ISLET CELL TRANSPLANTS HOLD PROMISE FOR DIABETICS

by Neerajh Sankaran

As a pet owner and veterinary surgeon, Kent Cochrum confesses to a special feeling of gratification watching Brownie chase after a ball while exercising. This happy, healthy beagle spells good news twice over: first as a success story for a transplantation strategy Cochrum developed; and secondly as a symbol of hope--that what has worked in this dog may be used to treat juvenile diabetes in human patients in the not-too-distant future.

Juvenile diabetes, also known as type I diabetes or insulin-dependent diabetes mellitus, is a condition characterized by insulin deficiency due to the malfunctioning of a specialized group of pancreatic cells called the islets of Langerhans. The causes for islet cell breakdown are not fully understood, but the major outcome of the disease is quite clear--without insulin, the body has no way of controlling its metabolism, and glucose levels in the bloodstream fluctuate wildly. This condition, through time, can lead to a host of chronic, secondary complications including the thickening of blood vessels, blindness, and kidney failure. The most prevalent form of treatment for this disease (type I diabetes, IDDM) is insulin, which can only be administered via injection.

But this approach is far from adequate.

"Not only are injections inconvenient, but the approach also fails to address the underlying problem, which is to maintain the blood glucose at a constant level," said UC Davis endocrinologist J. Stuart Soeldner.

The existing alternative--transplanting a working pancreas into the patient--addresses this problem, but introduces a whole new set of significant complications.

"Transplantation is a major surgical procedure requiring patients to be under anesthesia for five to eight hours," said transplant surgeon Richard Perez. "It poses major stress to the system."

Perhaps even more serious is the need for lifelong immunosuppression.

"In order to prevent the body's immune system from rejecting the transplant, we need to administer heavy doses of immunosuppressive drugs," he added. "This puts the individual receiving the transplant at a very high risk for a large number of opportunistic infections, and for the development of cancers."

Cochrum's approach--which was to insert specially coated, functional islet cells obtained from another animal species into the peritoneal cavity--appears to have countered both problems. Brownie, the canine equivalent of a type I diabetic, is the living proof. Despite the surgical removal of her pancreas, for three years she has lived normally, maintaining appropriate blood sugar levels without requiring any insulin treatments and without the aid of immunosuppressive drugs.

Encouraged by these results in the dog model, which researchers chose for the similarity of its immune system to that of humans, Perez, Cochrum, and Soeldner jointly submitted an application and received approval from the Food and Drug Administration to test their approach as a possible treatment for human diabetic patients. The investigators hope to begin the first human clinical trials within two years.

"The real breakthrough here is Kent's encapsulation technology," enthused Perez, who will head the human phase of these clinical trials. "The method enables us to protect the islet cells from attack by the immune system of the recipient. So there is no need to use immunosuppressants. Furthermore, implanting these cells is a very safe, simple procedure, compared to conventional transplantation surgery. It only takes a small incision, and can be performed in less than an hour, using a local anesthetic.

"If effective, we will have the means to normalize blood glucose levels very early in the course of the disease, and lessen the incidence of secondary complications."

"The major advantage of this approach is that there is a very high probability that a diabetic patient's blood glucose levels will remain within the normal range throughout the day," agreed Soeldner.

The key to the new approach's success is the discovery of a durable coating material for the islet cells, one which allows secreted insulin to diffuse into the bloodstream and to evade attack from the recipient's immune system.

"Since the 1970s, we have known that a diabetic state in rats could be cured quite easily using islet cells isolated from a genetically identical animal. Allogeneic grafts, however, which use animals of the same species that have a different genetic makeup, were rejected very rapidly," he said.

Over the years it was found that transplants had a greater chance of survival when coated with some substance that afforded the cells some protection from the recipient's immune system. But finding a truly biocompatible substance proved difficult; most substances would either elicit an immune reaction themselves or be degraded by enzymes in the host's body.

Cochrum's search led him to alginate, a polymer recovered from seaweed. Alginate has proven highly biocompatible, both in terms of its immumogenicity and hardiness.

"But this is true only of very highly purified material," he cautioned. Cochrum and UC Davis hold a number of patents on the purification protocols for alginate.

"At the moment we're working on scaling up the purification procedure, standardizing it according to the FDA-prescribed guidelines, and on performing additional preclinical tests," he said. "We will start the actual clinical trials only after satisfactorily completing the scale ups."

"The trial itself is designed in two phases," Cochrum explained. "First we will conduct a study on 12 animals using the planned protocols, and submit the data to the FDA. We will not start the human study until after the dog trials have been evaluated and approved, which will probably take about two years."

Meanwhile Cochrum hopes to improve certain aspects of the existing procedure.

"In the current protocol we are introducing the islets into the peritoneal cavity, which is not the best location for them," he said. "Eventually we want to place them so that they secrete directly into the portal system. This would be the most efficient way to get insulin into the bloodstream as well as the closest mimicry of the physiological state."

Although the first human patients will be receiving grafts of human islets, the investigators hope to apply this technology to attempt transplanting islet cells across unrelated species.

"Our ultimate goal is to be able to transplant islets from special strains of pigs to human diabetics," offered Cochrum. He has already achieved success using xenografts of rat and canine islets in mice, which he published in "Transplantation Proceedings" in 1995.

"The beauty of Kent's method is that the type of islet we put into the microcapsule does not have to be from the same species," said Perez. Although still a controversial topic, xenotransplantation, use of organs from different species, would provide several advantages, the researchers said, including greater availability and lower costs.

"At present, we are limited to cadaver tissue as a source for human islet cells, which poses a limitation on the number of patients we could treat," Perez explained. A consistent, more abundant supply of islets would be needed to use the method as a widespread treatment early in the course of diabetes, he added.

In addition, Cochrum said, "The risk of passing an infectious disease is much higher in a human-to-human graft than it is in a transplant from a pig to a human."

With reference to emotional and ethical objections, the scientists predict that the treatment, once proven successful, would be widely accepted. "Because of the tremendous impact of diabetes, both to individuals and the health care system, I think a safe, effective therapy that could benefit a large group of patients would be very will received by the public," said Perez.

"Juvenile diabetes places an enormous burden on society not just momentarily--last year alone this disease cost the American public some $138 billion--but also in terms of life span, and the quality of living," said Soeldner. "The most serious problems in diabetes are the secondary complications, such as amputation, blindness, and kidney failure."

Furthermore, the disease affects a huge population. The American Diabetes Association estimates that six percent of the U.S. population has diabetes, whether it is diagnosed or not, and this figure doesn't take into consideration the number of individuals who are placed in the caregiver role because of diabetes.

"This is a disease that usually strikes people at a very young age," added Cochrum. "Neither daily injections nor immunosuppressive drugs are viable options.

Any technique that offers a chance of curing diabetes would be welcomed."

About the Sources

Dr. Kent C. Cochrum earned his undergraduate and veterinary medicine degree at University of California-Davis in 1963 and 1965, respectively. He completed three post-doctoral fellowships in hematology and immunology and in the Department of Surgery at University of California-San Francisco, where he joined the staff as an assistant professor of veterinary medicine in surgery. In 1968 he worked as an immunologist in the Renal Transplant Service and established the Histocompatibility Laboratory for the transplant service there. In 1975 he was promoted to associate professor, and from 1972 to 1982 he served as director of the Histocompatibility Laboratory. In 1982 his research focused on transplantation of encapsulated islets as a means of treating diabetes. His first encapsulation methods and patents were developed then. In 1989 he joined the faculty at UC Davis as an associate professor of surgery, where he has continued his research studies in allotransplantation of encapsulated islets. He can be reached at (916) 752-3270.

Dr. Richard J. Perez earned his undergraduate degree at UC Santa Barbara and his medical degree at the University of Hawaii in 1982. He completed his internship and residency in general surgery and a research fellowship in the Division of Transplantation at the University of Cincinnati Hospitals in Ohio and the University of Minnesota Hospitals and Clinics. In 1991 he joined the faculty at UC Davis as an assistant professor of surgery. He can be reached at (916) 734-2679.

Dr. J. Stuart Soeldner earned has undergraduate degree at Tufts University in 1954 and his medical degree from Dalhousie University in Halifax, Nova Scotia, in 1959. He completed his internship and residency at Victoria General Hospital in Halifax and his research fellowship at Dalhousie University and Harvard Medical School. He joined the staff at Harvard Medical School as an instructor in medicine in 1964, rising through the ranks to become as associate professor. In 1987 he joined the faculty at UC Davis as professor of medicine in the Division of Endocrinology and Metabolism. He is the principal investigator of the Diabetes Clinical Research Unit and has been focusing his research on new and novel therapies for diabetes mellitus and also on long-term studies delineating the causes of both type I and type II diabetes. He can be reached at (916) 734-6152.

(Note: This article appeared in "Matrix," Volume 3, No. 11, published by the UC Davis School of Medicine. Reprinted with permission.)