Islet Cell Transplants

Islet Cell Transplants

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.)