Diabetes Treatment Offers Hope in Other Transplants

A remarkable new transplant technique used to cure diabetes in rats could potentially be applied to any type of transplant operation, eliminating the often-severe side effects of long-term use of immune-suppressing drugs, researchers at the University of Pennsylvania have reported.

The researchers cured diabetes by transplanting insulin-secreting cells into the rats’ thymus glands, where the cells were protected from the self-directed immune attack that causes the disease.

Physicians have been experimenting for several years with transplanting the insulin-secreting cells, called islet cells, into the abdomens of diabetic humans, but the procedure is difficult and the transplanted cells have survived for more than a year without being rejected in only two of the 75 patients in whom the procedure has been attempted.

But the Pennsylvania surgeons report in today’s Science that by transplanting the islet cells into the thymus gland, a key component of the immune system, the body develops tolerance for the cells, which survive for the rest of the animals’ lives without further treatment.

But some researchers cautioned that other experimental techniques to prevent rejection have proven successful in rats, only to fail in larger animals and humans.

“We’ll have to wait with bated breath while this is tested in larger animals,” said surgeon David Sutherland of the University of Minnesota Medical Center. But, he added, “I am hopefully optimistic about this work because it is different from other things that have been tried in the past.”

“It’s clearly premature to say that this is a major breakthrough, but it is certainly a significant step forward in understanding transplantation immunology,” added endocrinologist Edward S. Horton of the University of Vermont, president of the American Diabetes Assn.

Insulin-dependent diabetes, also known as juvenile-onset or Type 1 diabetes, affects between 750,000 and 1 million Americans, and 13,000 to 15,000 new cases are diagnosed each year.

Although insulin injections can control the overt symptoms--such as excessive thirst and urination--that can lead to coma, most diabetics eventually develop serious complications, including kidney damage, nerve damage in the arms and legs and vision loss.

Most researchers believe that these complications result from the wide swings in blood-sugar levels that result from injecting insulin only two to four times a day. They believe that transplants of the whole pancreas or of the insulin-secreting islets can minimize these complications by preventing the wide swings.

To date, about 2,000 pancreas transplants have been performed--a little more than 400 last year--and about 60% of the organs function for at least a year. But the transplants require large doses of immune-suppressing drugs and, except for the most severely debilitated patients, the side effects of the drugs are worse than the complications of diabetes.

Developing techniques to perform the transplants with lower doses of the drugs, or without them entirely, would lead to a large increase in the number of transplants, Sutherland said.

The Pennsylvania team has a long history of research on diabetes. Surgeon Clyde Barker, one of the co-authors, was the first to cure diabetes in animals with islet transplants 17 years ago. But in all previous studies, the transplanted islets were rejected within a few days unless heavy doses of immunosuppressive drugs were used.

Barker, surgeon Ali Haji and their colleagues decided to try the new approach because the thymus, near the thyroid gland at the base of the neck, plays a key role in the immune system. Primitive white blood cells produced in the bone marrow are processed by the thymus to become T-cells that can recognize and attack foreign substances and tissues.

Researchers have demonstrated that, in newborn animals, including humans, the immune system develops tolerance for the animal’s own tissues because they are present when the thymus begins processing the immature white cells. Naji and his colleagues devised a way to mimic this process.

They isolated islets from one strain of rats and injected them into the thymus of a different strain that was diabetic. At the same time, they administered a dose of anti-lymphocyte serum that killed more than 90% of the T-cells in the recipient’s body.

The new T-cells produced by the thymus did not attack the transplanted islets, and the islets survived for the life of the rats, producing insulin that cured the animals’ diabetes. In all, 10 rats were successfully treated.

After the initial treatment, a rat’s whole body became tolerant of the cells. And when the researchers subsequently transplanted islets from the donor rats elsewhere in the recipient’s body, these were also not rejected. It is this finding that would appear to make the new discovery applicable to other types of transplants.

While a heart, for instance, is too big to transplant into the thymus, a small bit of heart tissue from a potential donor could be transplanted into the thymus to induce tolerance and the heart subsequently transplanted.

“I think, from the point of view of transplantation immunology, that’s an important piece of news,” Horton said.

Naji said the Pennsylvania team is now experimenting with other types of transplants to examine the efficacy of the new approach.

Naji also said that the team is “thinking about doing this in humans,” but added that “we would like to establish this in another (animal) model first.” But because researchers are already transplanting islet cells to various sites in the human body, he said, “there might be individuals who would want to go ahead and do this sooner.”