Will successful islet cell transplantation spell the end of Type 1 diabetes for millions?

To some, it is nothing short of a miracle.

"I remember thinking, If someone could give me a present, I would ask for just one day that I wasn't diabetic," said junior-high-school teacher Mary Anna Kralj-Pokerznik, 30. "Now I've had 13 months. It's like being released from a prison you've been in for years and years."

The teacher was one of seven patients who received a revolutionary treatment for Type 1 diabetes, an autoimmune disease in which the body destroys the insulin-producing beta cells in the pancreas.

News of the successful islet cell-transplant procedure for Type 1 diabetes spread to every news program and newspaper in the world. And diabetes researchers tout the treatment as a major step forward in treating the disease; some even hail it as a "cure."

Certainly, the islet cell-transplant procedure, known as the Edmonton protocol, ushers in an era of renewed hope for the more than one million people with Type 1 diabetes. Patients with the disorder must constantly monitor their blood sugars and endure multiple insulin injections daily just to survive.

The islet cell transplant procedure was pioneered in clinical trials at the University of Alberta, and the antirejection protocol was designed by James Shapiro, M.D., director of the clinical islet transplant program.

The novel protocol departs from previous attempts at islet cell transplant in that it uses a novel steroid-free combination of three drugs to prevent rejection of the transplanted cells, a procedure that appears to prevent the autoimmune diabetes from returning.

Like many great medical discoveries, the new approach came to Dr. Shapiro as a hunch. While sitting in a hotel room on a rainy day in Baltimore, he sat down and wrote the protocol. He had been asked to return to the University of Alberta after a hiatus at the University of Maryland--and needed to come up with a new method of forcing the human body to produce its own insulin.

"I told myself I was going to give it one last try," said Shapiro, who with many other researchers from around the world had tried repeatedly to transplant islets to severe insulin-dependent patients with little success.

Using the steroid-free protocol, seven of seven patients in the trial--some of whom were administering up to 15 injections a day--are now insulin-independent, free of daily insulin injections and constant worry. The results of the trial were published in the New England Journal of Medicine.

"My life has totally changed," said Robert Teskey, a Type 1 diabetic who was part of the landmark trial. "Gone is the need to think about how much insulin to take at every meal. Gone is the need to test my blood endlessly. Gone is the need to mentally calculate the nutritional, and particularly the complex-carbohydrate and simple-sugar, content of every meal or snack. Most of all, gone is the fear of an incapacitating insulin reaction."

The research team, led by a 28-year veteran of islet cell transplant, Ray Rajotte, Ph.D., will now teach the Edmonton Protocol to centers around the world. Clinical trials in the United States and Europe will begin shortly.

To learn more about the breakthrough, we spoke with Jonathan Lakey, Ph.D., director of the Human Islet Isolation Laboratory at the University of Alberta and coauthor of the NEJM study, about the innovative transplant procedure.

Q: Could you tell us about the successful clinical study of islet transplantation for Type 1 diabetics?

A: The results showed that islet transplantation can reverse the hyperglycemia experienced in Type 1 diabetes and that islet transplantation is now a viable option for the treatment of diabetes. In the clinical trial reported in the NEJM, we had a series of seven patients who received islet cells isolated from donor pancreases. The cells were transplanted into these patients through the hepatic portal vein. The transplanted islets flowed through the vein up to the liver, where they were engrafted and are now secreting insulin. Basically, all patients are totally off insulin. Their hemoglobin A1C, which is a marker for glucose function, is normal and has remained normal for all follow-up visits. The longest patient has been insulin-free about 15 months; the average is about 12 months.

Q: Were you surprised by the results of the trial?

A: We were very surprised. But it is what we hoped we would see. When we did the first transplant about 15 months ago, we were ecstatic. The second transplant helped confirm what we were seeing in the first patient, as did the third, fourth, and fifth. It developed faster than we had hoped.

Q: Why the portal vein in the liver, since islet cells normally would reside in the pancreas?

A: The liver still provides portal blood drainage, meaning that the islets--if in the pancreas and still functioning--would be secreting insulin, and the insulin would be going through the portal system up through the liver. So you still get portal vein drainage. The reason that we didn't transplant into the pancreas is that putting a needle into the portal vein is much simpler than trying to go into the pancreas.

Q: How are these islet cells able to take residence in the liver and reproduce?

A: Basically, the liver is like a big filter, so the transplanted cells flow into the liver and get clogged, in the small bed of the liver. Once there, they start secreting insulin from that point on and develop a whole new blood supply as well. There has been some work in animal models showing this. It is really quite amazing.

Q: Previous attempts at islet cell transplantation have been somewhat disappointing. What did your research team do differently in this trial?

A: In the laboratory--and this is my area--we have been able to develop techniques to improve the recovery of both the number of islets and the functional viability of human islets. We changed the traditional method of isolating islets and developed newer techniques that deliver more viable cells for transplant. We accomplished that in a number of different ways. First, we worked with industry to develop a product, an enzyme blend called Liberase, that is used to help digest the donor pancreas into its tissue components. We have also developed a method to load that enzyme into the pancreas, using a regulated perfusion system that controls the flow of the temperature and the pressure. We feel that this method allows maximal delivery of the enzyme into the pancreas.

The second step was the dissociation. Using enzymes and mechanical methods, we break the pancreas apart, then separate the islets from the exocrine tissue based on differences in their density. That method has worked very well and consistently. We have also eliminated animal products. Typically, fetal calf serum is added during various steps of the islet isolation process to inactivate enzymes, as well as to provide nutrients.

Q: Does eliminating animal products reduce the possibility of rejection?

A: We think that it might. In the past, the islets have all been isolated with fetal calf serum. This fetal calf serum could be coding the islets and act like a big red flag to the body to destroy these cells when injected. We hope that by not using animal serum, we will not elicit such an active immune response.

Q: What immunosuppressants did you use?

A: Typically, all islet transplants in the past have used steroids. We eliminated steroids from our transplant protocol. We are using two new drugs; one is called Rapimmune, made by Wyeth-Ayerst, and the other is Tacrolimus, or FK506. Tacrolimus has been around for a while, but we are using it at a much lower dose. Typically, these two drugs would never be used together, because they both are going after the same binding proteins on molecules. We are finding that there is a real synergistic relationship between the two drugs.

Q: What was the source of the islet cells?

A: For each patient, we have used islets from two donor pancreases. Our goal is to improve the way in which we isolate islets, so that we can transplant islets from one donor to one recipient. That is happening already.

Q: This once again underscores the need for organ donation.

A: It certainly underscores the need to improve donor education and increase the number of organ donors in Canada and around the world. However, there are other issues related to finding an unlimited source, and we are working on alternative ways as well. One possibility is to develop an islet that we can grow in culture. There has been some press recently about a beta cell line growing in culture. Those cells are like cancerous cells in a way; they keep growing and producing insulin. I don't think that is the long-term goal, because that is only one cell. Islets are multicellular tissues that contain multiple cell types. Cells that secrete insulin are one of the types, but there are also cells that secrete a substance called glucagon. It is the relationship between the insulin and the glucagon that provides people with good, stable control of their glucose. The two act on each other. And there are other cells, such as the hormone somatostatin, that control both insulin and glucagon secretion. We are transplanting the whole machinery in an islet transplant, as opposed to just one single cell type.

Xenotransplantation is also an area that we are working on. We have some models here with Drs. Korbutt and Rajotte, who have developed some pig models that are providing what we think is a good source. But there ate immunological problems as well as ethical issues related to xenotransplantation.

Q: We have worked with Novartis in the past, one of the leaders in this field of pig organ transplant. They published a study recently on the porcine endogenous retrovirus (PERV) and its transmission in patients who had received pig transplants of various kinds over many years, and none had experienced the virus expression.

A: Exactly.

Q: Do you think that use of xenotransplant tissues, such as islet cells from pigs, might occur soon?

A: I think it is years away, unfortunately.

Q: How long will patients be on the antirejection drugs?

A: These patients are on the immunosuppressants for the rest of their lives. We are working on alternative drug therapies so that we can possibly transplant them and give patients a short course of new agents or antibodies--something for which humans can eventually develop a tolerance.

Q: Was the transplant procedure complicated?

A: No, transplant was the easy part. The difficult part is the islet isolation to get enough cells to transplant.

Q: And that is what you do?

A: That is my focus. That procedure takes four to five people six hours to retrieve the purified islets from the pancreas for transplant. The actual islet-transplant procedure is very simple.

We work with the interventional radiologist here at the University of Alberta. They transhepatically go through the liver with a very small needle into the portal vein, inserting a small catheter. We then collect the islets in a 60 cc syringe and inject them. The patient is awake, and the procedure takes about 15 minutes. It is becoming a one-day procedure, and patients are going home the next day.

Q: Have all patients returned to work?

A: Certainly. We have transplanted lawyers who are back practicing. The first couple of patients were teachers, and they couldn't teach, because their diabetes was so bad that they were basically bedridden. They are now healthy and productive members of society. That is very, very rewarding to know that we have made a significant impact on the lives of these people.

Q: Were the people in the study severe cases of Type 1 diabetes?

A: Yes, these are people with very "brittle" diabetes. By that, I mean that they cannot control their blood sugars despite optimal insulin therapies. They were measuring their blood glucose levels 10 to 15 times a day and injecting insulin three or four times a day or more. While trying their best, their bodies are just not reacting, and they are experiencing wide fluctuations. They also experience hypoglycemic unawareness, having lost that sensation of becoming low--and that situation is very scary. If driving or cooking, for example, they could basically black out as a result of their diabetes and not be aware of it.

Q: How quickly did you notice the results?

A: After the islet transplant, the results came very quickly. The sustained insulin independence we are watching now. They are all doing great. The one-year oral glucose tolerance test in our first patient is completely normal. That shows us we transplanted enough viable cells that they are doing well; the cells are not falling off, and you are not seeing an immunological destruction.

Q: The breakthrough has been described as a miracle.

A: Certainly, people keep throwing the word "cure" around. As scientists, we know that we are no way near a cure. There is still much work that needs to be done. But these patients talk about cure. And certainly for them, it is a cure. Their lives are totally changed. Instead of diabetes controlling them, they are controlling their diabetes.

Q: The first question that people with Type 1 diabetes will ask is, "How can I become a part of a clinical trial?"

A: We are now screening and enrolling patients who meet our criteria--brittle diabetes and hypoglycemic unawareness--into our trial here in Edmonton. There are also centers being selected for trials in the United States. The Immune Tolerance Network is funding four transplants in each of these different centers. Their goal is to duplicate what we have been able to accomplish here in Edmonton.

Q: And that is called the Edmonton protocol at this point?

A: Yes. The Edmonton Protocol. It contains the protocol that we have been discussing--from the way we isolate islets to the immunosuppressant agents used to the selection criteria for patients.

Q: Does the Immune Tolerance Network have a Web site where people can learn more about the trial?

A: Yes. You can access their Web site at www.paramount.bsd.uchicago.edu, or immunetolerance.org.

Q: The side effects of the procedure were minor, mainly mouth sores.

A: Yes, and they resolved themselves. We were using a liquid formulation of one of the drugs, and by changing it to a pill formulation, we no longer have seen that side effect.

Q: And you are working with additional patients in your trial?

A: Yes, the NEJM talked about 7. James Shapiro, M.D., reporting on the trial in Chicago, talked about 8. But we have done 11 now.

Q: In reading the NEJM study, I noticed that you administered vitamins E, [B.sub.6], and A in the regimen. What was the significance of this?

A: We were trying to cover all our bases by providing enough vitamins.

Q: Were these three vitamins specific to Type 1 diabetic deficiency?

A: No. They are just general vitamins that we thought important. A group in Germany has used a vitamin cocktail for a while.

Q: Will the vitamins continue to be part of the protocol?

A: I believe so, yes.

Q: Since diabetes is an autoimmune disorder, did you learn anything about autoimmune disorders during the course of the trial?

A: Our focus right now is restoring euglycemia, or normal blood glucose concentration, in these patients. We hope that immunological and autoimmune destruction of the islets will not occur using this type of immunosuppression. We, along with collaborators here at the university, are working on a vaccine to prevent diabetes.

Q: When will islet cell transplantation be widely available?

A: As the centers in Europe and the United States begin their trials, the momentum will increase and mushroom out to other centers in the U.S. and Canada. It is coming. For the very first time, we have been able to show that islet transplants do work. That is what the field needed. In the past, there was an 8 percent success rate; it was really more anecdotal than clinical success.

Q: This is amazing. The procedure will have a profound impact on Type 1 diabetes.

A: Yes, as long as we address the issue of having adequate sources of the tissue, which is the biggest challenge for us right now. And we must continue to improve the way we isolate the islet so that we can use one donor pancreas to one recipient. If we accomplish that, right off the bat we have doubled the number of transplants that we can do. And if we work with organ-donor organizations to educate others, we can increase donations, and that will have a big impact as well. Everyone knows someone with diabetes.

Q: We hope that our readers will help you through organ donations.

A: Thank you very much.

If you would like to contact the Islet Transplant Program for more information.

Islet Transplant Program University of Alberta Hospital 8440-112th Street Edmonton, AB T6G 2B7 Email: isletprogram@med.ualberta.ca Website: www.med.ualberta.ca/ research/groups/islet/

If you are interested in participating in U.S. trials, you can contact the Immune Tolerance Network for more information.

Immune Tolerance Network Suite 200 5743 South Drexel Avenue Chicago, IL 60637 Email: islet-info@immunetolerance.org Website: www.immunetolerance.org

RELATED ARTICLE: One Patient's Story: "Nothing Short of a Miracle"

The Post spoke with Robert Teskey, one of the first seven patients in the Edmonton trial. Since age 14, Robert has been dealing with the daily struggles that people with Type 1 diabetes face.

POST: How are you feeling?

TESKEY: I am feeling great.

POST: What was your life like prior to the islet cell transplant procedure?

TESKEY: I was diagnosed with Type 1 diabetes in 1960, so I have been diabetic for almost 40 years. I was on insulin the entire time. In the early days, I started with one injection a day, then later on two, followed by three, then four injections a day. Over 40 years, I probably had 40,000 injections--a number that gets people's attention. Most people identify the difficulty with Type 1 diabetes as being "on the needle." The fact is that for most diabetics, injections aren't the big issue; they get pretty used to it after that many times around the block. For me, the real difficulty was that I was beginning to run into long-term, significant complications of diabetes.

In my case, I had heart blockages that had to be reamed out with angioplasty. Coupled with cardiovascular problems, I had low blood sugar, or hypoglycemia. With low blood sugar, your brain just shuts down. If you are fortunate enough to be able to anticipate and predict when these situations are going to occur, you can fix them easily by consuming some sugar. But I was running into situations when I didn't feel them coming on. By the time others around me noticed that there was a problem, I was pretty far gone. In the community, we call that insulin reaction.

I began complaining to my specialist about my problems. With traditional insulin therapy, there is not a whole lot than can be done. They can do some fine-tuning, but the reality is that these are issues that are not easily resolved under traditional insulin therapy. About 15 months ago, I received a call telling me that a research team at the University of Alberta was going to try islet cell transplant again, and they asked me if I would be interested in becoming part of the test group.

POST: What happened in the procedure?

TESKEY: The procedure itself is very straightforward if you set aside all of the tests and aspects that relate to the research study. They take donor pancreases and, through a complex process, separate the islet, or insulin-producing, cells from the rest of the pancreatic tissue. The islets are a very small part of the total pancreas tissue mass. They end up with a couple of teaspoons of a cloudy yellow liquid that they inject into the main vein going into the liver. The vein carries the cells to the liver where the cells root, then start doing their thing.

POST: How long was it before you began noticing a difference?

TESKEY: Immediately, within a day.

POST: How often did they check your insulin levels after the transplant?

TESKEY: During those first days, probably every hour or hour and a half. The first procedure that I had, my insulin requirement dropped to about 35 percent of what it had been previously, and that effect was immediate.

POST: How many injections were you taking each day?

TESKEY: Four injections a day and a total of about 80 units of insulin.

POST: How did this dramatic shift feel?

TESKEY: It was amazing. You can hardly believe it. You keep expecting that something will reverse itself quickly. But it happened very quickly, and there was no turning back. After the last transplant, I have not had one injection of insulin.

POST: How long ago was that?

TESKEY: In August 1999.

POST: The implications of this procedure for people like you with Type 1 diabetes are very profound.

TESKEY: "Profound" is a very good choice of words. I view it as nothing short of miraculous.

POST: Do you feel that you are any different from other Type 1 diabetics in the same situation?

TESKEY: No. I feel some sense of guilt because I know that there are literally hundreds of thousands of other people around the world and North America whose situation is no different than mine. I just happened to be at the right place at the right time and fortunate enough to be in this study.

POST: Have you experienced any complications or side effects?

TESKEY: Since the first transplant, I have not had a low blood sugar episode. Part of what the cells do is to monitor the insulin level in the blood. They pump out insulin, but perhaps even more than that, they determine how much you need and simply provide it exactly when required in the exact amount you need. Even though I was taking some insulin, the cells then started to take that externally supplied insulin into account in terms of how much they pumped out.

POST: Could you tell me how your life has changed since the transplant? Were you and your family on any kind of special diet that may have changed since the procedure?

TESKEY: Certainly, my diet is significantly more relaxed. I was never quite as rigid in following a sugar-free diet as some people are. I am now in a position where I can eat anything. If I choose not to eat, I have that choice as well. For many diabetics, it is not so much about not eating as it is being required to eat because you have to be taking, in food to use up the insulin injected externally.

There is a dramatic difference in my life--having the ability not to have to eat, following a strict timetable during the day, not having to test my blood sugar levels, not having to take injections of insulin, and being able to sleep in. And most of all, not always trying to have to predict or anticipate when one of these low-blood-sugar episodes might be on the horizon.

POST: What drugs are you taking at this time?

TESKEY: I am on two antirejection drugs, which are key to the success of the program. Both drugs have not traditionally been used. Cyclosporine, or a derivative of cyclosporine and steroids, is what has usually been used. The drugs that we are using are different from other families of drugs, achieve the necessary immunosuppressive effect, are taken in very low doses, and have very few side effects.

POST: What side effects have you experienced?

TESKEY: The side effects are small compared to the benefits. Almost everyone in the study experienced mouth sores in the initial stage. But as they got the drug levels to the appropriate dose, those went away and were certainly not a permanent problem. The other side effect is so minor that it is embarrassing to note. The fingernails get thin, so you lose your ability to use them in the traditional way. They are just not strong enough anymore to pull things or pick things up.

POST: Are you back at work?

TESKEY: I worked throughout the whole procedure. Some of the patients had been in a serious enough condition that they had been off work for a long time. I was able to return to work within a day after discharge from the hospital, which gives a sense of the relatively minor nature of the procedure.

POST: What does your family think about the success?

TESKEY: I am a widower. My wife was killed a couple of years ago by a drunk driver. But I do have two children at home--18 and 21.

POST: Do either of your children have diabetes?

TESKEY: No.

POST: What do your kids think?

TESKEY: They are even more amazed. After my wife was gone, they were the people who had to worry about whether I was going to pass out in the night. For them, it has also been a great relief.

POST: To date, all the transplants have been successful. The first patient has been out of the trial for about 1 1/2 years.

TESKEY: Not quite a year and a half. The first one, Brian Best, had his transplant in late March 1999. Two others occurred in the following two months. I was number four, and I had mine in June of last year.

POST: We hope the Edmonton protocol reaches people with Type 1 diabetes around the world. It would save lives.

TESKEY: It really would. There are two very important messages in this story. One is clearly the need for more organ donations. Everyone knows at least one other person who is an insulin diabetic and would benefit from this treatment. My fondest hope is that sharing my story will raise awareness of the need for people to donate their organs. In terms of major roadblocks, it is the supply of donors. There may be ways that this can be solved other than getting more donors, but right now donors are key.

Of course, the other issue equally important is medical research funding. These developments just don't happen. A number of centers in the United States--Miami, Minnesota, Chicago--have been working on islet cell transplants. But research costs money.

POST: When the procedure becomes more widely available, do you think it will be expensive?

TESKEY: I think that ultimately it will be very inexpensive. If they are able to clone the cells and not have to rely on organ donations and get over the need for antirejection drugs, my hope is that any youngster diagnosed as a new diabetic would simply turn up at their doctor's office, get their injection, go home, and that would be the end of the matter. It would be less traumatic than, say, having a serious cold.

POST: That would have made a big difference in your life, wouldn't it?

TESKEY: It really would. I have been fortunate in that I have not let diabetes stand in the way of a full and fulfilling life. But the reality is that it is only when you have been freed as I have that you begin to realize how much difference not having all of this diabetic management makes in your life.

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