July 29, 2003
MEDIA CONTACT: Joanna Downer
Immune System Drug May Increase Availability of Liver Transplants
Animal research at The Johns Hopkins University School of Medicine has found that a drug already approved by the FDA for testing in people might one day dramatically expand the number of livers useable for human transplantation.
Studying rats with fatty livers, the researchers discovered that bathing the livers in a human immune system protein called interleukin-6 (IL-6) rescues them from failure when transplanted into other rats. The findings appear in the July issue of Gastroenterology.
Roughly 40 percent of adults in the United States have so-called "fatty" livers, which frequently fail to function at all or fail quickly when transplanted.
"IL-6 really works," says Zhaoli Sun, M.D., Ph.D., a scientist in the department of surgery. Sun cautions that IL-6's ability to "rescue" fatty livers for transplantation needs to be tested in larger animals, such as pigs, before human studies are undertaken.
"IL-6 is already approved for use in humans, but it has many negative effects when injected," says Sun. "Fortunately, our technique stores the liver in IL-6 before it's transplanted, rather than giving IL-6 to the organ recipient, so side effects should be minimized."
For his experiments, Sun developed two special rat colonies while an instructor in the laboratory of Andrew Klein, M.D., in collaboration with Anna Mae Diehl, M.D., a professor of gastroenterology whose research has focused on regeneration -- rather than transplantation -- of fatty liver. In humans, fatty livers generally stem from either diet or alcohol consumption, and the two rat models developed fatty livers under equivalent conditions.
After removing a fatty liver from one animal, and before transplanting it into another, Sun bathed the liver in a soup of nutrients that either did or did not include IL-6. Livers soaked in IL-6 had better blood flow and better function and allowed recipients to live, while fatty livers never exposed to IL-6 succumbed quickly to damage and never worked well enough to save their new hosts.
Sun says it's not known yet how IL-6 protects the fatty livers from damage or how it improves so-called "microcirculation," which helps prevent large chunks of the liver from dying. But while those questions are interesting scientifically, Klein, director of the Johns Hopkins Comprehensive Transplant Center, says clinical trials won't need to wait for those answers.
"Eventual clinical trials, if approved, would probably begin by looking for reduced damage or improved function in organs we would already use for transplant," says Klein, who notes that that a generally acceptable cutoff is a liver with no more than 30 percent of cells containing big droplets of fat. "Moving toward livers that currently would be borderline would be a gradual process."
Roughly 17,500 people are awaiting liver transplants in the United States, and 5,327 liver transplantations were performed last year across the country, according to statistics kept by the United Network for Organ Sharing. IL-6 has been administered to people as part of early phase clinical trials in adults and children with various cancers, but was limited by its toxicity.
The studies were funded by the National Institutes of Health, including the National Institute on Alcohol Abuse and Alcoholism, and the Johns Hopkins Department of Surgery.
Authors on the paper are Sun, Klein, Diehl and Sumito Hoshino of Johns Hopkins; Svetlana Radaeva, Osama El-Assal, Hong-Na Pan, Barbara Jaruga, Sandor Batkai, George Kunos and Bin Gao of the National Institute on Alcohol Abuse and Alcoholism; and Zhigang Tian, of the University of Science and Technology of China.
On the Web:
Johns Hopkins Comprehensive Transplant Program -- Liver
United Network for Organ Sharing