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History

The idea of islet transplantation is not entirely new. Islet transplantation has been in existence since the late 1800s, when Watson Williams, a Senior Assistant Physician in Bristol Royal Infirmary (UK) attempted the transplantation of a few pieces of freshly slaughtered sheep pancreas under the skin of a 15 year old end-stage diabetic boy (1). The boy's condition improved for a couple of days after the operation, but succumbed to the disease. In 1916, Frederick Pybus described patients transplanted under the skin with sliced human pancreata (plural for pancreas) (2). Experimental research had already started in 1911 with Bensley and collaborators (3) by staining of pancreatic islets, followed in 1964 by Hellerstrom (4), who used free-hand micro-dissection as a method of obtaining islets.

In 1965, Moskalewski (5) was able to isolate pancreatic islets from guinea pigs by collagenase digestion (enzymatic method). However, the real era of islet transplantation started in 1967 when Lacy and Kostianovski (6) isolated a large amount of rat islets using distention of the pancreas through its main duct with collagenase enzyme, followed by digestion and purification from the exocrine tissue. Reckard and Barker in 1973 effectively cured diabetes in animals for the first time (7).

The first series of clinical islet allografts were performed in 1977 by Najarian and Sutherland (8). However, the modern era of islet transplantation began in 1988, as a result of improvement in the methods for isolating islets of Langerhans by Camillo Ricordi and collaborators. They developed a new method for pancreas dissociation and islet purification (9).

Despite improvements in islet isolation techniques, the results of islet transplantation before the year 2000 continued to be dismal. In reports from the International Islet Transplant Registry (ITR) from 1990-1995, only 6 percent of type 1 diabetic islet recipients achieved insulin-independence 1 year post-transplantation (10). From 1990-1998, 12 percent of patients developed insulin-independence for more than seven days (11). In 1999, the ITR report (12) concluded that establishment of insulin independence after islet transplantation was associated with the following factors:

  1. pancreatic preservation times (less or equal to 8 h),
  2. islet mass transplanted is adjusted to body weight (6,000 islet equivalents (IE) per kilogram of body weight,
  3. intrahepatic transplantation, and
  4. induction with monoclonal or polyclonal T-cell antibodies.

Taking these factors into consideration, Shapiro and collaborators (13) developed a protocol and in 200 reported 100 percent success (insulin-independence) one year post transplantation in a series of 7 patients performed at the University of Alberta in Edmonton, Canada. This was the turning point in islet transplantation.

The Edmonton Protocol

The success of the Edmonton Protocol was based on the following factors:

  1. a new steroid-free immunosuppressive therapy combination of Sirolimus and low dose calcineurin inhibitor (Tacrolimus), and induction with an anti-IL2-receptor antibody (Daclizumab),
  2. sufficient number of high-quality human islets (over 10,000 IE/kg body weight of recipient), and
  3. recipient selection; brittle type 1 diabetic patients with normal kidney function and low insulin requirements (less than 0.7 Units/kg).

The potential causes of failure of islet transplants included failure of initial engraftment, inflammatory response at the transplant site, alloreactive(rejection) or autoimmune response, and immunosuppressive drug-induced b -cell (insulin producing cell in the islet) toxicity (14). The Edmonton Protocol not only addressed these issues, but further optimized islet function by controlled delivery of a purified low-endotoxin collagenase enzyme, immediate graft processing, and transplantation of a total average of 800,000 IE (just over 11,000 IE per kg recipient body weight) into the liver via portal vein (13). The experience of the Edmonton Trial has been reproduced in other centers through the Immune Tolerance Network (ITN) Trial, which started in the year 2000 and included Centers in Edmonton, Minneapolis, Miami, Seattle, St. Louis, Harvard, Geneva, Giessen and Milan. The objectives of this trial were to replicate the Edmonton Protocol at multiple sites, provide a base of qualified islet centers for future ITN tolerance trials, and to explore mechanisms of islet acceptance/rejection.

A complete and comprehensive report of this trial can be found in the New England Journal of Medicine 2006 Sep 28;355(13):1318-30. Two important factors affecting clinical success are:

  1. the center's skills in preparation of high-quality, high-yield islets following identical isolation protocol, and
  2. the center's ability to maintain the recipient's immunosuppressive drug levels within a specified target range after transplantation (15).

Despite some encouraging reports, the results of islet transplantation among different centers continue to be somewhat variable, and show limitations to this procedure (16). To date, after 5 year follow-up of patients in the Edmonton Protocol, most patients have reverted to using some insulin after achieving insulin independence for a period of time. C-peptide secretion (regarded as islet graft survival) has been maintained in most of the recipients, which is still beneficial for the internal regulation of blood glucose levels (glucose homeostasis) (17). This carries the hope that the controlled glucose homeostasis will prevent the devastating long-term secondary complications of diabetes (Eye, renal, cardiovascular, vascular and nerve disease).

The Emory Islet Transplant Program has also performed clinical trials using the Edmonton Protocol with similar success to the Edmonton experience as well as to other specialized centers around the world. Today islet transplantation continues to bring hope to patients with diabetes and their Doctors; much has been learned through past and current trials. The field is actively pursuing clinical and basic science research in hopes of finding the optimal method to achieve the cure for diabetes.

  1. Watson-Williams P. Notes on Diabetes Treated With Extract and by Grafts of Sheep's Pancreas. British Medical Journal 1894:1303.
  2. Pybus F. Notes on suprarenal and pancreatic grafting. Lancet 1924;ii:550.
  3. Gray DW, Millard PR, McShane P, Morris PJ. The use of the dye neutral red as a specific, non-toxic, intra-vital stain of islets of Langerhans. Br J Exp Pathol 1983;64(5):553-558.
  4. Ferguson J, Allsopp RH, Taylor RM, Johnston ID. Isolation and long term preservation of pancreatic islets from mouse, rat and guinea pig. Diabetologia 1976;12(2):115-121.
  5. Moskalewski S. Isolation and Culture of the Islets of Langerhans of the Guinea Pig. Gen Comp Endocrinol 1965;44:342-353.
  6. Lacy PE, Kostianovsky M. Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes 1967;16(1):35-39.
  7. Reckard CR, Ziegler MM, Barker CF. Physiological and immunological consequences of transplanting isolated pancreatic islets. Surgery 1973;74(1):91-99.
  8. Najarian JS, Sutherland DE, Matas AJ, Steffes MW, Simmons RL, Goetz FC. Human islet transplantation: a preliminary report. Transplant Proc 1977;9(1):233-236.
  9. Ricordi C, Lacy PE, Finke EH, Olack BJ, Scharp DW. Automated method for isolation of human pancreatic islets. Diabetes 1988;37(4):413-420.
  10. International Islet Transplant Registry. Giessen, Germany, University of Giessen. 1996;6(1).
  11. International Transplant Registry. Newsletter (8). 1999;8:1-20.
  12. Hering B, Brendel MD, A S, B S, Bretzel RG. International Islet Transplant Registry Newsletter. Giessen: University of Giessen; 1999.
  13. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343(4):230-238.
  14. Robertson RP, Davis C, Larsen J, Stratta R, Sutherland DE. Pancreas and islet transplantation for patients with diabetes. Diabetes Care 2000;23(1):112-116.
  15. Shapiro AM, Ricordi C. Unraveling the secrets of single donor success in islet transplantation. Am J Transplant 2004;4(3):295-298.
  16. Frutos MA, Ruiz P, Mansilla JJ. Pancreas donation for islet transplantation. Transplant Proc 2005;37(3):1560-1561.
  17. Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, Kneteman NM et al. Five-year follow-up after clinical islet transplantation. Diabetes 2005;54(7):2060-2069.