Scott King:

breakthrough (n): A significant or sudden advance that removes a barrier to progress. It is a word perhaps used too freely. One recent application, however, may be appropriate.

A new protocol for islet transplantation has been developed at the University of Alberta (Edmonton, Alberta, Canada). So far the "Edmonton protocol" has a success rate of 100% - eight out of eight patients receiving islet implants do not require insulin injections. The best previous protocol has a success rate of about 15%.

This is indeed a breakthrough! The Edmonton Protocol moves islet transplantation from a curiosity to a proven clinical therapy!

Before telling you more about this breakthrough we must ask, "Is this a clinical therapy for all diabetics? Is this a cure for diabetes?" No, it is not. It is a treatment for a rare form of diabetes, hypoglycemia unawareness (click here to read more about hypoglycemia). Injected insulin treatment failed these patients with type 1 diabetes. The eight patients in the trial, aged 29-53, had severe low blood sugar-induced blackouts (hypoglycemia). The usual "therapy" for this condition is keeping the blood sugars high. This leads to accelerated vascular decay, so the dangers of immune suppression therapy are justified because the patients are so fragile. If you have type 1 diabetes and your control is good - and you can sense when your blood sugar is low - your are not a candidate for this therapy. But the success of this therapy should give you hope, because researchers at Edmonton and elsewhere are working to extend it to everyone with type 1 diabetes.

Some of the Edmonton patients have been free of injected insulin for well over a year. It remains to be seen if these people are cured, forever free of insulin, because the islets may have a finite lifespan. Should this come to pass there is no reason to suspect that future "boosters" of more islets would not prolong efficacy. The duration of response in these patients will provide valuable information about islet lifespan and replication.

Now, what is new about this Edmonton protocol? High quality islets and steroid-free immune suppression. Dr. Jonathan Lakey, Director of the Human Islet Isolation Laboratory at the University of Alberta, uses exacting and ingenious methods to isolate islets from the pancreases of organ donors. (Dr. Lakey is on the Science Advisory Board of Islet Sheet Medical, of which I am President.) Although the press reports focus on improved immune suppression, Jonathan says that the quality of the islets is also important. He has developed improvements such as serum-free media that produce islets of high functionality. In addition, Edmonton has developed assays for islet function - they can actually predict islet functionality before injecting the islets.

Another important improvement in the Edmonton Protocol is the use of heart-beating pancreas donors. Most organ donors in the US are not maintained on life support while the organs are harvested. When the heart stops the digestive enzymes produced by the exocrine tissue of the pancreas stop flowing into the intestine, and begin digesting the pancreas instead! Shortening this period of autodigestion improves the quality of the islets.

And the quantity of islets used in the Edmonton protocol is larger than typically used in the past. Islets from two donors and pooled into one recipient. The benchmark is 10,000 islets per kilogram. That is nearly the number of islets in the pancreas of someone who has not developed diabetes.

Dr. Shapiro, Associate Professor of Surgery and Director, Clinical islet and Pancreas Transplant Programs at the University of Alberta, developed the new immune suppression protocol, a steroid-free combination of three drugs (Tacrolimus, Sirolimus, and Daclizumab) which together prevents rejection and also prevents the autoimmune diabetes from coming back. These three agents work in synergy. Tacrolimus (or FK506) is a macrolide immunosuppressant produced by the fungus Streptomyces tsukubaensis. It suppresses both humoral and cellular immune responses by inhibiting the phosphatase enzyme calcineurin, which prevents the activation of T-cell-specific transcription factors that are involved in lymphokine expression. Sirolimus (or rapamycin) was discovered more than 25 years ago from the soil of Easter Island. Structurally, sirolimus resembles tacrolimus and binds to the same intracellular binding protein or immunophilin known as FKBP-12. However, sirolimus has a novel mechanism of action. Whereas tacrolimus and cyclosporine block lymphokine (e.g., IL2) gene transcription, sirolimus acts later to blocks IL2-dependent T lymphocyte proliferation and a serine-threonine kinase that is important for cell cycle progression. Therefore, sirolimus is believed to act in synergy with tacrolimus (or cyclosporine) in suppressing the immune system. Daclizumab is a humanized monoclonal antibody produced by recombinant DNA technology which recognizes the IL2-receptor. Daclizumab is a composite of human (90%) and murine (10%) antibody sequences. The most important point is that Imuran and Cyclosporin are not used: they are proven to be toxic to islets of Langerhans. While rapamycin has been around for several decades, Tacrolimus received FDA approval only in 1994 and Daclizumab in 1997. The latter two drugs are the product of modern science: molecular techniques that have allowed us to create new compounds not found in nature. Thus the "islet-sparing" immune suppression portion of the Edmonton Protocol was not possible until very recently.

What is it like to have type 1 diabetes and be cured at Edmonton? First, you are screened to see if you have hypoglycemia unawareness. If you pass this initial screening you are entered onto the waiting list, and you are given a beeper. If it goes off, you know that a suitable islet donor is becoming available and you go immediately to the hospital. While Dr. Lakey and his team are making the islets you have a small tube inserted into your portal vein by a radiologist. (The portal vein conducts blood to the liver from the gut; click here for more.) This usually takes 2 hours. During this time you take your first doses of the immune suppressors, as you will for the rest of your life. Then the cells are injected into the portal vein where they migrate to the liver and engraft. The transplanted islets respond to the glucose levels in the portal vein and produce sufficient insulin in response for almost perfect control of blood sugar. The next morning you go home.

When will this cure be available to everyone with type 1 diabetes? When two things happen:
  • an unlimited source of islet tissue is available;

  • toxic immune suppression is not needed.

At Islet Sheet Medical we work to make immune suppression obsolete with a bioartificial Islet Sheet. The breakthrough at Edmonton brings us much closer to the day when islet transplantation can be used to cure everyone with type 1.

Scott R. King

NEJM article on the "Edmonton protocol"

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