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Milestones in the history of diabetes therapy include the discovery of insulin and successful methods of beta cell replacement including whole pancreas and islet cell transplantation options. While pancreas transplantation remains the gold standard for patients who have difficulty controlling their symptoms with exogenous insulin, islet allotransplantation is now able to provide similar results with some advantages that make it an attractive potential alternative.
The Edmonton Protocol, which incorporated a large dose of islets from multiple donors with steroid-free immunosuppression helped to establish the modern era of islet transplantation almost 20 years ago. While islet allotransplantation is recognized around the world as a powerful clinical therapy for type 1 diabetes it is not yet recognized by the Federal Drug Administration of the United States.
Large-scale clinical trials administered by the Clinical Islet Transplantation Consortium have recently demonstrated that the well-regulated manufacture of a human islet product transplanted into patients with difficult to control type 1 diabetes and with a history of severe hyperglycemic episodes can safely and efficaciously maintain glycemic balance and eliminate the most severe complications associated with diabetes. The results of these clinical trials have established a strong basis for licensure of clinical islet allotransplantation in the US.
Recognition by the Federal Drug Administration would likely lead to third party reimbursement for islet allotransplantation as a therapeutic option in the United States and would make the treatment available to many more patients.
The high costs of rampant diabetes justify the expense of the treatment, which is in-line with the costs of clinical pancreas transplantation.
While much enthusiasm and hope is raised toward the development and optimization of stem cell therapy, the islet transplantation community should push toward licensure, if that means broader access of this procedure to patients who may benefit from it. Even as we prepare to take the first steps in that direction, we must acknowledge the new challenges that a shift from the experimental to clinical will bring.
Clinical islet allotransplantation in the United States would be a game-changing event in the treatment of type 1 diabetes and also generate enthusiasm for continued research. The central roles of the pancreas and insulin producing islets of Langerhans in the development of diabetes were established in the late nineteenth century. For over 50 years, islet transplantation has been rigorously studied in animal models with the hope of establishing a basis for human transplantation.
After the recently concluded and successful phase 3 clinical trials conducted by the Clinical Islet Transplantation Consortium, we have the best chance yet to establish islet allotransplantation as a treatment for type 1 diabetes in the US, as it is 6408 recognized in other parts of the world. If the Federal Drug Administration FDA were to finally license islet allotransplantation, major US insurance companies would most likely follow suit to establish the procedure as a covered treatment, making it available to many more individuals who could benefit from the therapy.
It is important that the islet transplantation community pursues FDA licensure to bring islet therapy to the clinic before newer treatments options can overtake it. Physicians from antiquity knew of a disease that caused excessive output of urine that had sweetness to it, that today we would call diabetes mellitus.
Medical literature from the great centers of learning in the ancient world 64800 Egypt, China, and India documented early attempts to categorize this disease 12.
By AD, the Greek physician Arateus was able to provide a recognizable diagnosis and coined the name diabetes meaning siphon 1 — 3. Without a better understanding of the disease, which was well beyond their means, ancient physicians could do little more than prescribe dietary changes and watch their patients die. Gradually, as the practice of medicine became more of a science, a better understanding of the disease and its causes came into focus. While the honey-like sweetness mel, mellis of urine had long been associated with diabetes, [mellitus being added to the name in late seventeenth century 124it was not until that Matthew Dobson was able to scientifically demonstrate excess sugar in the urine of those effected by the disease in his famous series of experiments, by boiling urine to dryness and observing the crystalized remains 124.
In Claude Bernard discovered a substance in the liver that he named glycogen, which was converted into glucose and then secreted into the blood, an action that he believed to be the cause of diabetes 124. The second half of the nineteenth century saw scientific discussions centered on whether the primary cause of diabetes rested in the kidney or the pancreas. German physiologist Paul Langerhans first described the cells that would eventually be known as islets of Langerhans inalthough it would be ldi to others, years later, to determine their purpose 25.
InOskar Minkowski and Joseph von Mering definitively concluded that diabetes was a disease of the pancreas by removing the pancreas from a dog, leading to diabetes.
Transplantation of autologous pancreatic fragments under the skin showed transient improvement in glycosuria lie26. Many experiments were conducted even into the twentieth century in which pancreatic fragments were transplanted into animals in mostly unsuccessful attempts to cure diabetes 78. Beginning with the discovery of insulin 4680 Frederick Banting and Charles Best in 129for which Banting, but not Best, won a Nobel Prize the following year, diabetes went from being a terminal disease to a chronic one.
Refinements in the understanding of the human insulin sequence eventually led to the production of recombinant human insulin which replaced animal extracted insulin While the multiple failures of pancreatic fragment transplantation and, more importantly, the beginning of insulin ee curtailed further experimentation with pancreatic fragments, ideas destined to play significant roles in treatment of diabetes thus transplantation of the tissues that produce insulin were first broached in this era.
One hypothesis first elucidated at this time was that exocrine acinar tissue was detrimental to the viability and function of the endocrine pancreatic graft. This led to the separation of endocrine tissue from the exocrine tissue before transplantation, which was first proposed in and finally implemented in the s 6.
Early methods of separation described by Claes Hellerstroem required arduous microdissection under the microscope 11 and, perhaps not surprisingly, due to the small amount of endocrine tissue available, did not immediately reinvigorate diabetes research efforts focused on animal pancreatic fragment transplantation. It was not until the discovery that collagenases broke down pancreatic fragments and the introduction of collagenase-based enzymatic processing described by Stanislaw Moskalewski in that research took off again The renewed enthusiasm and research efforts of many lead to Paul Lacy’s dual phase technique of islet dissociation and purification which became the ds for rodent islet isolation and led to an explosion of studies on pancreatic islets in rodents In Ballinger and Lacy achieved kei first experimental reversal of diabetes in rats using transplanted islets Soon afterwards, Kemp et al demonstrated that islets leu via portal vein to the liver of rats was superior to intraperitoneal infusion 15 9177, thus establishing the site of choice for clinical islet infusion that remains primary to this day.
The results of these studies led to a sustained burst of research utilizing rodent models, which were invaluable to the advancement of islet isolation, yet the techniques thus established were unsuccessfully in 1797 animal studies.
This lead to the removal of the purification steps in an attempt to maintain sufficient tissue to reverse diabetes in ed animals. By the late s, Horaguchi and Merrell developed a novel technique, which lfi the recovery of sufficient islets for transplantation in dogs. This, in turn, allowed Ray Rajotte and colleagues at the University of Alberta 4680 develop advanced experimental models of immunosuppression and islet cryopreservation By the end of the s doctors at the University of Minnesota began applying the techniques developed in the laboratory over the last decade for clinical application in patients with type 1 diabetes T1D.
Despite resulting in poor metabolic control and the inability to solve crucial problems associated with inadequate immunosuppression, this proved to be a valuable step toward eventual success 18 Around this same time, and with better results, some of the same physicians 19777 the University of Minnesota carried out the first autologous islet transplantations as part of a palliative therapy in patients suffering from chronic pancreatitis and undergoing total pancreatectomy The University of Miami reported promising results of allogeneic islet transplantation in although ultimately ending in graft failure, which was determined to be most likely due to inadequate immunosuppression 6.
A major turning point in islet transplantation occurred in when Camillo Ricordi, working with Lacy at Washington University in St.
Louis, developed his automated method of pancreas dissociation. The development of the Ricordi automated system allowed clinical islet transplantation to begin in earnest and it remains, to this day, one of the bedrocks of human and large animal islet isolation.
During the s and 90s several groups continued to improve the techniques of islet isolation and the outcomes of islet transplantation resulting in many new protocols being developed throughout the world. Semiautomated density gradient separation of islets was introduced by Stephen Lake at the Leicester Royal Infirmary 24while doctors at the University of Miami and Washington University were among those who improved gradients and added cold preservation solutions to enhance successful outcomes 25 A team at the University of Pittsburgh under the direction of Thomas Starzl and Camillo Ricordi confirmed the ability of allogeneic islet transplantation to restore long-term normoglycemia in immunosuppressed diabetic but not T1D patients.
They reported on 9 patients who became diabetic after upper-abdominal exenteration and liver transplantation to remove extensive tumors. Patients received islets from either the liver donor or from a pool including an additional donor, with most maintaining sustained insulin independence or near independence for over 6 months.
These cases, however, were without the added complications of T1D autoimmunity By insulin independence in T1D patients following intraportal islet transplantation utilizing a single islet source was reported at the San Raffaele Institute, Milan, Italy 28 and, utilizing a pool of two islet preparations of which some islets were cryopreservedat Washington University Continued trials in Pittsburgh and Miami incorporated gravity infusion of the islets to reduce portal pressure and reduce the risk of portal hypertension The Islet Transplant Registry collected data from islet transplants voluntarily reported by several Centers from to It reported that The results were promising but not consistent.
Proper immunosuppression remained a key piece of the puzzle yet to be figured out in order to improve long-term graft function and consistent insulin independence. The year was a milestone in the advancement of islet transplantation with the publication of the Edmonton Protocol, which produced results far more promising than what had been previously reported in the registry.
Novel features of the protocol included the transplantation of a large number of fresh islets from more than one donor, without culture, human albumin instead of fetal bovine serum in cell-processing medium, and, importantly, steroid-free immunosuppression based on sirolimus, tacrolimus, and anti-IL-2 antibody It seemed, at last, that the obstacle presented by immunosuppression had finally been overcome.
The future was promising for islet allotransplantation to become a primary therapeutic option for T1D.
Other centers were quick 680 attempt to duplicate the success of Edmonton. The Edmonton Protocol was then widely adopted either intact or in a modified form by many centers worldwide. The extended follow-up from these trials demonstrated progressive loss of insulin independence over time and the need to renew exogenous insulin. Even without insulin independence, however, some benefits of islet transplantation were observed such as the stabilization of glycemic control that would later take on more importance in discussions of the risk to reward ratio for the procedure.
While islet allotransplantation remained an interesting experimental treatment, the road to the clinic remained longer than leu. After the initial success of the Edmonton Protocol and the positive results of the international multi-center trial, the islet transplantation community began to greatly expand.
Over 30 centers from around the world voluntarily reported their activities to CITR while an undetermined number choose not to participate 6. While the establishment of the 4680 Protocol was immediately looked upon as the ds of an epoch in islet transplantation, several advancements that were developed later have contributed significantly to the current state of islet transplantation.
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The adoption of new pancreas preservation techniques has enhanced the effectiveness of University of Wisconsin UW Solution for pancreas transportation 35 — 37 leading to higher islet yields. The description of instant blood mediated inflammatory response IBMIR after the portal infusion of islets by Olle Korsgren and colleagues at the Uppsala University and Karolinska Institute in Sweden 38 led to targeted anti-inflammatory strategies aimed at improving graft survival.
Doctors at the University of Miami and other centers incorporated tumor necrosis factor TNF alpha-blockers to supplemental islet infusions 39where they have been associated with improved results.
These consortia allowed larger groups to take advantage of the experience earned at top centers, facilitated the sharing of information between members, and helped streamline procurement, islet isolation, and transplantation. Its multifaceted mission was to conduct studies aimed at improving the isolation and viability of islets, reducing complications associated with the transplant procedure and side effects of immunosuppression, to achieve good blood glucose control without hypoglycemia, to determine what happens to islets after transplantation, why dde sometimes fail, and to evaluate new methods to prevent immune rejection To complete its mission, the CITC designed, standardized, and optimized 19977 to regulate large-scale multi-center international clinical trials of islet allotransplantation.
A historical timeline of significant events in the progression of scientific investigation culminating in the successful clinical trials of islet allotransplantation. The Clinical Islet Transplantation CIT protocol regulated a phase 3 clinical trial on the efficacy of islet after kidney transplantation.
Subjects who had previously been diagnosed with End Stage Renal Disease ESRD and had undergone kidney transplantation, who were dw with T1D, and satisfied all other eligibility criteria were recruited into this multi-center study to undergo islet transplantation. Subjects received up to 3 separate islet transplantations. Immunosuppression required to prevent rejection of the kidney transplant was maintained with the addition of an induction protocol consisting of antithymocyte globulin ATGwith Daclizumab or Basiliximab IL-2 receptor antagonists replacing ATG for subsequent transplantations and etanercept Anti TNFalpha antibodies at the time of islet allotransplantation.
Islet transplantation has always been an easier sell when the recipient is already committed to life-long immunosuppression for example, from kidney transplantthus, removing one of the major stumbling blocks for it’s utilization. Subjects who were diagnosed with T1D but who had not undergone kidney transplantation not diagnosed with ESRD 66480 randomly assigned to either a phase 3 multi-center clinical trial of islet transplantation regulated under CIT protocols or site specific clinical studies investigating specific immunosuppressive agents 197, lisofylline, CIT, deoxyspergualin, CIT, LEA29Y BelataceptCIT, rituximab] in the context of islet transplantation only.
Under CIT, subjects received up to 3 separate islet transplantations from carefully chosen donors although the majority received 1 or 2.
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Basiliximab was used in place of ATG after the initial transplantation in subjects who required multiple doses of islets. Subjects also received a regimen of etanercept. CIT was an observational trial that provided extended follow-up for 75 subjects who had completed one of the parent CIT studies in order to collect islet function data and information about the safety of the medications that were required by the CIT protocols.
The islet transplant community eagerly awaited the results of these clinical trials. These conditions were achieved by As a secondary measurement, insulin independence was reported as Several subjects who either withdrew their consent for the study or were not able to be evaluated at the time point were included in data as failures and potentially skewed the overall results lower.
More importantly, recipients also demonstrated significant improvements in additional measures of glycemic control and the restoration of hypoglycemia awareness even without insulin independence.
In year 1, 22 serious adverse events SAEs were attributed to the transplant procedure or immunosuppression and 2 more in year 2. The clinical study regulated under CIT was the first phase 3 trial of any therapy to demonstrate effectively restoration of sustained normoglycemia while offering protection from SHEs for patients with long-standing T1D and a history of SHEs.
Hering concluded that in subjects with IAH and SHEs, islet allotransplantation provides glycemic control, restores hypoglycemia awareness, and protects the recipient from SHEs.
It is well known that the quality of islets for transplantation is affected by characteristics of the donor and the organ recovery process; therefore, in order to provide a consistent and successful product for transplantation, the CITC established stringent selection criteria and optimal organ recovery practices.