Islet cell transplant

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Islet of Langerhans surrounded by exocrine tissue, HE stained

The islet cell transplantation or islet transplantation , in research and clinical practice abbreviated partly as ITx , is a surgical therapies for the treatment of insulin-dependent diabetes mellitus . During this treatment, the patient is implanted with cell clusters called islets of Langerhans from the pancreas of organ donors , usually in the blood vessel system of the liver . In clinical practice, implantation is minimally invasive by means of interventional radiology , in experimental research it is sometimes also carried out using conventional surgery .

In addition to the transfer of a complete pancreas known as pancreas transplantation , islet cell transplantation is currently the only therapeutic method that, if successful, frees the treated patients from the need for regular external insulin supply . It comes closest to curing insulin-dependent diabetes mellitus. In addition, an islet cell transplant can also be carried out as a so-called autologous transplant, i.e. as a transplant of the body's own tissue in patients whose pancreas has been removed due to severe pancreatitis ( inflammation of the pancreas). The retransmission of the islets after removal of the inflamed surrounding tissue prevents the occurrence of diabetes mellitus in this situation.

Due to certain side effects and disadvantages as well as a lack of knowledge about the long-term effects, islet cell transplantation is still considered an experimental therapy. From 1974 to August 2002 583 transplants were registered worldwide, 493 of them after 1990. Since 1999 the number of transplants carried out has increased significantly and in the period from 1999 to 2005 was 593 in North America alone.

Background information

Langerhans Islands

Main article: Langerhans Islands
Immunohistochemical image of a Langerhans island.
Fluorescence microscopy :
green - beta cells
red - alpha cells
blue - cell nuclei

The islets of Langerhans are compact and demarcated groups of cells with a diameter of 50 to 500 micrometers , which are distributed in the pancreas. They can be detected immunochemically in microscopic tissue preparations and thus due to their coloration differing from the surrounding tissue or by immunohistochemical markings. The islands each consist of around 1000 to 2000 cells . Around 60 to 80 percent of these are insulin-producing beta cells . In addition, there are alpha cells (15 to 20 percent) in the islands that release glucagon , the antagonist of insulin. Chance furthermore occur Delta cells, PP cells and EC cells, which somatostatin , pancreatic polypeptide or serotonin , motilin and substance P form.

The task of the beta cells is to release the blood sugar-lowering hormone insulin, regulated by the blood sugar level and the hormone glucagon. The islets of Langerhans have a dense network of capillaries (small blood vessels). Due to a special structure, these enable contact between the blood and the islet cells and thus the direct reaction to the blood sugar level by releasing the pancreatic hormones into the blood.

A healthy adult pancreas contains around one million islets of Langerhans with a total mass of 1 to 1.5 grams. This corresponds to around two to four percent of the mass of the pancreas. The totality of all islands of a pancreas is also referred to as the endocrine pancreas or the islet organ , since the islets differ significantly in terms of their function from the rest of the pancreas, the so-called exocrine pancreas . The job of the exocrine tissue of the pancreas is to produce digestive enzymes .

Indications for a transplant

Main article: Diabetes mellitus

The aim of islet cell transplantation is to restore physiological insulin production in diabetic patients. A loss of the body's own insulin production is known as an absolute insulin deficiency and can have various causes.

Type 1 diabetes, which affects around 90 percent of primarily insulin-dependent diabetics, is due to the autoimmunological destruction of beta cells. In type 2 diabetes, on the other hand, there are two different mechanisms for the existence of insulin dependence, depending on the duration of the disease. On the one hand, if there is sufficient or even increased insulin production by the body's beta cells, the response of the body cells to the insulin may be reduced. This condition is referred to as insulin resistance or relative insulin deficiency and is not an indication for islet cell transplantation. In the late phase of type 2 diabetes, the beta cells can also be destroyed, probably due to chronic overload as a result of prolonged elevated levels Insulin production. As in type 1 diabetes, this results in an absolute insulin deficiency, for the treatment of which an islet cell transplantation is fundamentally an option under certain conditions.

The exocrine part of the pancreas is not affected by the disease in diabetics and is therefore usually healthy. A sole transplant of the islets is therefore a possible alternative to transferring a complete pancreas for the treatment of insulin-dependent diabetes mellitus. Islet cell transplantation is also an option for non-diabetic patients who have to have their pancreas removed due to severe inflammation of the exocrine part ( pancreatitis ). By implanting the body's own islets, the inevitable development of a diabetic metabolic situation could be reversed.

In current practice, the main target groups for islet cell transplantation are diabetic patients with kidney failure requiring dialysis and diabetics who have already received a kidney transplant, as well as patients with unstable diabetes with frequent severe hypoglycaemia or with a decreased awareness of hypoglycaemia symptoms. In principle, an islet cell transplant would be an option for all patients with an absolute insulin deficiency. The current exclusion criteria, such as those laid down in the Giessen Protocol, restrict the selection of patients to a small group of type 1 diabetics. These contraindications include, for example, an age of less than 18 or more than 65 years, an age of onset after the age of 35, a diabetes duration of less than 10 years and the presence of obesity or insulin resistance.

Practical aspects

Performing the transplant

Schematic representation of the process of an islet cell transplant (Illustration: Giovanni Maki)

Various standardized regulations have been established for the extraction and implantation of the islands and have been optimized over the years, for example the Edmonton Protocol or the Giessen Protocol. First, it is necessary to isolate the islets from the donor's pancreas, a process that takes four to six hours in total. To do this, the pancreatic tissue is enzymatically digested using collagenase . The islands are then separated off by density gradient centrifugation . In the past, the islets were regenerated by cultivating them in a cell culture mixture for a certain period of time , but this step is omitted in more recent protocols.

The actual implantation, which is carried out by means of interventional radiology and takes less than an hour if it is as planned, is carried out in a minimally invasive manner under local anesthesia by injection into the portal vein of the liver. During the infusion of the islets in around 200 milliliters of medium, the pressure in the portal vein is monitored in order to detect a thrombosis in the vascular system of the liver caused by the islets and, if necessary, to end the transplant prematurely. With the bloodstream , the islets are distributed in the liver vessels and remain there. The liver has so far proven to be superior to other implantation sites, especially with regard to the supply of nutrients and the reaction to blood sugar levels. So far, at least 6,000 islets have been transplanted per kilogram of body weight. With the introduction of the Edmonton Protocol, a number of 10,000 islands has become the standard. So-called island equivalents are assumed, i.e. an average diameter of 150 micrometers.

The implantation would in principle be possible on an outpatient basis . As things stand, however, a hospital stay of seven to ten days follows in order to monitor and research the immediate effects. In the period immediately after the transplantation, conventional insulin therapy is initially carried out in order to put as little stress on the islets as possible during the growing-in phase. As is usual with other organ transplants, in islet cell transplants the recipient and donor are selected according to specific tissue characteristics in order to achieve the greatest possible match. Until 1999, islet cell transplants were carried out in almost all cases in combination with a kidney transplant , either as a simultaneous transplant of the islet cells and the kidney or after a previous kidney transplant. Since 1999, the proportion of transplants without an accompanying kidney transplant has increased significantly.

Advantages and benefits

Compared to transplanting a complete pancreas, islet cell transplantation has two major advantages.

On the one hand, due to the minimally invasive injection technique, the method is methodologically much easier to carry out than a pancreas transplant . The surgical effort and the risk of certain surgical complications are significantly lower because, for example, no blood vessels and no ducts have to be connected between the body and the new organ, as is the case with the transfer of a complete pancreas. If islets are implanted alone without an accompanying kidney transplant, the abdominal cavity will not be opened. Most importantly, this reduces the risk of serious bleeding and infection . Multiple treatments in the event of a loss of function of the islets, as well as a stepped implantation for optimal adjustment of the number of islets, are comparatively easy.

Another advantage over pancreas transplantation is that islet cell transplantation only replaces tissue that no longer functions adequately. The amount of exogenous tissue and thus also the probability of the occurrence of corresponding immunological complications is thus reduced. The patient's exocrine pancreatic tissue is not affected by a possible failure of the islet implant due to a rejection reaction , whereas if a complete pancreas is rejected, its exocrine function would also be lost. The so-called transplant pancreatitis (English graft pancreatitis ) does not apply to an islet cell transplant. This is an inflammation of the exocrine tissue of a transplanted pancreas, which occurs in almost all patients in a temporary and mild form. In around 10 to 15 percent of those affected, however, there is more severe, longer-lasting or repeated inflammation, which can also lead to a loss of function.

If successful, an islet cell transplant leads to the complete liberation of the patient from the need for external insulin and constant blood sugar control. In addition, a significant reduction in insulin requirements and the frequency of occurrence of metabolic complications are rated as partial success. The main advantage compared to treatment with regular blood sugar measurements and the supply of insulin based on this is that the insulin supply by the implanted islets and the resulting blood sugar regulation essentially corresponds to the function of the body's own islets in a healthy pancreas.

Disadvantages and side effects

3D structure of rapamycin (sirolimus), one of the immunosuppressive drugs currently used after an islet cell transplant

The main disadvantage of islet cell transplantation, as with all organ transplants, is the need to permanently suppress the rejection reaction that the body's immune system emits against the exogenous tissue. To do this, patients have to regularly take so-called immunosuppressants , i.e. drugs that weaken the immune response. The immunosuppressive treatment increases the susceptibility to infections and the risk of certain cancers in the medium and long term . Experience so far has shown that a further disadvantage is that in most cases, with the currently available immunosuppressants, it is not possible to completely suppress the autoimmune process that led to the destruction of the body's own islets. In addition, some established immunosuppressants, such as steroids , rapamycin and calcineurin inhibitors such as tacrolimus or ciclosporin , impair the function of the islets or the effect of the insulin. This effect, known as post-transplant diabetes mellitus , is also known from other organ transplants and, depending on the active ingredient, is based on a reduction in the release of insulin from the beta cells, an increase in insulin resistance , an increase in the apoptosis rate of the beta cells, direct toxicity on the islet cells or a combination of these effects. In addition, negative side effects on the kidneys are known for these drugs, which limit the applicability of islet cell transplantation in patients with intact kidney function.

From a methodological point of view, the yield of islets is not optimal with the current isolation protocols. Usually two to three pancreases are needed to obtain the number of islets necessary for an islet cell transplant. In only a few cases has it been possible to date to ensure that patients are insulin-free after islets have been transplanted from a single donor organ. Since, for various reasons, comparatively few pancreatic transplants are performed, this does not currently lead to restrictions in the availability of donor organs. However, this problem stands in the way of a larger application of islet cell transplantation.

Due to the small number of islet cell transplants carried out worldwide to date, there are still no reliable findings on the long-term effects and therapeutic benefits. This relates in particular to the question of whether the transplantation extends the patient's life or reduces the frequency and severity of late-stage diabetic complications, and whether the potential therapeutic benefits justify the risks and side effects associated with immunosuppressive therapy. The question of the extent to which islet cell transplantation may have a negative effect on further organ transplantation has also not yet been clarified. In addition, there is insufficient information on the long-term effects on the patient's liver. The presence of the islands in the hepatic vessels results, for example, in an increased pressure in the portal vein and in the vascular system of the liver.

In addition to the specific risks of transplantation that result from immunosuppressive therapy, there are also risks associated with any surgical treatment with islet cell transplantation, such as unpredictable side effects of narcotics, wound infections and internal bleeding from injuries. Due to the minimally invasive implementation under local anesthesia, these risks are significantly lower than, for example, with a pancreas transplant, but would not exist with conventional lifelong treatment through external administration of insulin. There are cost-benefit analyzes of islet cell transplantation (e.g. Beckwith et al. 2012 and Wallner et al. 2016). The total cost of a transplant is estimated to be around $ 76,000 to $ 150,000, compared to an annual cost of about $ 3,500 per patient per year for intensive insulin therapy. So far, however, there is no experience with the costs of additional measures that are required that can result from both therapeutic options in long-term use, such as for the treatment of late diabetic complications.

Historical information and outlook

Medical history of islet cell transplantation

The first experimental transfer of pancreatic tissue was presented on December 18, 1891 by Oskar Minkowski in a lecture. He had transplanted fragments of the pancreas under the skin of the abdomen in a dog that had become diabetic after the removal of the pancreas. As early as December 20, 1893, the doctor Patrick Watson-Williams, together with a colleague at the Royal Infirmary Hospital in Bristol, tried a corresponding operation on a person for the first time. To do this, they transplanted three pieces of a pancreas from a freshly slaughtered sheep to a 15-year-old boy with type 1 diabetes. Despite a temporary improvement in the diabetic symptoms, the boy died a few days later, probably due to the hyperacute rejection of the animal tissue and thus the loss of its function. The first successful human pancreas transplant was performed in 1966 by Richard Lillehei at the University of Minnesota. In terms of the possible benefit, however, clinical application of the method initially proved to be unacceptable in less than three percent of patients due to a mortality of around 60 percent and a function of the transplant after one year, so that further research was carried out in the following period. Until about 1990 pancreatic transplantation was considered an experimental therapy. Since then, it has also been performed in clinical practice under certain conditions, although not as frequently as other organ transplants . As was the case with islet cell transplantation until 1999, in most cases it is carried out in combination with a kidney transfer; 75 percent take place in parallel with a kidney transplant and 15 percent afterwards.

Following successes with islet transplantation in experimental studies on rats in the early 1970s, it was assumed that islet cell transplantation would replace pancreas transplantation in clinical practice in the near future. These results were made possible by the development of a method for the effective isolation of the islets from the pancreatic tissue in 1967, which was improved by various scientists in the following years. The first successful islet cell transplantation in rats was carried out in 1972. One year later, it was shown that implantation in the vasculature of the liver was advantageous over transplantation in the abdominal cavity. The first clinical studies began as early as 1974, but none of the patients achieved the goal of independence from externally supplied insulin. In 1977 in Minneapolis, so-called allogeneic transplants of autologous islets were carried out for the first time in patients whose pancreas had been removed due to severe pancreatitis. The treatment prevented diabetes mellitus from occurring. In 1990, the effectiveness of allografting after therapeutic removal of the pancreas was demonstrated in a successful clinical series in Pittsburgh. The success rate of this treatment is around 70 percent, the long-term function of the transplant and thus the absence of insulin is more than 20 years in some patients.

Another important milestone on the way to clinical application for the treatment of diabetes mellitus was the development of a method for the automated isolation of human islets in 1986. The first successful islet cell transplant in a diabetic patient was performed four years later at Washington University Medical Center in St. Louis. On November 26, 1992, the first successful transplant in the area of Eurotransplant was carried out at the University of Giessen . Seven years later, the Edmonton Protocol introduced a new treatment strategy, the effectiveness and superiority of which was demonstrated by seven consecutive successful transplants in 2000, in which all patients were insulin-free for at least one year. As a result of the improvements associated with the Edmonton Protocol, the proportion of patients who could manage without external insulin administration one year after transplantation rose from around eight percent to around 50 percent in those treated after 1999. The increase in the yield and thus the number of implanted islets due to the new protocol as well as the waiver of certain immunosuppressants through the use of a combination of tacrolimus and sirolimus as well as the temporary use of the therapeutic antibody daclizumab immediately after the transplantation contributed in particular to this . The first islet cell transplant based on a living donation, in which islets were transferred to a 27-year-old female patient from her healthy 56-year-old mother, was performed on January 19, 2005 at Kyoto University Hospital.

Statistics and research

Human embryonic stem cells, the use of which may be an alternative to islet cell transplantation

At the University of Giessen there has been an international register for islet cell transplants ( International Islet Transplant Registry , ITR) since the beginning of the 1990s . Around 95 percent of all transplants carried out worldwide are reported to this. According to these data, 583 islet cell transplants were performed worldwide from 1974 to August 2002. Of these, 493, or around 85 percent, took place after 1990; the number rose from 27 in 1990 to 69 in 2002. The one-year survival rate of the patients was 96 percent. In around 40 percent of the cases, the function of the transplanted islets was still detectable after one year, and the goal of insulin independence was achieved in around every fourth patient. The longest recorded case of being insulin-free was six years in 2003.

With the introduction of the Edmonton Protocol in 1999, there was a significant increase in the number of transplants. In North America alone, a total of 593 islet cell transplants were performed with 319 patients between 1999 and 2005, including more than 100 transplants per year since 2002. The number of active centers that perform at least one transplant per year has also increased significantly, to 31 in North America during that period. Another trend is that the proportion of patients with first islet cell transplants is increasing and has been around half of all recorded cases since 2003. The number of transplants without an accompanying kidney transplant has also risen to around 89 percent. In addition to Giessen, the leading centers in Europe for this method include Milan and Geneva , in the USA Minneapolis , Miami , Pittsburgh and St. Louis and in Canada Edmonton .

However, most patients are no longer insulin-free five years after the transplant. In around 80 percent of those treated, however, the islets still have residual function after this time, which at least results in an improved blood sugar control with a reduced occurrence of hypoglycaemia. The main reasons for the so far only limited success of islet cell transplantation are probably mainly in chronic rejection reactions and the recurrence of the autoimmunity which is responsible for the destruction of the body's own islets. In addition, the effects of immunosuppressants on the islands also play a role as well as increasing exhaustion of the islands. This effect occurs because as the islands die off, the remaining beta cells become more and more stressed.

Research to optimize islet cell transplantation is therefore focused on several areas. On the one hand, attempts are being made to improve the isolation yield and to achieve a ratio of “one donor organ, one recipient” in order to be able to transplant more islets in this way. In addition to the liver, other implantation sites are being investigated for their suitability and possible advantages, in particular with regard to shielding against immunological reactions and thus the long-term survival of the islets. By encapsulating the islands with various biomaterials , protection against rejection reactions and autoimmune processes should be achieved. Reducing the side effects of immunosuppressants by optimizing therapy and developing new, specific drugs is also an essential part of the research.

Possible alternatives to the transplantation of islets from donor organs, which are currently in the research stage, include the use of animal islets as part of a so-called xenotransplantation or the transplantation of stem cells or beta cells grown from stem cells. In addition, the stimulation of the regeneration of beta cells in the patient's pancreas and the genetic manipulation of the patient's own liver cells to stimulate the production, storage and blood sugar-controlled release of insulin (so-called PDX-1 liver cells) are also being investigated . An animal model used for methodological reasons for certain research aspects is the use of island tissue from fish , as this is available in compact form in the form of the so-called Brockmann bodies and is therefore easy to isolate.

Individual evidence

  1. Alp Sener, Matthew Cooper, Stephen Bartlett: Is There a Role for Pancreas Transplantation in Type 2 Diabetes Mellitus? In: transplant . 90 (2) / 2010, pp. 121–123
  2. Reinhard Bretzel, Daniel Brandhorst, Heide Brandhorst, Michael Eckhard, Wolfgang Ernst, Schirin Friemann, Wigbert Rau, Bernd Weimar, Klaus Rauber, Bernhard Hering, Mathias Brendel: Improved Survival of Intraportal Pancreatic Islet Cell Allografts in Patients with Type-1 Diabetes Mellitus by Refined Peritransplant Management. In: Journal of Molecular Medicine . 77, 1999, pp. 140-143.
  3. a b A.M. James Shapiro, Jonathan RT Lakey, Edmond Ryan, Gregory Korbutt, Ellen Toth, Garth Warnock, Norman Kneteman, Ray Rajotte: Islet Transplantation in seven Patients with Type 1 Diabetes Mellitus using a Glucocorticoid-Free Immunosuppressive Regimen. In: The New England Journal of Medicine 343 (4) / 2000. Massachusetts Medical Society, pp. 230-238, ISSN  0028-4793
  4. ^ A b Elisa Cantarelli, Lorenzo Piemonti: Alternative Transplantation Sites for Pancreatic Islet Grafts. In: Current Diabetes Reports. 11 (5) / 2011. Springer, pp. 364-374, ISSN  1534-4827
  5. Cinzia Labruzzo, Adil R. El Tayar, Nadey Hakim: Graft Pancreatitis: Literature Review. In: International Surgery. 91 (2) / 2006. Minerva Medica, pp. 107-111, ISSN  0020-8868
  6. a b c d Mark Naftanel, David Harlan: Pancreatic Islet Transplantation. In: PLoS Medicine 1 (3) / 2004. The Public Library of Science, pp. E58ff., ISSN  1549-1277
  7. George W. Burke III, Francesco Vendrame, Antonello Pileggi, Gaetano Ciancio, Helena Reijonen, Alberto Pugliese: Recurrence of Autoimmunity Following Pancreas Transplantation. In: Current Diabetes Reports. 11 (5) / 2011. Springer, pp. 413-419, ISSN  1534-4827
  8. Alfred Penfornis, Stéphanie Kury-Paulin: Immunosuppressive Drug-Induced Diabetes. In: Diabetes & Metabolism. 32 (5) / 2006. Masson, pp. 539-546 ISSN  1262-3636
  9. a b Shaheed Merani, AM James Shapiro: Current Status of Pancreatic Islet Transplantation. In: Clinical Science. 110/2006. Portland Press, pp. 611-625, ISSN  0143-5221
  10. ^ Oskar Minkowski: Further information on diabetes mellitus after extirpation of the pancreas. In: Berliner Klinische Wochenschrift. 29/1892, pp. 90-94
  11. Patrick Watson-Williams: Notes on Diabetes Treated with Extract and by Grafts of Sheep's Pancreas. In: British Medical Journal 2/1894, p. 1303
  12. ^ William Kelly, Richard Lillehei, Fred Merkel, Yasumo Idezuki, Frederik Goetz: Allotransplantation of the Pancreas and Duodenum along with the Kidney in Diabetic Nephropathy. In: Surgery. 61 (6) / 1967. Elsevier, pp. 827-837, ISSN  0039-6060
  13. Paul Lacy, Mery Kostianovsky: Method for the Isolation of Intact Islets of Langerhans from the Rat Pancreas. In: Diabetes. 16/1967. American Diabetes Association , pp. 35-39, ISSN  0012-1797
  14. ^ Walter Ballinger, Paul Lacy: Transplantation of Intact Pancreatic Islets in Rats. In: Surgery. 72 (2) / 1972. Elsevier, pp. 175-186, ISSN  0039-6060
  15. Camillo Ricordi, Paul Lacy, Edward Finke, Barbara Olack, David Scharp: Automated Method for Isolation of Human Pancreatic Islets. In: Diabetes. 37/198. American Diabetes Association , pp. 413-420, ISSN  0012-1797
  16. David Scharp, Paul Lacy, Julio Santiago, Christopher McCullough, Lamont Weide, Luca Falqui, Piero Marchetti, Ronald Gingerich, Allan Jaffe, Philip Cryer, Charles Anderson, M. Wayne Flye: Insulin Independence After Islet Transplantation into Type I Diabetic Patient. In: Diabetes. 39 / (4) / 1990. American Diabetes Association , pp. 515-518, ISSN  0012-1797
  17. Shinichi Matsumoto, Teru Okitsu, Yasuhiro Iwanaga, Hirofumi Noguchi, Hideo Nagata, Yukihide Yonekawa, Yuichiro Yamada, Yusuke Nakai, Michiko Ueda, Akemi Ishii, Emi Yabunaka, AM James Shapiro, Koichi Tanaka: Insulin Single Living of Independence After Unstable Patient Donor Islet Transplant. In: Transplantation Proceedings. 37 (8 )/2005. Elsevier Science, pp. 3427-3429, ISSN  0041-1345
  18. ^ ITR - International Islet Transplant Registry; WWW: http://www.med.uni-giessen.de/itr/
  19. CITR - Collaborative Islet Transplant Registry of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); WWW: http://www.citregistry.org/
  20. Emily Alexander, Kent Dooley, Bill Pohajdak, Bao-You Xu, James Wright Jr .: Things We Have Learned From Tilapia Islet Xenotransplantation. In: General and Comparative Endocrinology. 148 (2) / 2006. Elsevier, pp. 125-131, ISSN  0016-6480

literature

  • Nadey Hakim, Robert Stratta, Derek Gray: Pancreas and Islet Transplantation. Oxford University Press, Oxford and New York 2002, ISBN 0-19-263255-8
  • Jonathan Lakey, Mohammadreza Mirbolooki, AM James Shapiro: Current Status of Clinical Islet Cell Transplantation. In: Transplantation Immunology - Methods and Protocols. Series: Methods in Molecular Biology. Volume 333/2006. Humana Press, pp. 47-104, ISBN 1-58-829544-3
  • Richard Downing: Historical Review of Pancreatic Islet Transplantation In: World Journal of Surgery . 8/1984. Société Internationale de Chirurgie, pp. 137-142, ISSN  0364-2313
  • Mark Naftanel, David Harlan: Pancreatic Islet Transplantation. In: PLoS Medicine 1 (3) / 2004. The Public Library of Science, pp. E58ff., ISSN  1549-1277
  • AN Balamurugan, Rita Bottino, Nick Giannoukakis, Cynthia Smetanka: Prospective and Challenges of Islet Transplantation for the Therapy of Autoimmune Diabetes. In: pancreas. 32 (2) / 2006. Lippincott Williams & Wilkins, pp. 231-243, ISSN  0885-3177

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This article was added to the list of excellent articles on September 23, 2007 in this version .