Islet cell transplantation

The concept of islet cell transplantation is not new. ^[4] Already, researchers such as the English surgeon Charles Paybus ( Frederick Charles Pybus ) (1882-1975), tried to engraft pancreatic tissue to cure diabetes. Most experts, however, believe that the modern era of islet cell transplantation has come along with the research of the American physician Paul Lacy ( Paul Lacy ) and has more than three decades. In 1967, the Lacy group described a collagenase- based innovative method (later modified by Dr. Camillo Ricordi, then working with Dr. Lacy) of isolating Langerhans islets, which paved the way for future experiments with them in vitro (in vitro) and in vivo (on living organisms) . ^[5]

Subsequent studies have shown that transplanted islets can reverse the course of diabetes in both rodents and non-human primates . ^{[6] [7]} Summing up the 1977 seminar on islet transplantation of pancreatic cells in diabetes, Lacey commented on the appropriateness of “islet transplantation as a therapeutic approach [for] the possible prevention of complications of diabetes in humans.” ^[8] Improvements in isolation methods and immunosuppression schemes made it possible to conduct the first clinical trials of human islet transplantation of Langerhans in the mid-1980s. The first successful trials of islet transplantation of human pancreatic islet cells leading to long-term relief of diabetes were conducted at the University of Pittsburgh in 1990. ^[9] However, despite continued improvements in transplant technology, only about 10% of islet cell recipients reached euglycemia (normal blood glucose) in the late 1990s.

In 2000, James Shapiro and his colleagues published a report on seven patients in a row who managed to achieve euglycemia as a result of islet transplantation using a protocol that eliminated the use of steroids and a large number of donor islets. Since then, the technique has been called the Edmonton Protocol. ^[10] This protocol has been adapted by islet cell transplant centers around the world and significantly increased transplant success.

The goal of islet cell transplantation is to instill a sufficient number of islets to control blood glucose ( glycemia ), eliminating the need for insulin injections. For a medium-sized person (70 kg), a typical transplant requires about one million islets isolated from two donor pancreas. Because good blood glucose control can slow or prevent the development of diabetes-related complications, such as nerve damage ( diabetic neuropathy ) or the eye ( diabetic retinopathy - a retinal disease), successful transplantation can reduce the risk of these complications. But the transplant recipient will need to take immunosuppressants that stop the immune system from rejecting the transplanted islets.

Researchers use a mixture of highly purified enzymes ( collagenases ) to isolate pancreatic islets of a deceased donor. A solution of proteolytic enzymes is introduced into the main pancreatic duct . Penetrating into all departments of the pancreas, the solution causes the destruction of its tissue. After collagenase treatment, the donor’s gland is cut into small fragments and transferred to the Ricordi chamber, in which pancreatic islets are released. The process of cleaning isolated islets from the rest of the pancreatic tissue is called purification.

Under local anesthesia, the recipient is injected with a catheter into the portal vein of the liver under the control of ultrasound and fluoroscopic imaging methods. Thus, donor pancreatic islets are catheterized into the portal portal vein of the liver. In case of contraindications for local anesthesia, the surgeon transplants pancreatic islets under anesthesia through a small incision. Possible risks of surgery include bleeding or blood clots.

It takes time to attach the islets to new blood vessels and begin to secrete insulin. Your doctor will prescribe a lot of tests to check your blood glucose after a transplant, and you may need to inject extra insulin until control of your own level is achieved.

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  X-ray image of the portal vein and its branches at the transplant recipient before the introduction of isolated islets.

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  Post-transplant radiographic image of the tree-like growth of the portal vein of the recipient.

The Edmonton Protocol uses a combination of immunosuppressive drugs, including daclizumab (Zenapax), sirolimus (Rapamune) and tacrolimus (Prograf). Daclizumab is administered intravenously immediately after transplantation, and then discontinued. Sirolimus and tacrolimus, the two main drugs that keep the immune system from destroying transplanted islets, should be taken throughout life.

Despite the significant progress achieved in the field of islet cell transplantation ^[11] , many obstacles to its widespread use remain at present. Two of the most important limitations are currently insufficient funds to prevent islet cell rejection and a limited supply of islets for transplantation. Current immunosuppression regimens can prevent islet rejection for months to several years, but the active substances used in these procedures are expensive and can increase the risk of specific cancers and opportunistic infections. In addition, and, to some extent, it is paradoxical that the most commonly used agents (for example, calcineurin inhibitors and rapamycin) have been found to impair normal islet function and / or insulin action. In addition, like all medicines, these substances have other associated toxic effects, with side effects such as ulcers, peripheral edema, anemia , weight loss, hypertension , hyperlipidemia , diarrhea, and fatigue. ^[12] Perhaps the greatest interest to the patient and the doctor is the harmful effects of certain widely used immunosuppressants on kidney function . For a patient with diabetes mellitus, renal function is a decisive factor in determining long-term results, and calcineurin inhibitors ( tacrolimus and cyclosporin) are significantly nephrotoxic . Thus, while some patients with pancreatic transplantation have a good tolerance to immunosuppressants, and in such patients diabetic nephropathy may gradually improve, in other patients the overall effect (reduced risk due to better control of blood glucose, but increased risk from immunosuppressant drugs) may impair renal function. Indeed, Ojo et al published an analysis indicating that among patients treated with non-renal allografts, 7-21% ultimately suffer from renal failure as a result of transplantation and / or subsequent immunosuppression. ^[13]

On the other hand, patients with insufficient heart, liver, lung, or renal insufficiency have an unfavorable prognosis for survival, and the toxicity associated with immunosuppression is reasonable (the benefits of transplant survival outweigh the risks associated with drugs). But for a subgroup of patients with diabetes mellitus and preserved kidney function, even with a long and difficult to control disease, the prognosis of survival is comparatively much better. In addition to the toxicity of immunosuppressants, there are other risks associated with the islet cell transplant procedure itself, including the risk of intra-abdominal bleeding after transplantation, and portal vein thrombosis. The presence of a rather good alternative to islet cell transplantation (that is, modern intensive insulin therapy regimens) makes us consider any new, more risky therapeutic measures from a critical point of view.

Like all transplants, islet transplants also suffer from a limited donor circle. At least 1 million Americans suffer from type 1 diabetes, and only a few thousand pancreatic donors are available every year. To get around this organ deficiency 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. To further aggravate the problem (and, unlike kidney, liver, and heart transplants, where only one donor is needed for each recipient), most islet transplant recipients require islet cells from two or more donors to achieve euglycemia. Finally, modern methods for isolating islet cells need to be improved, since only about half of the isolation attempts result in islets that are ready for transplantation.

While studies on islet cell transplantation have made significant progress and success stories are encouraging, long-term predictions of the safety and effectiveness of the procedure remain unclear. Other problems associated with this area include questions about the effect of the presence of insulin-producing foreign cells in the hepatic parenchyma , the long-term effects of portal hypertension resulting from the introduction of islets and the fact that the islet of the recipients may be hypersensitive to types of donor tissue, making it difficult to find a suitable donor if another transplant is required to save a future life. In addition, in the four years after transplantation, very few recipients in four years after transplantation of cells retained euglycemia without the use of any exogenous insulin. Thus, while most islet recipients achieve better glycemic control and suffer less from severe hypoglycemia, islet cell transplantation is still not the ultimate treatment for diabetes.

Just as the first studies of islet transplantation of pancreatic cells gave promising results, current research should overcome the obstacles identified in recent experiments on transplanting this type of cell. New immunomodulators give the greatest hope for a revolution in this area. New treatment regimens that can tolerate transplanted islets will allow recipients to preserve their transplants without a general suppression of immunity and the associated toxic effects. Although many options are being investigated, none of them are ready for use in clinical practice.

Islet cells can also be provided with a special coating that protects them from the immune system, while at the same time not interfering with the release of insulin. It is reported that this is done in ßAir's “bioreactor” , “a proprietary (that is, proprietary) implantable bio-artificial pancreas” ^[14] developed by the Israeli medical technology company Beta-O ₂ Technologies Ltd. The company was founded in 2004. The first implantation for a sick person was carried out in 2012 followed by medical observation at the Technical University of Dresden (Germany) for 10 months, and the ßAir Phase I safety / efficacy study ( clinical trial) began in 2014 at Uppsala University Hospital in Sweden ^[15] . According to the developers, free from the need to check blood glucose and administer insulin, a patient with implanted ßAir will still have to inject daily doses of oxygen into the implant using a separate device to maintain cell viability ^[16] .

• Chicago Diabetes Project: Global Collaboration for a Faster Cure (Chicago Diabetes Project: Global Collaboration to Find a Better Cure).
• NIH Clinical Islet Transplant Consortium (CIT) (NIH Clinical Consortium of National Institutes of Health for Islet Transplantation (CIT))
• Collaborative Islet Transplant Registry (CITR) (Eng. Joint Registry of Islet Transplantation (CITR))
• Uppsala University Hospital ( Uppsala University Hospital ) Updated September 20, 2012
• VIDEO: Update on Islet Transplantation at the University of Wisconsin Dr. Luis Fernandez, November 2007. (VIDEO: Update on Islet Cell Transplantation at the University of Wisconsin Dr. Luis Fernandez, November 2007).
• Clinical Islet Transplant Program - University of Alberta (Eng. Clinical Islet Transplant Program - University of Alberta, Canada)
• Diabetes Research Institute (DRI) (Diabetes Research Institute (DRI))
• Diabetes Clinical Trials (Diabetes. Clinical Trials)
• Miami: islet cell recipients [1]
• Mayo Clinic: Islet cell transplant: Emerging treatment for type 1 diabetes (Mayo Clinic: islet cell transplantation: new treatments for type 1 diabetes)
• Islet Cell Transplant Program - UW Health (University of Wisconsin Department of Medicine and Health Edition).
• Immune Tolerance Network (Immune Tolerance Network)