Islet cell transplant research attracts interest
Researchers hopeful of cure or long-term treatment
Islet cell transplant research got a transfusion of research funding just over a year ago, and already promising results are generating the kind of excitement that even allows the word "cure" to be whispered from time to time.
Research that was once hindered by a lack of funding received a huge boost in September 1998, when the Juvenile Diabetes Association and Harvard Medical School received a five-year $20 million grant from the Florence A. DeGeorge Islet Research Foundation.
"It’s wonderful. The entire field has new energy now," says Gordon Weir, MD, head of the JDF Center for Islet Cell Transplantation in Boston.
Weir’s team of 30 researchers is targeting several areas:
• The mechanics of islet cell transplantation.
Only about 250 islet cell transplants have been performed worldwide. So far, scientists haven’t been able to keep the transplanted islet cells going for more than a year.
• A way to transplant without recipients needing a lifetime of immunosuppressants.
• The search for a way to "turn off" the body’s autoimmune response that is an underlying cause of Type 1 diabetes.
• Expansion of islet cell supply, either through bioengineering or through animal sources.
It takes somewhere between 500,000 and 1 million islet cells to accomplish a transplant — that’s about what can be harvested from two to four cadaver pancreases. Since only about 5,000 human pancreases become available each year, it is unlikely that there will be sufficient resources to help most of the 700,000 Type 1 diabetics in the United States, many of whom could benefit from transplants.
Weir says science is making progress in finding ways to transplant islet cells without making patients rely on anti-rejection medication. "There’s been a big push in the area of autoimmunity, and a big section is working on growing new beta cells by engineering them or learning from fetal tissues," he says.
The group is also working with pig islet cells, Weir says, since pigs provide the most promising potential animal source for cells to be transplanted into humans.
While immunosuppressant-free transplants are a goal, they are still far from becoming available. Today researchers are also looking at a gentler generation of immunosuppressants to make post-transplant life easier.
Researchers in an affiliated program at the University of Miami are looking at an immunosuppressant called anti-CD154 with exciting results, Weir says. "It looks like it is a good immunosuppressant; it’s surprisingly benign and acts as a good immunobarrier. Monkey islets transplanted into other monkeys have done very well with CD-154."
Some of the monkeys were even weaned from immunosuppressants altogether without rejecting the transplants.
An affiliated program at the University of Washington in Seattle is looking at immunosuppressants from a slightly different perspective. "Several immunosuppressants, especially steroids, commonly used in kidney transplants are toxic to islet cells," says Christopher Marsh, MD, assistant director of the university’s transplant program and a professor of surgery. "We’re looking at a few that would be less toxic and may still be effective in patients who have had a kidney transplant."
It’s a complex situation, he says, because of the cross-purposes that kidney transplants and islet cell transplants may have. Ideally, patients in the future will have islet cell transplants long before they are in need of a kidney transplant, Marsh says.
But before that day comes, islet cell transplants are likely to be linked to a kidney transplant from the same donor, decreasing the likelihood of rejection. Currently, patients receiving kidney-pancreas transplants usually receive them from a single cadaver donor.
Since the procedure is not generally available yet, it is not known how insurance companies and Medicare and Medicaid will approach the issue, Weir says.
Marsh notes the research of the past few years is resulting in increasing success. "There is a the hope that somewhere down the road patients will receive an IV infusion of cells that will last for decades, perhaps a lifetime," he says. "But that is still fairly far off."
Clinical trials incorporating some of the new technologies in the field will begin around the first of the year at several centers, including Joslin Diabetes Center in Boston and the University of Washington in Seattle. Other centers, including some in Europe and Canada, are already conducting clinical trials.
Protecting the cells
Duke researchers are looking at ways to protect the fragile islet cells from antibody attack, while allowing the free transit of glucose and insulin. Emmanuel Opara, PhD, director of Duke Univer-sity Medical Center’s islet cell research program in Durham, NC, has developed tiny permeable spheres to shield the islet cells. The layered spheres are formed from a complex carbohydrate known as alginate that hardens and is later liquefied after it is dropped into a calcium solution and is coated with an outer layer of alginate.
"They are large enough to surround one or two cells and have pores large enough to allow glucose to enter and insulin to exit, but they’re small enough to keep the immune system’s cells from attacking the islet cells," he says.
His team has tested the spheres in animal models and expects to begin tests on baboons in the coming weeks. Duke’s program is also looking at the possibility of using pig islet cells for transplants and using specially bred pigs with human genes inserted into their genetic makeup, on the theory that when the cells are transplanted into humans, they will escape detection by the immune system. "We have kept them in a freezer for up to a month and find they can still sense glucose concentration changes and respond appropriately," Opara says.
Pig islet cells could provide an easily available and readily replaceable source of islet cells, since 90 million pigs are slaughtered each year for food.
Dukes’ team members admit they don’t know how long the cells will last, "But even if we needed to implant new cells every six months to a year, that would still be better for the patient injecting insulin several times a day," Opara says.
[Contact Gordon Weir at (617) 732-2400, Christopher Marsh at (206) 548-4919, and Emmanuel Opara at (919) 684-4120.]
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