Islet Cell Transplantation: Working Toward a Cureby Robert S. Dinsmoor
The treatment of Type 1 (insulin-dependent) diabetes has come a long way since the discovery of insulin, but a cure has remained elusive. That may change in the not-so-distant future. In the quest to end diabetes, researchers have looked for ways to restore normal pancreatic functioning. Scientists hope that pancreatic tissue transplants will become an effective and practical way to help the body produce its own insulin and thus avoid the complications of Type 1 diabetes.
Whole Pancreas TransplantsPancreas transplantation has long held promise as a cure for people with diabetes. A properly functioning transplanted pancreas can make insulin injections unnecessary, and it can offer a degree of precision in glycemic control that is impossible to mimic with insulin injections. Doctors have been transplanting whole pancreases into people with diabetes since 1966, and studies have shown that transplants can normalize blood glucose levels and may help prevent long-term diabetic complications.
Unfortunately, there's a catch. Transplanting a whole adult pancreas is a major, technically complex operation with many obstacles. For starters, it requires the use of immunosuppressive drugs to prevent organ rejection, and these drugs often have harmful side effects. Because of these hazards and the fact that whole pancreas transplantation is not a lifesaving procedure, it is usually performed only in people who also require a kidney transplant because of kidney failure, which is life- threatening.
Another pressing issue is the relative shortage of adult pancreases available. Even as whole pancreas transplantations are being performed on an increasing number of people, it is clear that there are not enough adult pancreases for everyone who might benefit from one. If transplantation were ever to become completely safe and effective, then the estimated one million Americans with Type 1 diabetes (and 40 million people worldwide) would theoretically be candidates for surgery. Yet, only 1,000 to 1,500 adult pancreases are available for transplantation in the United States each year.
The problems inherent in whole pancreas transplantation have caused surgeons to explore other types of transplantation, such as transplanting only the insulin-producing islet cells from adult human or animal pancreases, transplanting pancreatic tissue from human fetuses, and implanting genetically engineered beta cells. Each of these therapies holds great promise for the future, but remember, it will probably be at least several years before their use becomes widespread.
Human Islet CellsSince only the islet cells of the pancreas, the cells that manufacture and secrete insulin, are necessary to correct Type 1 diabetes, one approach has been to transplant just these cells. These transplants were made possible when, in the 1960's, researchers at Washington University in St. Louis, Missouri, discovered a way to isolate islet cells using enzymes that digest the surrounding tissue. One of the benefits of islet cell transplantation is that it doesn't require major surgery. The islet cells can be injected into a vein, through which they move on to the liver, or they can be placed under the skin, in the abdominal cavity, or in other locations.
Islet cell transplants are plagued by some of the same problems as whole pancreas transplantation, particularly the need for immunosuppression, but scientists are exploring better ways to prevent the immune system from rejecting transplanted islet cells. For example, researchers are constantly searching for better immunosuppressive drugs to specifically block islet cell rejection without severely hampering the entire immune system. Cyclosporine is currently the most effective immunosuppressant, but researchers are also studying other agents, such as FK506 and rapamycin, alone or in combination with cyclosporine, to try to prevent rejection with few side effects. Another possibility is to treat the transplanted cells so that they will not trigger an immune response. One promising method for treating the transplanted islet cells is to expose them to radiation, an approach that has been used successfully in mice and rats.
One of the most promising approaches to preventing islet cell rejection is a technology called immunoisolation. This involves shielding the islets with a selectively permeable membrane. This membrane lets glucose, oxygen, and insulin pass in and out of the blood stream, but keeps out the antibodies and T cells of the immune system, which would otherwise destroy the islets.
Researchers are currently experimenting with the best way to use these special membranes in transplantation. One approach uses a perfusion device, a capsule that is grafted to an artery where it makes direct contact with the body's circulating blood; in this way, the device can draw nutrients from the blood and release insulin to circulate throughout the body. However, because this approach requires major surgery, researchers are also exploring less traumatic methods, such as coating small groups of islet cells (macroencapsulation) or individual islet cells (microencapsulation) and implanting them inside the abdominal cavity. While these devices would have limited contact with the circulation, nutrients and insulin would be exchanged by way of the body fluids permeating the tissues in which they are implanted.
Human islet transplantation has been tried experimentally in humans with some success. In 1993, surgeons at the Islet Transplant Center at St. Vincent's Medical Center in Los Angeles successfully transplanted microencapsulated islets into two people with diabetes. The two people were candidates for the procedure because they had already had kidney transplants and were on immunosuppressants. After the procedure, both people drastically reduced their insulin dosages, and their diabetic complications actually improved.
However, like whole pancreas transplantation, the feasibility of adult islet cell transplantation is hindered by a shortage problem; again, only 1,000 to 1,500 whole pancreases become available each year. If only the islets are used, three to four adult pancreases are needed per procedure, narrowing the number of potential recipients to only 250 to 500.
Fetal TissueThe shortage of adult human pancreases has led researchers to explore other sources of pancreatic tissue. One partial solution to this problem might be found in the highly controversial use of fetal pancreatic tissue. Studies have shown that human fetal pancreas tissue is easy to culture and that it can grow and mature once it is transplanted. It has also been shown that the tissue can be frozen and will function again once it is thawed. These factors could help to make such transplants available to a greater number of people.
There are roughly 1.5 million induced abortions in the United States each year although only a very small percentage of them yield usable tissue. Yet, if only 10% of these pancreases were available, using 10 to 20 fetal pancreases to treat each person, fetal tissue could potentially cure 7,500 to 15,000 people with diabetes. While this number still falls dramatically short of the number of people who could benefit from transplants, it could offer one more source of pancreatic tissue.
Work with fetal pancreas transplants began in the late 1970's when researchers in Los Angeles and Melbourne, Australia, grafted bits of fetal rat pancreas into diabetic rats of the same species. The implants not only survived, but grew and matured. After 3 to 12 weeks, they were able to normalize blood glucose levels and halt the early stages of retinopathy and kidney disease. Clinical transplantation of fetal tissue has also been reported in small studies in China, Europe, Russia, and the United States. In each case, fetal tissue transplantation lowered insulin requirements, but did not completely reverse diabetes. And, as with other types of pancreatic transplantation, the success was short-lived and the grafts were eventually rejected.
Research into this area was slowed considerably in 1988, when the Reagan Administration banned federal funding for research using tissue obtained from induced abortions. In 1993, the Clinton Administration lifted the ban, and research into this area is expected to continue.
Animal Islet CellsIslet cell transplants from pig pancreases may become another solution to the shortage problem. Pig insulin is very similar to human insulin, differing only by one molecule. In fact, before the advent of artificially produced human insulin, pork insulin was the insulin of choice. Since nearly 100 million pigs are used for food every year in the United States, slaughterhouses could easily supply enough pancreas tissue for everyone who wanted a transplant.
But again, there is the problem of immune system rejection. In addition to the immune response seen with human islet cells, other immune mechanisms guard against tissue from other species. However, this problem may be overcome by one of the immune isolation techniques now being developed. In fact, some biotechnology firms are banking on it.
BioHybrid Technologies, a biotechnology company in Lexington, Massachusetts, has been working on various versions of a bioartificial pancreas, a device containing pig islets that may some day be mass produced and implanted into people with diabetes. In 1991, in a paper in the journal Science, researchers from BioHybrid, in conjunction with surgeons at New England Deaconess Hospital and Harvard Medical School, reported successfully implanting bioartificial pancreases containing canine islets into diabetic dogs. The devices, which were roughly the size of hockey pucks, succeeded in maintaining near-normal fasting blood glucose levels in some of the dogs. Some of these devices continued to produce insulin for up to 3 1/2 years.
Over the last few years, these devices have evolved into microreactors, that is, small, resilient structures containing a small number of islets, which can be injected with a syringe. In dogs given low doses of immunosuppressants, implanted islets from the same species have survived and functioned for up to 5 1/2 months, and preliminary results with cross-species transplants also look promising. By the end of this year, BioHybrid researchers plan to seek approval from the Food and Drug Administration for clinical trials, and they may actually start those clinical trials by the end of 1996.
Another biotechnology firm, Neocrin Company, is developing a way to make a bioartificial pancreas that can be maintained by the body. Neocrin covers encapsulated islet cells with a membrane that not only blocks out the immune attack, but also allows new blood vessels to grow right up to its surface. This means that blood can feed the islet cells within the capsule, transport the insulin the cells produce, and cart away their waste products. Neocrin researchers have completed several years of studies in small animals and are now testing larger devices in large animals. Researchers at Neocrin have approached the Food and Drug Administration for approval to begin clinical trials and hope to begin human studies soon.
Artificial Beta CellsYet another approach to solving the shortage problem is to create artificial beta cells that could be mass produced and used in an artificial pancreas. Researchers all over the country are pursuing this goal. While the individual approaches vary widely, they share a basic thread: All involve inserting new genes into naturally occurring cells. Some groups have already made significant strides in this line of research.
For example, in a study published in the January 15, 1992 issue of Proceedings of the National Academy of Sciences, researchers at the University of Dallas Southwestern Medical Center reported that they had created artificial beta cells using laboratory-grown cells from the University of California at San Francisco. The cells, originally derived from the pituitary glands of mice, were genetically altered so that they not only produced insulin, but could also respond to the rise and fall of blood glucose, just as normal pancreatic beta cells do. They did not implant them into animals or humans, however, because they still had to tackle the problem of rejection by the immune system.
Researchers at Albert Einstein College of Medicine in Bronx, New York, are also working on ways to mass produce genetically engineered beta cells that won't provoke rejection by the immune system. To solve the problem of immune rejection, these researchers are trying to camouflage the beta cells from the immune system. They hope to accomplish this by changing certain molecules on the beta cell surface that are normally red flags for an immune attack.
These are just two approaches among many for creating artificial beta cells, an experimental avenue that is still in its infancy. Meanwhile, the field of pancreatic tissue transplantation is growing rapidly. As researchers continue to develop ways to safely bypass the body's immune system, other approaches to pancreatic tissue transplantation may only be a few years away. And that means that, eventually, researchers may find a way to halt the progression of diabetes.
Robert Dinsmoor is a freelance writer living in the Boston area. He is a Contributing Editor of Diabetes Self-Management.
Copyright 1995, Diabetes Self-Management. Used by permission.
Last Updated: Thursday August 29, 2002 20:59:50
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