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Pancreatic Islet Transplantation

The process of clinical islet transplantation for the treatment of diabetes mellitus

Graphic credit: Giovanni Maki – Naftanel MA, Harlan DM (2004) Pancreatic Islet Transplantation. PLoS Med 1(3): e58 (image link), CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=1357565


Islet transplantation is the transplantation of isolated islets from a donor pancreas into another person. It is an experimental treatment for type 1 diabetes mellitus. Once transplanted, the islets begin to produce insulin, actively regulating the level of glucose in the 1) ___. Islets are usually infused into the patient’s liver. If the cells are not from a genetically identical donor the patient’s body will recognize them as foreign and the immune system will begin to attack them as with any transplant rejection. To prevent this, immunosuppressant 2) ___ are used. Recent studies have shown that islet transplantation has progressed to the point that 58% of the patients in one study were insulin independent one year after the operation.


The concept of islet transplantation is not new. Investigators as early as the English surgeon Charles Pybus (1882-1975) attempted to graft pancreatic tissue to cure diabetes. Most, however, credit the recent era of islet transplantation research to Paul Lacy’s studies dating back more than three decades. In 1967, Lacy’s group described a novel collagenase-based method to isolate islets, paving the way for future in vitro and in vivo islet experiments. Subsequent studies showed that transplanted islets could reverse diabetes in both rodents and non-human primates. In a summary of the 1977 Workshop on Pancreatic Islet Cell Transplantation in Diabetes, Lacy commented on the feasibility of “islet cell transplantation as a therapeutic approach [for] the possible prevention of the complications of diabetes in man“. Improvements in isolation techniques and immunosuppressive regimens ushered in the first human islet transplantation clinical trials in the mid-1980s.


The first successful trial of human islet allotransplantation resulting in long-term reversal of 3) ___ was performed at the University of Pittsburgh in 1990. Yet despite continued procedural improvements, only about 10% of islet recipients in the late 1990s achieved euglycemia (normal blood glucose). In 2000, Dr. James Shapiro and colleagues published a report describing seven consecutive patients who achieved euglycemia following islet transplantation using a steroid-free protocol and large numbers of donor islets, since referred to as the Edmonton protocol. This protocol has been adapted by islet transplant centers around the world and has greatly increased islet transplant success. The goal of islet transplantation is to infuse enough islets to control the blood glucose level removing the need for 4) ___ injections. For an average-size person (70 kg), a typical transplant requires about one million islets, isolated from two donor pancreases. Because good control of blood glucose can slow or prevent the progression of complications associated with diabetes, such as nerve or eye damage, a successful transplant may reduce the risk of these complications. But a transplant recipient will need to take immunosuppressive drugs that stop the immune system from rejecting the transplanted islets. A mixture of highly purified enzymes (Collagenase) is used to isolate islets from the pancreas of a deceased donor. Collagenase solution is injected into the pancreatic duct which runs through the head, body and tail of the pancreas. Delivered this way, the enzyme solution causes distension of the pancreas, which is subsequently cut into small chunks and transferred into so-called Ricordi’s chamber, where digestion takes place until the islets are liberated and removed from the solution. Isolated islets are then separated from the exocrine tissue and debris in a process called purification. During the transplant, a radiologist uses ultrasound and radiography to guide placement of a catheter through the upper abdomen and into the portal vein of the liver. The islets are then infused through the 5) ___ into the liver. The patient will receive a local anesthetic. If a patient cannot tolerate local anesthesia, the surgeon may use general anesthesia and do the transplant through a small incision. Possible risks of the procedure include bleeding or blood clots.


In 2000, the Edmonton protocol used a combination of immunosuppressive drugs, including daclizumab (Zenapax), sirolimus (Rapamune) and tacrolimus (Prograf). Daclizumab is given intravenously right after the transplant and then discontinued. Sirolimus and tacrolimus, the two main drugs that keep the immune system from destroying the transplanted islets, must be taken for life. While significant progress has been made in the islet transplantation field, many obstacles remain that currently preclude its widespread application. Two of the most important limitations are the currently inadequate means for preventing islet rejection, and the limited supply of islets for transplantation. Current immunosuppressive regimens are capable of preventing islet failure for months to years, but the agents used in these treatments are expensive and may increase the risk for specific malignancies and opportunistic infections. Perhaps of greatest concern to the patient and physician is the harmful effect of certain widely employed immunosuppressive agents on renal function. For the patient with diabetes, renal function is a crucial factor in determining long-term outcome, and calcineurin inhibitors (tacrolimus and ciclosporin) are significantly nephrotoxic. Thus, while some patients with a pancreas transplant tolerate the immunosuppressive agents well, and for such patients diabetic nephropathy can gradually improve, in other patients the net effect (decreased risk due to the improved blood glucose control, increased risk from the immunosuppressive agents) may worsen kidney function. Indeed, Ojo et al. have published an analysis indicating that among patients receiving other-than-kidney allografts, 7%-21% end up with renal 6) ___ as a result of the transplant and/or subsequent immunosuppression. Seen another way, patients with heart, liver, lung, or kidney failure have a dismal prognosis for survival, so the toxicity associated with immunosuppression is warranted (the benefits of graft survival outweigh the risks associated with the medications). But for the subset of patients with diabetes and preserved kidney function, even those with long-standing and difficult-to-control disease, the prognosis for survival is comparatively much better.


Like all transplantation therapies, islet transplantation is also handicapped by the limited donor pool. The numbers are striking; at least 1 million Americans have type 1 diabetes mellitus, and only a few thousand donors are available each year. To circumvent this organ shortage problem, researchers continue to look for ways to “grow“ islets – or at least cells capable of physiologically regulated insulin secretion – in vitro, but currently only islets from cadaveric donors can be used to restore euglycemia. Further exacerbating the problem (and unlike kidney, liver, and heart transplants, where only one donor is needed for each recipient) most islet transplant patients require islets from two or more donors to achieve euglycemia. Lastly, the current methods for islet isolation need improvement, since only about half of attempted isolations produce transplant-ready islets.


While islet transplantation research has made important progress and the success stories are encouraging, the long-term safety and efficacy of the procedure remain unclear. Other concerns relating to the field include questions about the impact of having insulin-producing foreign cells within the hepatic parenchyma, the long-term consequences of elevated portal pressures resulting from the islet infusion, and the fact that islet recipients can be sensitized against donor tissue types, making it more difficult to find a suitable donor should another life-saving transplant be required in the future. Also, very few islet transplant recipients have remained euglycemic without the use of any exogenous insulin beyond four years post-transplant. Thus, while most islet recipients achieve better glycemia control and suffer less serious hypoglycemia, islet transplantation continues to fall short of the definitive diabetes cure. Pancreatic islet 7) ___ has been reappraised based on accumulated clinical evidence. Although initially expected to therapeutically target long-term insulin independence, islet transplantation is now indicated for more specific clinical benefits. With the long-awaited report of the first phase 3 clinical trial in 2016, allogeneic islet transplantation is now transitioning from an experimental to a proven therapy for type 1 diabetes with problematic hypoglycemia. Islet autotransplantation (IAT) has already been therapeutically proven in chronic pancreatitis with severe abdominal pain refractory to conventional treatments, and it holds promise for preventing diabetes after partial pancreatectomy due to benign pancreatic tumors. Based on current evidence, this review focuses on islet transplantation as a realistic approach to treating diabetes. Recently, the French-Swiss GRAGIL Network successfully reproduced the long-term outcome achieved with the Edmonton protocol in terms of the graft survival rate (~80%), with a 58% rate of HbA1c levels at < 7% and lack of severe hypoglycemia 5 years after islet transplantation . Several cases of partial islet graft function have also been reported in Korea (ROK). Studies revealed that the islet yield and islet function in this clinical setting was superior to those of allogeneic islet transplantation, in which islets are isolated from brain-dead donors . Additionally, it was showed that transplanted islets can promote the regeneration of endogenous beta-cells in experimental models of IAT after partial pancreatectomy. In summary, IAT after partial pancreatectomy for benign tumors could be a promising indication for clinical islet transplantation. In this setting, IAT may improve the metabolic milieu after pancreatic resection and offers a unique opportunity to understand the biological effects of intraportal islet transplantation beyond the simple replacement of islet cell mass. Recent results from international cohort studies and the phase 3 clinical trial of allogeneic islet transplantation prompt reappraisal of this method as an important component of the stepwise approach to the treatment of problematic hypoglycemia. The 5-year insulin-independence rate of islet transplantation patients has also improved at some experienced centers. IAT has already been proven to be an effective therapy for intractable pain due to advanced chronic pancreatitis. Partial pancreatectomy for the treatment of benign pancreatic 8) ___ could be another indication for the use of IAT in the near future.


Successful islet 9) ___ transplantation can provide the following benefits:


1. Restore or improve the body’s ability to regulate blood sugar levels. The need for frequent blood sugar measurements and daily insulin injections can be reduced, and in a minority of patients, eliminated three years after transplantation. Although being free from insulin injections may only last several months or a year, islet cell transplantation reduces episodes of low blood sugar for a longer time.

2. Improve the quality of life.

3. Reduce the progression of long-term complications of diabetes, including heart disease, kidney disease, stroke, and nerve and eye damage.


Because it is still considered an experimental therapy, islet cell transplantation for diabetes is not widely available. There are currently 17 U.S. centers participating in islet cell research programs. The American Diabetes Association recommends that pancreas or islet cell transplantation be performed only in certain major centers, which are best equipped to handle the complex and long-term medical and personal needs of transplant patients. Collecting enough islet cells to do the transplant: Obtaining enough islet cells for transplantation is a major challenge. In most cases, islet cells from several different donors are needed. Because the need surpasses the number of human donors available, researchers are studying the use of cells from other sources, including fetal tissue and animals such as pigs. Researchers are also attempting to grow human islet cells in the laboratory. Preventing rejection: Researchers are continuously seeking to develop new and better anti-rejection drugs. Many advances have been made in anti-rejection 10) ___ over the past 15 years. Newer drugs — such as tacrolimus (FK506) and rapamycin — have fewer and less harmful side effects than some older drugs like cyclosporine and prednisone. Researchers are also working to develop methods of transplanting islet cells that will reduce or eliminate the risk of rejection and the need for immunosuppression. One approach involves coating the islet cells with a special gel that prevents the immune system from recognizing and targeting the donor cells.

Sources: Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI13C0954); Sang-Man Jin1 and Kwang-Won Kim2





ANSWERS: 1) blood; 2) drugs; 3) diabetes; 4) insulin; 5) catheter; 6) failure; 7) transplantation; 8) tumors; 9) cell; 10) drugs



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