Successful Islet Transplantation for Patients with Diabetes -- Fact or Fantasy?
The New England Journal of Medicine -- July 27, 2000 -- Vol. 343, No. 4
Editorial
Medical history is replete with sagas of scientists who doggedly pursue dreams of better ways to treat disease. In these tales, somewhere on the road between the first success and the maturation of an important new therapy, enthusiasts' smiles broaden and skeptics' frowns deepen. It is then that the question is asked: Is this the dawn of a new treatment era, or are we still dreaming?
Separating fact from fantasy is central to answering this question. In the case of pancreatic islet transplantation as a treatment for diabetes mellitus, the facts are clear. This procedure first gained attention in the early 1970s, when Lacy and colleagues demonstrated that hyperglycemia in diabetic rodents could be treated by transplantation of islets. (1) Through the 1970s and 1980s, many attempts to apply this treatment in humans with diabetes met with failure. In the 1990s, reports of a few successes appeared, with some recipients of islets needing no insulin treatment for hyperglycemia for up to a year. (2) Yet, using this criterion, the Islet Transplant Registry estimated in 1996 that only 6 percent of islet transplantations in the years from 1990 to 1995 were successful. (3)
In this issue of the Journal, Shapiro and his colleagues report that seven of seven transplant recipients with type 1 diabetes who received an average of approximately 800,000 islets (delivered to the liver by injection into the portal vein) maintained normal blood glucose concentrations and glycosylated hemoglobin values without exogenous insulin for an average of one year. (4) These results provide proof of the principle that islet transplantation can be reproducibly successful, at least for one year.
The keys to this impressive outcome include transplanting islets of very high quality as soon as possible after harvest from cadaveric donors and bstantially modifying the conventional immunosuppressive regimen. The modifications involved eliminating glucocorticoids, using a low dose of tacrolimus and a conventional dose of sirolimus, and adding daclizumab. Which of these variables was the most important in preventing rejection or failure of the islets cannot be determined with certainty, but glucocorticoids and tacrolimus are known to affect beta-cell function and survival adversely. It seems probable that these two drugs and cyclosporine, which formed the usual regimen in prior trials, were the likely culprits leading to islet failure, especially since they are highly concentrated in the liver (the site of the transplanted islets) after oral administration.
How long will these treatment successes last? Can other groups reproduce them? What about the adverse effects of immunosuppression? If success is long-lasting, who will decide who is eligible for this treatment, who will be allowed to administer it, and where will all the islets come from?
Shapiro et al. will provide information on the permanence of the results and the frequency of drug side effects as they follow their patients over the next several years. On an optimistic note, a few patients who had islet allografts and autografts that functioned for up to 9 and 13 years, respectively, were described at this June's American Diabetes Association meeting. (5,6) The reproducibility of the results will be assessed by the Immune Tolerance Network, whose upcoming effort will be funded by the Juvenile Diabetes Foundation and the National Institutes of Health. Over the next several years, that multicenter trial will assess whether this new approach will be equally successful in the hands of others. This will be a critical time, during which we will learn whether there is delayed allorejection or autoimmune attack on transplanted islets. Moreover, we will learn whether the failure of glucagon secretion from intrahepatic islets during hypoglycemia has an important clinical effect. (7) If so, transplantation sites other than the liver may have to be considered -- perhaps even the pancreas itself. (8)
The problem of supply and demand is huge. The rate of organ donation in the Western Hemisphere is low. The willingness of people without diabetes to donate their organs after death will have to improve greatly before there can be sufficient islets to treat many diabetic patients. Perhaps the pervasiveness of this disease will engender greater enthusiasm for organ donation. In this context, the use of two pancreases per patient, as reported by Shapiro et al., may not be a necessity. There are an estimated 1 million islets in a healthy pancreas. Efficiency in harvesting islets is sure to increase. Data on islet autografts in nondiabetic patients who have undergone pancreatectomy indicate that the presence of as few as 300,000 islets is associated with insulin independence for more than two years in approximately 75 percent of recipients. (9)
Other possible solutions to the shortage of islets include cultured human islet-cell lines, islets or beta-cell lines from animals, and beta-cell expansion, but their practical availability appears to be rather far down the road. (10,11) Currently, transplantation of whole pancreases results in insulin independence and normalization of glycosylated hemoglobin values for three years in 70 to 80 percent of patients. (12) At some point, the less invasive procedure of islet transplantation should take precedence, but there will inevitably be an intermediate period during which the pancreases in the best condition will continue to be used for whole-organ transplantation.
The selection of recipients will be one of the most difficult issues. Doubtless, severity of diabetes and its complications, especially metabolic instability with a high risk of severe recurrent hypoglycemia despite optimal medical therapy, will be among the criteria. However, it is relevant to ask whether it would be more effective to provide transplants to patients without microvascular complications of diabetes, making their blood glucose concentrations normal and averting the complications. Although the initial plan is to provide transplants only to patients with type 1 diabetes, this may soon change, because the severity and prevalence of secondary complications, corrected for the duration of disease, are just as devastating for patients with type 2 diabetes.
Is successful islet transplantation fact or fantasy? The fact is that one group of investigators has had remarkable preliminary success with islet transplantation. It is no fantasy that this is a giant stride. If success continues over the next few years, it is the supply-and-demand issue that will determine whether islet transplantation will become a readily accessible therapeutic option for patients with diabetes.
R. Paul Robertson, M.D.
Pacific Northwest Research Institute
Seattle, WA 98122 |
