Advances and Significant Dates in the History of Islet Transplantation
1892: Minkowski discovers that the removal of a dog's pancreas will cause diabetes.
1893: Minkowski transplants fragments of a sheep's pancreas into a diabetic 15-year-old boy. The boy dies three days after the operation.
1922: Insulin therapy is discovered.
1924: Pybus tries to transplant human cadaveric pancreas tissue in an attempt to cure diabetes, but the grafts are rejected due to lack of immunosuppression.
Fig. 1 Oskar Minkowski
1963: The immunosuppressant Azathioprine is discovered, starting an organ transplant revolution.
1966: The first whole pancreas transplant is performed. Eventually, many diabetics suffering from severe complications would receive new pancreases.
Fig. 2 Azathioprine
1972: Ballinger and Lacy find that islet transplantation can cure chemically induced diabetic symptoms in rodents.
1974: Researchers begin the first clinical trial of islet transplantation, using steroids and azathioprine as immunosuppressants. None of these patients achieve insulin independence.
1977: Najarian injects 50,000 impure islet cells into a diabetic patient's intraperitoneal space. The patient's blood glucose levels drop slightly.
Fig. 3 Dr. Paul E. Lacy
1980: Researchers find that, for patients whose pancreases have been removed to relieve chronic pancreatitis, injection of some of the removed islet cells into the patient's liver will prevent the development of diabetic symptoms.
1990: A few islet transplant recipients achieve prolonged and consistent insulin independence using steroid-free, tacrolimus based immunosuppression.
1990s: Many researchers around the world test various techniques and immunosuppressants in an attempt to improve outcomes, but achieve only modest success.
1994: The Giessen group innovatively uses antioxidant and insulin therapy during the perioperative period to relieve demands on the graft, allowing 30% of the patients to eventually achieve insulin independence. For immunosuppression, they use steroids and cyclosporine.
1997: The Milan group achieves a 45% success rate by giving their patients more islet cells, as many as 11,000 islet equivalents/kg recipient body weight. They too use steroids and cyclosporine for immunosuppression.
Fig. 4 The Islet Transplantation Registry at Justus-Liebig University, Giessen, Germany
1999: The Edmonton group uses a new procedure to achieve an initial 100% success rate by using tacrolimus and sirolimus rather than cyclosporine and steroids, by injecting large numbers of islets—often from multiple donors, and by avoiding islet cryopreservation and exposure to fetal calf serum. Other sites quickly adopt these protocols.
2003: Preliminary results of multisite trials show that only some centers have been able to duplicate the Edmonton group's success. It is suggested that some groups do not have the necessary experience to properly isolate islet cells.
References:
- Robertson RP. Islet transplantation as a treatment for diabetes—a work in progress. The New England Journal of Medicine 2004;350:694-705
- Ricordi C, Clinical islet transplantation: advances and immunological challenges. Nature Reviews: Immunology 2004;4:259-268
- Shapiro AMJ, Nanji S, Lakey J. Clinical islet transplant: current and future directions towards tolerance. Immunological Reviews 2003;196:219-236
- Hirschberg B, Rother KI, Digon BJ, Venstrom J, Harlan DM. State of the art: islet transplantation for the cure of type 1 diabetes mellitus. Reviews in Endocrine & Metabolic Disorders 2003;4:381-389
- Berney T, Buhler LH, Mentha G, Morel P. Immunosuppression for pancreatic islet transplantation. Transplantation Proceedings 2004;36:362S-366S
- Shapiro AMJ, Lakey JRT, Ryan EA et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. The New England Journal of Medicine 2000;343:230-238
- Burridge PW, Shapiro AMJ, Ryan EA, Lakey JRT. Future trends in clinical islet transplantation. Transplantation Proceedings 2002;34:3347-3348
- Starzl, TE. History of clinical transplantation. World Journal of Surgery 2000;24:759-782
Image References:
Fig. 1: http://clendening.kumc.edu/dc/pc/minkowski.jpg
Fig. 2: http://www.bedfordlabs.com/products/images/600_20.jpg
Fig. 3: http://www.celltx.org/abstracts/images/lacy.jpg
Fig. 4: http://www.insulinfreetimes.org/02_fall/brendel.htm
