new use for sirolimus will benefit the most patients," Morris said. He added that Johnson & Johnson is continuing to test a sirolimus-coated stent that may reach the market within the next one or two years.

In addition to Morris and Dambrin, Stanford researchers in the study included Bernard Hausen, MD, PhD, senior research scientist; Peter Fitzgerald, MD, associate research professor of cardiovascular medicine; Gerald Berry, MD, associate professor of pathology; and postdoctoral fellows Jochen Klupp, MD, Tudor Birsan, MD, Jorge Luna, MD, Takeshi Suzuki, MD, Tuan Lam, MD, Peter Staehr, MD.

Kidney transplant rejection prevented without drugs (5/1/02)

Helping the immune system accept transplanted organs (6/28/00)