ISLET CELL TRANSPLANTATION:� IS THIS THE CURE?

�by Peter J. Nebergall, Ph.D.

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When a Canadian research team recently announced that they had successfully transplanted cadaveric insulin‑producing islet cells into type 1, insulin‑dependent diabetics, a good many were quick to proclaim the cure wasat hand. �Is it?� Let's look at the evidence.

���� Ever since the pancreatic islet cells were identified as the source of endogenous insulin production, and islet cell deficiency identified as the physical source of type 1 diabetes, doctors have explored the issue of transplantation.� Whole pancreas transplantation is available, and, while tillradical surgery, it is enjoying increasing acceptance.

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     A number of researchers have tried various ways to get new islet cells into the diabetic's body, without the major surgery of pancreas transplantation.� The procedure is simple:� Obtain a sufficient number of viable islet cells from a cadaveric donor, then induce them into the pancreas,or the liver, of the diabetic.� We can get them in there.

���� The problem has been huge:� Rejection.� The body attacks and destroys cells it perceives as "foreign."� All transplantation surgery must take this into account. Traditionally, transplantation has followed careful genetic matching (the closer the match, the less the risk of rejection), and has itself been followed by a lifetime regimen of immunosuppressive medications.

���� There have been many different attempts to transplant islet cells.�Until now, almost none of the transplanted islet cells have remained viable, have continued to "produce insulin", for more than a week.� The Canadian researchers point out that many current immunosuppressive medications,while otherwise perfectly functional, damage beta cells or induce peripheral insulin resistance.

���� The Canadian researchers followed a different strategy. Viewing thetraditional mix of immunosuppressants as "the problem," they developed a new "cocktail," utilizing Rapamune (Sirolimus, from Wyeth‑Ayerst), Prograf (Tacrolimus, from Fujisawa), and Zenepax (Daclizumab, from Roche).�

���� The team, doctors Shapiro, Lakey, Ryan, Korbutt, Toth, Warnock,Kneterman, and Rajotte, selected seven candidates for a test of their new "protocol."� These seven were all uncontrolled "brittle" diabetics (average 35 years with diabetes) who'd had a history of severe hypoglycemia and diabetic coma, and for whom the risks of transplantation and immunosuppression were judged less than the risks of remaining uncontrolled.

���� These people were carefully selected, and so were the donors, all brain‑dead individuals, "selected according to the results of a multivariate analysis of the factors that influence the success of islet transplantation."� The researchers note that no "xenoproteins", no "animal products," were used at any time.

� ���� Results have been promising:� All seven patients had a history of repeated episodes of severe hypoglycemia before the transplantation.� None have had any episodes since.� All seven patients have ceased injecting insulin, as the transplanted islets are providing sufficient insulin of their own.

���� None of the patients have died, and none of the patients have experienced acute rejection, but the researchers note that six of the seven patients required a second transplantation, to become insulin‑independent, andone of the patients required a third.�

���� Using normal testing criteria, none of the seven patients are currently "diabetic."� Is this a cure, then?

���� Not yet.� There are a number of problems.� First, it is a very smalltest, seven people in one place.� Another test, of more than forty individuals, at ten different institutions, is now underway, thoroughly checking the findings of the original team.

���� Second, transplantation is expensive, so it is important that the technique not only work but that it last. How long will these people remain insulin‑independent?� If this new approach proves to yield a durable "cure," look for wide acceptance.

���� Third, like many forms of transplantation, this one is now dependent on the availability of donors.� The Canadian researchers strictly used human donors, but until there is some other source (perhaps pig islets, xenotransplantation), there will simply not be enough islets for all who could use them.

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���� For now, islet transplantation is an experimental technique.� This new method, the "Edmonton Protocol," shows promise, but has not yet been sufficiently tested to know if this is it.� Remember, the only way we'll know if it lasts for years ‑‑ is to study it for years.� This will be done.

���� The Immune Tolerance Network needs volunteers to participate in the study of islet cell transplantation. There are very specific requirements, and only a few dozen individuals can be selected at this time.� Selection will close on January 1, 2001.� If you are interested in participation, and are a United States citizen, you'll need to contact:� The Immune Tolerance Network, Suite 200, 5743 South Drexel Ave., Chicago, IL 60637.� Application material is downloadable from their website:

http://www.immunetolerance.com

���� For further information, see the NEW ENGLAND JOURNAL OF MEDICINE, for July 27, 2000.� The article is titled:� "Islet Transplantation in Seven Patients with Type 1 Diabetes Mellitus Using a Glucocorticoid‑free Immunosuppressive Regimen," by Shapiro, Lakey, Ryan, et. al.

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