Why Islet Transplantation?

The goal of current treatments for type 1 diabetes is to establish a normalization of blood glucose levels - good glycemic control reduces the long-term risk of diabetes complications. The Diabetes Control and Complications Trial (1), the most definitive study to date, clearly showed that intensive insulin therapy may significantly reduce the risk of microvascular complications. However, the same therapy was found to be associated with a threefold increased risk of severe hypoglycemia. This study, and others, therefore provide the rationale for the development of improved methods to achieve glucose control.

Whole-pancreas transplantation has become accepted as an alternative therapy for subjects who are undergoing simultaneous kidney transplants. Although rates of rejection are generally low - ~14% (2,3) - the significant risks associated with whole organ transplantation limit its use to co-transplantation with other organs.

Islet transplantation is a much simpler and less costly procedure – it is much less invasive procedure than whole-pancreas transplantation, offers the hope that if performed earlier it will result in excellent glucose control and prevent long-term complications. Over the years, the technique has had a poor record of accomplishment in achieving independence from exogenous insulin - approximately 10% of subjects were off insulin at 1 year, although 37% may have continued C-peptide production (4).

The goal of islet transplantation is to achieve glycemic control with minimal risks (5,6). It is a much less invasive procedure than whole-pancreas transplantation and offers the hope that if performed earlier, it will result in excellent glucose control and prevent long-term complications.

The Edmonton Protocol

In June 2000, the field of islet transplantation took a remarkable leap forward with the publication of Dr. James Shapiro and colleagues’ Edmonton Protocol, which resulted in 8 of 8 patients with stable islet function and no evidence of rejection, some over a year post-transplant(7). Although this method relies upon the use of life-long maintenance immunosuppression, the effectiveness of this protocol remains a significant advance over previous methods and is currently the gold-standard for beta-cell replacement therapies.

The ITN is currently conducting a multicenter clinical trial of the Edmonton Protocol at 9 centers around the world. The purposes of the trial are several - to validate the technique in a multicenter environment; to establish a network of clinical centers well-trained in the techniques for islet isolation and preparation; and to provide a baseline measure to which trials of new tolerance therapies may be compared.

Tolerance Protocols in Islet Transplantation

Whereas the Edmonton Protocol appears to be less nephrotoxic than standard cyclosporine and higher-dose tacrolimus-based regimens, even low-dose tacrolimus should be used with caution in the face of significant impairment in baseline renal reserve (as evidenced by an increased serum creatinine level). As well, the long-term effects of maintenance immunosupression remain ill-defined, although it is generally believed to carry increased risks of infection and certain types of cancer. For this reason, the ITN is actively pursuing protocols that seek to investigate tolerogenic protocols in islet transplantation. As an initial foray into tolerance protocols, the ITN is placing its current emphasis on protocols that use novel tolerogenic agents combined with short-term immunosuppressive therapy that will be withdrawn following approximately 1 year, should circumstances prove efficacious. Two such trials are currently being pursued by ITN investigators.