Human Islet Autotransplantation: The Trail Thus Far and the Highway ...

Chapter 31

Human Islet Autotransplantation: The Trail Thus Far and the Highway Ahead Martin Hermann, Raimund Margreiter, and Paul Hengster

Abstract Human islet transplantation is one of the three treatment modalities besides the daily administration of exogenous insulin and pancreas transplantation, which can be applied for the treatment of type 1 diabetic patients. Although the metabolic control achieved after islet transplantation is superior compared to exogenous insulin administration, many hurdles remain to be overcome before islet transplantation can be called a routine therapy for type 1 diabetic patients. In contrast to many other therapeutic approaches, proof of principle has been obtained for islet transplantation: As demonstrated in islet autotransplantation, the transplanted islets are not only able to survive in another organ, namely the liver, but also able to retain their functional role, in some patients even for decades. The main challenge for islet allotransplantation is, therefore, to imitate this success, thereby providing type 1 diabetic patients with a cellular therapy lasting for decades and thus circumventing the daily injections of insulin. Keywords Allotransplantation · Pancreatitis · Total pancreatectomy · Pancreatectomy · Islet shipment · Real time live confocal microscopy · Chronic pancreatitis · Autotransplantation · Human islet allotransplantation · Human islet autotransplantation · Type I diabetes

31.1 Introduction Type 1 diabetes is a chronic, progressive autoimmune disease resulting from the immune-mediated destruction of the insulin-producing β-cells within the pancreatic islets. One treatment option for such patients aims at replacing the β-cells through islet transplantation.

M. Hermann (B) Department of Visceral-, Transplant- and Thoracic Surgery, KMT-Laboratory, Center of Operative Medicine, Innsbruck Medical University, A-6020 Innsbruck, Austria e-mail: [email protected] M.S. Islam (ed.), The Islets of Langerhans, Advances in Experimental Medicine and Biology 654, DOI 10.1007/978-90-481-3271-3_31, C Springer Science+Business Media B.V. 2010

711

712

M. Hermann et al.

In spite of the numerous advances in islet cell transplantation [1, 2], its transition from the stage of clinical investigation to routine clinical routine is still hindered by several yet unresolved issues [3-5]. While short-term results have been very promising, with 82% of patients maintaining insulin independence at 1 year after islet allotransplantation, long-term results show a decline in the proportion of recipients maintaining insulin independence after the first year posttransplant [1, 4]. While the 5-year post-islet transplantation graft survival is approximately 80% (as measured by C-peptide positivity), insulin independence shows a much lower rate, close to 10%, after 5 years [4]. Although the reasons for this functional decline still remain unclear, several factors can be causally linked to this deterioration ranging from alloimmune rejection, autoimmune recurrence, toxicity of immunosuppressive medications, to the inhospitability of the liver itself as a site of implantation. However, the latter possibility is challenged by the already verified long-term function of islets after autotransplantation [6, 7].

31.2 Total Pancreatectomy in Combination with Islet Autotransplantation Chronic pancreatitis (CP) is a progressive inflammatory disease causing irreversible structural damage to the pancreatic parenchyma. Besides affecting the pancreatic exocrine function, in severe cases, the endocrine function may also be impaired leading to the onset of diabetes mellitus [8]. As in many patients CP is clinically silent, its prevalence can only be estimated, and ranges from 0.4 to 5% before the onset of clinically apparent disease. Besides heavy consumption of alcohol (150–170 g/day), pancreatic obstructions such as post-traumatic ductal strictures, pseudocysts, mechanical or structural changes of the pancreatic-duct sphincter and periampullary tumours may result in chronic pancreatitis. Of high importance is the recent recognition of a set of genetic mutations such as the loss of function mutations of pancreatic secretory trypsin inhibitor (SPINK1), which were shown to be present in CP cases that previously had been considered idiopathic (for review see [9]). Also, Sphincter of Oddi dysfunction (SOD) has increasingly been recognized as being present in CP [10]. Due to the progress in imaging techniques such as endoscopic retrograde cholangiopancreatography, magnetic resonance imaging and cross-sectional imaging, we now have a better understanding of the pathophysiology and origin of inflammation and pain in CP. Nevertheless, chronic pancreatitis still remains an inscrutable process of uncertain pathogenesis, unpredictable clinical course and difficult treatment [8, 11]. Chronic pancreatitis is associated with a mortality rate that approaches 50% within 20–25 years. Approximately 15–20% of patients die of complications associated with acute attacks of pancreatitis [8]. Complications such as biliary or duodenal stenosis, as well as intractable pain, are the current indications for surgery in patients with CP. Surgical drainage of the duct in CP has largely been replaced by endoscopic duct drainage procedures of sphincterotomy and stent placement in the duct. Patients with CP whose pain persists after endoscopic pancreatic duct drainage are candidates for total pancreatectomy and islet autotransplantation (IAT) [12].

31

Human Islet Autotransplantation

713

In the Cincinnati series of total pancreatectomy in combination with simultaneous IAT, unremitting abdominal pain refractory to high dose narcotics was the indication for surgery [13, 14]. Narcotic independence due to pain relief after total pancreatectomy and islet autotransplantation was achieved in 58–81% of the patients [6, 13]. Interestingly, in a recently performed retrospective survey, more than 95% of the patients stated they would recommend total pancreatectomy in combination with islet autotransplantation [6]. Mortality as well as morbidity associated with pancreatic resections in patients suffering from chronic pancreatitis was shown to be very low and normally leads to adequate pain control in the majority of CP patients. One drawback of surgical resection is the development of exo- and endocrine insufficiencies. Therefore, surgical resection of the pancreas is considered as a final option in the treatment of CP. Nevertheless, the addition of an islet autotransplant offers the possibility of a postoperative glucose control and should therefore always be a considerable option. Besides being applicable to prevent surgical diabetes after extensive pancreatic resection for chronic pancreatitis, islet autotransplantation is additionally pertinent in benign tumours located at the neck of the pancreas. Even without pancreatic inflammation, extensive pancreatic resection of more than 70% of the pancreas may cause diabetes [15]. Islet autotransplantation, after extended pancreatectomy performed for the resection of benign tumours of the mid-segment of the pancreas, was shown to be a feasible option with excellent metabolic results and low morbidity. Due to the noninflammatory nature of the pancreata, higher islet yields and, consequently, higher transplanted islet masses were achieved compared to those from organs resected for chronic pancreatitis. At a median follow-up of 5 years (range, 1–8 years), all patients (n = 7) had β-cell function as assessed by a positive C-peptide level. Six out of the seven patients were insulin independent [16]. Pivotal for such an approach is the unequivocal diagnosis of the benign nature of the tumour, before making the decision to perform the isolation and transplantation procedure. The first total pancreatectomy in combination with islet autotransplantation to treat chronic pancreatitis (CP) in humans was performed 30 years ago at the University of Minnesota [5]. Besides aiming to relieve the pain of the CP patient in whom other measures had failed, the additional goal was to preserve β-cell mass and insulin secretion in order to avoid the otherwise inevitable surgical diabetes. Since then, more than 300 islet autotransplantations have been performed and reported worldwide, most of them at the University of Minnesota. With a few exceptions, the intraportal site has been predominantly applied as an implantation site for the transplanted islets [6, 19]. Since 1990 the results of autologous islet transplantation have been reported to the International Islet Transplant Registry (ITR) in Giessen, Germany [20]. Combined pancreatectomy and islet autotransplantation can be performed in adults, as well as in paediatric patients. For both patient populations, the procedures are identical and described in detail elsewhere [19, 21, 22]. Performing islet autotransplantations provides the possibility to compare the metabolic outcomes between islet autografts and islet allografts, the latter still being subject to declining function with time [1]. Besides, and prior to, the outstanding results from the Edmonton study fuelling the whole field of islet transplantation with new energy,

714

M. Hermann et al.

the “Minnesota islet autotransplantation” provided the pivotal biological “proof of principle” for the feasibility of a long-lasting successful glucose control after islet transplantation. Islet allotransplantation shows a 5-year post-islet transplantation graft survival of approximately 80% and an insulin independence around 10% at 5 years [4]. Differences in the success of allogeneic islet transplantation among different centres illustrate the complexity of the procedure [1]. Therefore the ultimate goal, defined by insulin independence in the long term being achieved on a regular basis, has still not been achieved. Notably, the results from islet autotransplantation obtained so far clearly show that long-term insulin independence after islet transplantation is a goal which can be realized, although also here, not on a regular basis [6, 23, 24]. In a recently published study, the outcomes of islet function over time were compared between intraportal islet autotransplant recipients at the University of Minnesota and diabetic islet allograft recipients as reported by the Collaborative Islet Transplant Registry (CITR). With regard to insulin independence, 74% of islet autotransplant recipients retained insulin independence at 2 years posttransplant vs. only 45% of the CITR allograft recipients who initially became insulin independent. Notably, 46% of the islet autotransplant patients were still insulin independent at 5 years and 28% at 10 years posttransplant [25].

31.3 What Can/Did We Learn from Islet Autotransplantations? Three metabolic states were described in patients after islet autotransplantations: One-third of islet autotransplantation in the University of Minnesota series were long-term insulin independent, another third of the recipients became fully diabetic and the last third achieved near normoglycaemia and were therefore partially insulin independent requiring only one daily injection of insulin (Fig. 31.1a) [6].

Fig. 31.1a Schematic representation of the three metabolic states described in patients after islet autotransplantations. One-third of islet autotransplantation in the University of Minnesota series were insulin independent in the long term, another third of the recipients became fully diabetic and the last third achieved near normoglycaemia and were therefore partially insulin independent requiring only one injection of insulin daily [6]

31


715

Fig. 31.1b In contrast to islet autografts, islet allografts are subject to several additional cell stress conditions. Brain death [26], longer cold ischaemia times before islet isolation from the donor pancreas [63], the patients’ alloimmune response to the donor tissue, the autoimmunity against β-cells [29, 30] and the diabetogenic effect of the immunosuppressive medications [64] are the main reasons limiting long-term success of islet allotransplantation. Obviously the transport of the pancreas to the islet procurement center and the need for immunosuppression are the two main reasons limiting long-term success of islet allotransplantation

A remarkable result when comparing islet allo- with islet autotransplantation is the generally higher long-term success rate of the latter [4, 24]. There are at least three known causes (Fig. 31.1b) for organ/cell stress which are present in islet allotransplantation but not in autotransplantation, thereby possibly explaining the better long-term success rates of the latter: 1. Brain death: In islet allotransplantation, the organ is obtained from brain-dead patients. In animal models, brain death was shown to negatively affect islet yield as well as function due to the activation of pro-inflammatory cytokines [26]. 2. Ischaemia: In islet autotransplantation, the organ is not subjected to prolonged cold ischaemia times which are normally present in islet allotransplantation due to the transport of the organ to the islet procurement centre. Such cold ischaemia times are known to damage the organ and impair cell viability, as well as function [27]. 3. Immunosuppression: Besides ischaemia-associated organ damage, the need for immunosuppression in islet allotransplantation is the third major limiting cause in the long-term success of islet allotransplantation [27]. In human islet allotransplantation, immunosuppressive regimens are implemented in order to cope with both auto- as well as alloimmunity after transplantation. However, many of the immunosuppressive drugs are known to be directly β-cell toxic. Using a transgenic mouse model for conditional ablation of pancreatic β-cells in vivo, Nir and co-workers elegantly demonstrated that β-cells have a significant regenerative capacity which is prevented by the addition of the

716

M. Hermann et al.

immunosuppressant drugs Sirolimus and Tracrolimus [28]. As shown in humans, up to 15% of nondiabetic patients who received solid organ transplantation were shown to develop posttransplant diabetes as a result of calcineurin inhibitor therapy (i.e. tacrolimus) [27]. Therefore, the declining function of β-cells after human allotransplantation may also be explained by the inhibition of β-cell turnover due to the administration of immunosuppressive drugs [3]. Allograft rejection and recurrent autoimmunity, both conditions not present in islet autotransplant recipients, may additionally contribute to the decreasing insulin independence over time observed in the allogeneic setting [29, 30]. Recently it was shown that immunosuppression with FK506 and rapamycin after islet transplantation in patients with autoimmune diabetes induced homeostatic cytokines that expand autoreactive memory T cells. It was therefore proposed that such an increased production of cytokines might contribute to recurrent autoimmunity in transplanted patients with autoimmune disease, and that a therapy that prevents the expansion of autoreactive T cells will improve the outcome of islet allotransplantation [30]. Another recently published study reports that cellular islet autoimmunity associates with the clinical outcome of islet allotransplantation. In this study, 21 type 1 diabetic patients received islet grafts prepared from multiple donors, while immunosuppression was maintained by means of anti-thymocyte globulin (ATG) induction, tacrolimus and mycophenolate treatment. Immunity against auto- and alloantigens was measured before and during 1 year after transplantation. Interestingly, cellular autoimmunity before and after transplantation was shown to be associated with delayed insulin independence and lower circulating C-peptide levels during the first year after islet allotransplantation. While seven out of eight patients without pre-existent T-cell autoreactivity became insulin independent, none of the four patients reactive to both islet autoantigens GAD and IA-2 achieved insulin independence. Consequently, tailored immunotherapy regimens targeting cellular islet autoreactivity may be required [29]. An additional explanation for the lack of long-term insulin independence after islet transplantation was suggested to be the detrimental effect of hyperglycaemia on β-cell physiology. As shown in mice, increased apoptosis and reduced β-cell mass were found in islets exposed to chronic hyperglycaemia [31]. Consequently, both (auto- as well as allo-) human islet recipients usually receive insulin early on to maintain euglycaemia as much as possible. However, no study in humans has been performed so far comparing islet engraftment with and without this measure.

31.4 Still Open Issues in Islet Autotransplantation 31.4.1 Islet Mass The timing of the pancreatectomy and simultaneous islet allotransplantation has a direct impact on islet yield. The highest islet yields and insulin independence can

31


717

be achieved when the islet autotransplantation is performed earlier in the disease course of CP [14, 32]. Interestingly, while most groups see a correlation between insulin-free status and IEQ transplanted [33], there are exceptions: One patient who received only 954 IEQ/kg remained insulin free even 4 years after transplantation [7, 34]. Considering the scarcity of available organs, such results are a crucial proof of principle showing that even very low amounts of transplanted islets may be sufficient to provide long-term insulin independence. One of the central goals for the future will be to rationalize the diversity in insulin-dependence response observed in patients. Elucidating the causes for such differences might enable us to design new therapeutic strategies, thereby allowing the successful engraftment and function of even low amounts of islets. Interestingly islet autografts show durable function and, once established, are associated with a persisting high rate of insulin independence, although the β-cell mass transplanted is lesser than that used for islet allografts [25]. Evaluating and comparing the different outcomes after islet allo- vs. autotransplantations may help clarify the extent to which different stress parameters account for islet damage resulting in limited success rates of islet allotransplantation. There are several causes for cellular stress in islet autotransplantation.

31.4.2 Islet Shipment Exposure of islets to a series of damaging physicochemical stresses already during explantation of the pancreas may amplify the damage caused during cold storage as well as the following islet isolation procedure. There is consensus among the major islet transplantation centres that islet yields and quality can be improved with better pancreas procurement techniques such as in situ regional organ cooling which protects the pancreas from warm ischaemic injury (for review see [35]). In addition, the development of more sophisticated pancreas preservation protocols promises to translate into an improved islet yield as well as quality. While pancreatectomy can be performed at most hospitals, only a few centres are able to perform islet isolations. Therefore human islet autotransplantation is often limited due to the absence of an on-site islet processing facility. The setup of an islet isolation facility, designed according to the rules of good manufacturing practice, is a technically challenging, cost and time-intensive process [36, 37]. Consequently, several institutions have decided to perform transplantation of islets isolated at another centre with already established expertise. Such an “outsourcing solution” was shown to be applicable not only in human islet allotransplantation [37–39] but also in human islet autotransplantation [40, 41]. In the latter, the resected pancreata were transferred to an islet processing laboratory, which then sent back the freshly isolated islets that were transplanted into the same patient. All five patients experienced complete relief from pancreatic pain and three of the five patients had minimal or no insulin requirement, thereby demonstrating the feasibility of islet shipment for autotransplantation (median follow-up of 23 months) [41].

718

M. Hermann et al.

Although practicability as well as feasibility of islet transportation has already been proven, many questions such as the one addressing the optimal transport conditions for islets remain to be answered. While there is a worldwide consensus of how to isolate islets under GMP conditions, this is not the case for the transport of the freshly isolated islets. Many different media and transport devices have been used, ranging from 50 ml flasks, syringes and gas permeable bags [38]. Other solutions such as rotary devices avoiding detrimental cell compaction [42] may be an alternative, especially when vitality parameters such as temperature, pH or oxygen concentration are actively controlled [43]. Determining the optimal conditions for the transport of islets promises to yield better islet quality after the transport of islets and consequently an improved transplantation outcome. In addition, a gain of knowledge concerning the issues addressing the regeneration potential of freshly isolated islets may help not only to avoid unnecessary additional cellular stress but also to counterbalance it in a pre-emptive way. In this context, the topic of islet quality assessment has to be mentioned: Similar to the transport conditions of human islets, this issue remains a matter of debate. Predicting the outcome of islet transplantation is still not possible due to the lack of reliable markers of islet potency, which might potentially be used to screen human islet preparations prior to transplantation. According to these pre-transplant criteria, islet preparations that failed to reverse diabetes were indistinguishable from those that exhibited excellent function [38]. Therefore, one of the primary challenges also in islet autotransplantation is to identify and understand the changes taking place in islets after the isolation, culture and transport. Description of such changes in living islet cells offers insights not achievable by the use of fixed cell techniques. Combining real-time live confocal microscopy with three fluorescent dyes, dichlorodihydrofluorescein diacetate (DCF), tetramethylrhodamine methyl ester perchlorate (TMRM) and fluorescent wheat germ agglutinin (WGA), offers the possibility to assess overall oxidative stress, time-dependent mitochondrial membrane potentials and cell morphology [44, 45]. The advantage of such a method resides in the fast and accurate imaging at a cellular and even subcellular level. Taking into account the use of other fluorescent dyes which can be used to visualize additional cell viability parameters such as calcium concentrations (measured with rhod-2) or apoptosis (measured with annexin-V), such an approach promises to be of great value for a better future islet assessment, post-isolation, culture and/or transport.

31.4.3 Cell Death A significant proportion of the transplanted islet mass fails to engraft due to apoptotic cell death. Several strategies have been implemented to inhibit this process by blocking the extrinsic apoptosis inducing signals (cFLIP or A20), although only with limited impact. More recently, investigations of downstream apoptosis inhibitors that block the final common pathway (i.e. X-linked inhibitor of apoptosis protein [XIAP]) have shown promising results, in human [46–48] as well

31


719

as rodent [49] models of islet engraftment. XIAP-transduced human islets were significantly less apoptotic in an in vitro system that mimics hypoxia-induced injury. In addition, transplanting a series of marginal mass islet graft transplants in streptozotocin-induced diabetic NOD-RAG–/– mice resulted in 89% of the animals becoming normoglycaemic, with only 600 XIAP-transduced human islets [47]. Moreover, XIAP overexpression has been shown to prevent the diabetogenicity of the immunosuppressive drugs tacrolimus and sirolimus in vitro [48].

31.5 Which Are the Best Islets – Does Size Matter? In islet allo- as well as autotransplantation, it is still a matter of debate to define the features of an ideal islet able to ensure proper long-lasting glucose homeostasis after transplantation into the liver. The central question is whether bigger islets are better suited than smaller islets. In the early phase after transplantation, the islets are supplied with oxygen and nutrients only by diffusion. In addition, data obtained from rat islet transplantations have shown that, being in the portal vein, islets encounter a hypoxic state with an oxygen tension of 5 mmHg compared to 40 mmHg in the pancreas [50]. In a study determining whether the size of the islets could influence the success rates of islet transplantations in rats, the small islets (150 μm). The superiority of small islets was shown in vitro, via functional assays, as well as in vivo after transplanting them under the kidney capsule of diabetic rats. Using only marginal islet equivalencies for the renal subcapsular transplantation, large islets failed to produce euglycaemia in any recipient rat, whereas small islets were successful in 80% of the cases [51]. A recent study analysed the influence of islet size on insulin production in human islet transplantation. The results convincingly showed that small islets are superior to large islets with regard to in vitro insulin secretion and higher survival rates [52]. Therefore islet size seems to be of importance for the success of human islet transplantation, and at least regarding islets it might be stated that “Small is beautiful!” The question that remains to be answered is how to improve the transplantation outcome when using large islets. Besides applying measures that promote islet engraftment, such as the addition of the iron chelator deferoxamine which increases vascular endothelial growth factor expression [53], an alternative would be to customize large islets into small “pseudoislets” using the hanging drop technique [54].

31.6 The Role of the Surrounding Tissue: Site Matters! To what extent is the surrounding tissue necessary or beneficial for islet function? Besides the long-lasting functionality of autologous transplanted islets, there are at least two additional findings in islet autotransplantation that merit attention: the relatively low amounts of islets needed to achieve normoglycaemia and the impurity of transplanted islets.

720

M. Hermann et al.

In islet allotransplantation, about 850,000 islets, normally obtained from two to four pancreases, are needed to achieve insulin independence in a single type 1 diabetic patient. As a consequence, the available pool of pancreata for islet allotransplantation is limited and is therefore one of the foremost problems in islet transplantation. Interestingly islet autotransplantation has shown us that even low amounts of islets may result in long-lasting insulin independence [24, 55]. Due to extensive fibrosis, which is often present in pancreata of pancreatitis patients, the digestion process is incomplete. Theoretically, such an incomplete digestion might result in lower success rates after islet transplantation. Surprisingly, in a recent study, 8 of 12 patients who showed insulin independence after islet autotransplantation had less than 40% islet cleavage [7]. Therefore, a protective role of the tissue surrounding the islets might be postulated. Besides postulating such a protective role of the surrounding tissue, one could speculate that the digestion process may also lead to the loss of the basement membrane surrounding the islets [56] which might be detrimental as it is a well-recognized fact that the extracellular matrix provides the islets with biotrophic support [56-58]. Besides the innate surrounding tissue of the islets, the ectopic site into which the islets are implanted also seems to exert an influence on their biology: While autoislet β-cell biology can be normal (as shown by fasting glucose and haemoglobin A1c levels and intravenous glucose disappearance rates) for up to 13 years [24], there seem to be abnormalities in α-cell responsiveness to insulin-induced hypoglycaemia. Although responses from intrahepatically autotransplanted islets to intravenous arginine were shown to be present, their responsiveness to insulin-induced hypoglycaemia was absent [59]. Similar observations were also made in islet allotransplantation: Two normoglycaemic type 1 diabetic patients who had been successfully transplanted with alloislets into the liver also failed to secrete glucagon during hypoglycaemia [59]. These findings led to a study comparing the α-cell function between autoislets transplanted either in the liver or in the peritoneal cavity of dogs. As expected from the situation in humans, the animals that received their islets transplanted into the liver did not have a glucagon response during hypoglycaemic clamps. Interestingly, in the animals that received their autoislets transplanted into the peritoneal cavity, the glucagon response was present. Both groups showed similar responses to intravenous arginine [60]. Although the underlying mechanisms are still unclear it could be said that “Site matters!”

31.7 Conclusion The technical feasibility of islet autotransplantation has been demonstrated by several centres [14, 33 , 61]. In spite of the problems that autologous transplanted islets encounter in their new surrounding, pancreatic islet autotransplantation has prevented the onset of diabetes in pancreatectomized patients for more than two decades [62]. Therefore the biological proof of principle, for a long-lasting stable

31


721

glucose control by islets transplanted into the liver, has already been established. This success is equally surprising as well as inspiring for the more difficult task of islet allotransplantation. Understanding how autotransplanted islets can sustain their homeostasis and function in the liver, even for decades, might help us to find answers for still open questions regarding the molecular and cellular basis necessary for a successful islet allotransplantation. Islet autotransplantation can abrogate the onset of diabetes and may therefore be considered as a valuable addition to surgical resection of the pancreas, The results obtained after islet autotransplantation have definitively provided a significant proof of principle: Islets are able to regulate glucose homeostasis over decades when transplanted into the liver. In times like these, when the enthusiasm regarding clinical islet allotransplantation has been dampened by the inadequate long-term results, such a proof of principle is a vital beacon reminding us of the ultimate goal and prospects of islet transplantation.

References 1. Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, Secchi A, Brendel MD, Berney T, Brennan DC, Cagliero E, Alejandro R, Ryan EA, DiMercurio B, Morel P, Polonsky KS, Reems JA, Bretzel RG, Bertuzzi F, Froud T, Kandaswamy R, Sutherland DE, Eisenbarth G, Segal M, Preiksaitis J, Korbutt GS, Barton FB, Viviano L, Seyfert-Margolis V, Bluestone, J, Lakey, JR. International trial of the Edmonton protocol for islet transplantation. N Engl J Med 2006;355:1318–30. 2. Ricordi C, Strom TB. Clinical islet transplantation: advances and immunological challenges. Nat Rev Immunol 2004;4:259–68. 3. Ruggenenti P, Remuzzi A, Remuzzi G. Decision time for pancreatic islet-cell transplantation. Lancet 2008;371:883–4. 4. Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, Kneteman NM, Lakey JR, Shapiro AM. Five-year follow-up after clinical islet transplantation. Diabetes 2005;54:2060–9. 5. Sutherland DE, Matas AJ, Najarian JS. Pancreatic islet cell transplantation. Surg Clin North Am 1978;58:365–82. 6. Blondet JJ, Carlson AM, Kobayashi T, Jie T, Bellin M, Hering BJ, Freeman ML, Beilman GJ, Sutherland DE. The role of total pancreatectomy and islet autotransplantation for chronic pancreatitis. Surg Clin North Am 2007;87:1477–501,;x. 7. Webb MA, Illouz SC, Pollard CA, Gregory R, Mayberry JF, Tordoff SG, Bone M, Cordle CJ, Berry DP, Nicholson ML, Musto PP, Dennison AR. Islet auto transplantation following total pancreatectomy: a long-term assessment of graft function. Pancreas 2008;37:282–7. 8. Steer ML, Waxman I, Freedman S. Chronic pancreatitis. N Engl J Med 1995;332:1482–90. 9. Naruse S, Fujiki K, Ishiguro H. Is genetic analysis helpful for diagnosing chronic pancreatitis in its early stage? J Gastroenterol 42 Suppl 2007;17:60–5. 10. McLoughlin MT, Mitchell RM. Sphincter of Oddi dysfunction and pancreatitis. World J Gastroenterol 2007;13:6333–43. 11. Riediger H, Adam U, Fischer E, Keck T, Pfeffer F, Hopt UT, Makowiec F. Long-term outcome after resection for chronic pancreatitis in 224 patients. J Gastrointest Surg 2007;11:949–59. 12. Evans KA, Clark CW, Vogel SB, Behrns KE. Surgical management of failed endoscopic treatment of pancreatic disease. J Gastrointest Surg 2008;12:1924–9. 13. Ahmad SA, Lowy AM, Wray CJ, D’Alessio D, Choe KA, James LE, Gelrud A, Matthews JB, Rilo HL. Factors associated with insulin and narcotic independence after islet autotransplantation in patients with severe chronic pancreatitis. J Am Coll Surg 2005; 201:680–7.

722

M. Hermann et al.

14. Rodriguez Rilo HL, Ahmad SA, D’Alessio D, Iwanaga Y, Kim J, Choe KA, Moulton JS, Martin J, Pennington LJ, Soldano DA, Biliter J, Martin SP, Ulrich CD, Somogyi L, Welge J, Matthews JB, Lowy AM. Total pancreatectomy and autologous islet cell transplantation as a means to treat severe chronic pancreatitis. J Gastrointest Surg 2003;7:978–89. 15. Slezak LA, Andersen DK. Pancreatic resection: effects on glucose metabolism. World J Surg 2001;25:452–60. 16. Berney T, Mathe Z, Bucher P, muylder-Mischler S, Andres A, Bosco D, Oberholzer J, Majno P, Philippe J, Buhler L, Morel P. Islet autotransplantation for the prevention of surgical diabetes after extended pancreatectomy for the resection of benign tumors of the pancreas. Transplant Proc 2004;36:1123–4. 17. Mirkovitch V, Campiche M. Successful intrasplenic autotransplantation of pancreatic tissue in totally pancreatectomised dogs. Transplantation 1976;21:265–9. 18. Mehigan DG, Bell WR, Zuidema GD, Eggleston JC, Cameron JL. Disseminated intravascular coagulation and portal hypertension following pancreatic islet autotransplantation. Ann Surg 1980;191:287–93. 19. White SA, Robertson GS, London NJ, Dennison AR. Human islet autotransplantation to prevent diabetes after pancreas resection. Dig Surg 2000;17:439–50. 20. Bretzel RG, Jahr H, Eckhard M, Martin I, Winter D, Brendel MD. Islet cell transplantation today. Langenbecks Arch Surg 2007;392:239–53. 21. Bellin MD, Carlson AM, Kobayashi T, Gruessner AC, Hering BJ, Moran A, Sutherland DE. Outcome after pancreatectomy and islet autotransplantation in a pediatric population. J Pediatr Gastroenterol Nutr 2008;47:37–44. 22. Wahoff DC, Papalois BE, Najarian JS, Kendall DM, Farney AC, Leone JP, Jessurun J, Dunn DL, Robertson RP, Sutherland DE. Autologous islet transplantation to prevent diabetes after pancreatic resection. Ann Surg 1995;222:562–75. 23. Robertson RP, Sutherland DE, Lanz KJ. Normoglycemia and preserved insulin secretory reserve in diabetic patients 10–18 years after pancreas transplantation. Diabetes 1999;48:1737–40. 24. Robertson RP, Lanz KJ, Sutherland DE, Kendall DM. Prevention of diabetes for up to 13 years by autoislet transplantation after pancreatectomy for chronic pancreatitis. Diabetes 2001;50:47–50. 25. Sutherland DE, Gruessner AC, Carlson AM, Blondet JJ, Balamurugan AN, Reigstad KF, Beilman GJ, Bellin MD, Hering BJ. Islet autotransplant outcomes after total pancreatectomy: a contrast to islet allograft outcomes. Transplantation 2008;86:1799–802. 26. Contreras JL, Eckstein C, Smyth CA, Sellers MT, Vilatoba M, Bilbao G, Rahemtulla FG, Young CJ, Thompson JA, Chaudry IH, Eckhoff DE. Brain death significantly reduces isolated pancreatic islet yields and functionality in vitro and in vivo after transplantation in rats. Diabetes 2003;52:2935–42. 27. Emamaullee JA, Shapiro AM. Factors influencing the loss of beta-cell mass in islet transplantation. Cell Transplant 2007;16:1–8. 28. Nir T, Melton DA, Dor Y. Recovery from diabetes in mice by beta cell regeneration. J Clin Invest 2007;117:2553–61. 29. Huurman VA, Hilbrands R, Pinkse GG, Gillard P, Duinkerken G, van de LP, van der MeerPrins PM, Versteeg-van der Voort Maarschalk MF, Verbeeck K, Alizadeh BZ, Mathieu C, Gorus FK, Roelen DL, Claas FH, Keymeulen B, Pipeleers DG, Roep BO. Cellular islet autoimmunity associates with clinical outcome of islet cell transplantation. PLoS ONE 2008;3:e2435. 30. Monti P, Scirpoli M, Maffi P, Ghidoli N, De TF, Bertuzzi F, Piemonti L, Falcone M, Secchi A, Bonifacio E. Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells. J Clin Invest 2008;118:1806–14. 31. Biarnes M, Montolio M, Nacher V, Raurell M, Soler J, Montanya E. Beta-cell death and mass in syngeneically transplanted islets exposed to short- and long-term hyperglycemia. Diabetes 2002;51:66–72.

31


723

32. Ahmed SA, Wray C, Rilo HL, Choe KA, Gelrud A, Howington JA, Lowy AM, Matthews JB. Chronic pancreatitis: recent advances and ongoing challenges. Curr Probl Surg 2006;43: 127–238. 33. Gruessner RW, Sutherland DE, Dunn DL, Najarian JS, Jie T, Hering BJ, Gruessner AC. Transplant options for patients undergoing total pancreatectomy for chronic pancreatitis. J Am Coll Surg 2004;198:559–67. 34. Webb MA, Illouz SC, Pollard CA, Musto PP, Berry D, Dennison AR. Long-term maintenance of graft function after islet autotransplantation of less than 1000 IEQ/kg. Pancreas 2006;33:433–4. 35. Iwanaga Y, Sutherland DE, Harmon JV, Papas KK. Pancreas preservation for pancreas and islet transplantation. Curr Opin Organ Transplant 2008;13:445–51. 36. Hengster P, Hermann M, Pirkebner D, Draxl A, Margreiter R. Islet isolation and GMP, ISO 9001:2000: what do we need – a 3-year experience. Transplant Proc 2005;37:3407–8. 37. Guignard AP, Oberholzer J, Benhamou PY, Touzet S, Bucher P, Penfornis A, Bayle F, Kessler L, Thivolet C, Badet L, Morel P, Colin C. Cost analysis of human islet transplantation for the treatment of type 1 diabetes in the Swiss-French Consortium GRAGIL. Diabetes Care 2004;27:895–900. 38. Ichii H, Sakuma Y, Pileggi A, Fraker C, Alvarez A, Montelongo J, Szust J, Khan A, Inverardi L, Naziruddin B, Levy MF, Klintmalm GB, Goss JA, Alejandro R, Ricordi C. Shipment of human islets for transplantation. Am J Transplant 2007;7:1010–20. 39. Yang Z, Chen M, Deng S, Ellett JD, Wu R, Langman L, Carter JD, Fialkow LB, Markmann J, Nadler JL, Brayman K. Assessment of human pancreatic islets after long distance transportation. Transplant Proc 2004;36:1532–3. 40. Rabkin JM, Leone JP, Sutherland DE, Ahman A, Reed M, Papalois BE, Wahoff DC. Transcontinental shipping of pancreatic islets for autotransplantation after total pancreatectomy. Pancreas 1997;15:416–9. 41. Rabkin JM, Olyaei AJ, Orloff SL, Geisler SM, Wahoff DC, Hering BJ, Sutherland DE. Distant processing of pancreas islets for autotransplantation following total pancreatectomy. Am J Surg 1999;177:423–7. 42. Merani S, Schur C, Truong W, Knutzen VK, Lakey JR, Anderson CC, Ricordi C, Shapiro AM. Compaction of islets is detrimental to transplant outcome in mice. Transplantation 2006;82:1472–6. 43. Wurm M, Lubei V, Caronna M, Hermann M, Margreiter R, Hengster P. Development of a novel perfused rotary cell culture system. Tissue Eng 2007;13:2761–8. 44. Hermann M, Pirkebner D, Draxl A, Margreiter R, Hengster P. “Real-time” assessment of human islet preparations with confocal live cell imaging. Transplant Proc 2005;37:3409–11. 45. Hermann M, Margreiter R, Hengster P. Molecular and cellular key players in human islet transplantation. J Cell Mol Med 2007;11:398–415. 46. Emamaullee J, Liston P, Korneluk RG, Shapiro AM, Elliott JF. XIAP overexpression in islet beta-cells enhances engraftment and minimizes hypoxia-reperfusion injury. Am J Transplant 2005;5:1297–305. 47. Emamaullee JA, Rajotte RV, Liston P, Korneluk RG, Lakey JR, Shapiro AM, Elliott JF. XIAP overexpression in human islets prevents early posttransplant apoptosis and reduces the islet mass needed to treat diabetes. Diabetes 2005;54:2541–8. 48. Hui H, Khoury N, Zhao X, Balkir L, D’Amico E, Bullotta A, Nguyen ED, Gambotto A, Perfetti R. Adenovirus-mediated XIAP gene transfer reverses the negative effects of immunosuppressive drugs on insulin secretion and cell viability of isolated human islets. Diabetes 2005;54:424–33. 49. Plesner A, Liston P, Tan R, Korneluk RG, Verchere CB. The X-linked inhibitor of apoptosis protein enhances survival of murine islet allografts. Diabetes 2005;54:2533–40. 50. Carlsson PO, Palm F, Andersson A, Liss P. Markedly decreased oxygen tension in transplanted rat pancreatic islets irrespective of the implantation site. Diabetes 2001;50:489–95.

724

M. Hermann et al.

51. MacGregor RR, Williams SJ, Tong PY, Kover K, Moore WV, Stehno-Bittel L. Small rat islets are superior to large islets in in vitro function and in transplantation outcomes. Am J Physiol Endocrinol Metab 2006;290:E771–9. 52. Lehmann R, Zuellig RA, Kugelmeier P, Baenninger PB, Moritz W, Perren A, Clavien PA, Weber M, Spinas GA. Superiority of small islets in human islet transplantation. Diabetes 2007;56:594–603. 53. Langlois A, Bietiger W, Mandes K, Maillard E, Belcourt A, Pinget M, Kessler L, Sigrist S. Overexpression of vascular endothelial growth factor in vitro using deferoxamine: a new drug to increase islet vascularization during transplantation. Transplant Proc 2008;40:473–6. 54. Cavallari G, Zuellig RA, Lehmann R, Weber M, Moritz W. Rat pancreatic islet size standardization by the “hanging drop” technique. Transplant Proc 2007;39:2018–20. 55. Pyzdrowski KL, Kendall DM, Halter JB, Nakhleh RE, Sutherland DE, Robertson RP. Preserved insulin secretion and insulin independence in recipients of islet autografts. N Engl J Med 1992;327:220–6. 56. Rosenberg L, Wang R, Paraskevas S, Maysinger D. Structural and functional changes resulting from islet isolation lead to islet cell death. Surgery 1999;126:393–8. 57. Ilieva A, Yuan S, Wang RN, Agapitos D, Hill DJ, Rosenberg L. Pancreatic islet cell survival following islet isolation: the role of cellular interactions in the pancreas. J Endocrinol 1999;161:357–64. 58. Pinkse GG, Bouwman WP, Jiawan-Lalai R, Terpstra OT, Bruijn JA, de HE. Integrin signaling via RGD peptides and anti-beta1 antibodies confers resistance to apoptosis in islets of Langerhans. Diabetes 2006;55:312–7. 59. Kendall DM, Teuscher AU, Robertson RP. Defective glucagon secretion during sustained hypoglycemia following successful islet allo- and autotransplantation in humans. Diabetes 1997;46:23–7. 60. Gupta V, Wahoff DC, Rooney DP, Poitout V, Sutherland DE, Kendall DM, Robertson RP. The defective glucagon response from transplanted intrahepatic pancreatic islets during hypoglycemia is transplantation site-determined. Diabetes 1997;46:28–33. 61. Clayton HA, Davies JE, Pollard CA, White SA, Musto PP, Dennison AR. Pancreatectomy with islet autotransplantation for the treatment of severe chronic pancreatitis: the first 40 patients at the Leicester general hospital. Transplantation 2003;76:92–8. 62. Robertson RP. Islet transplantation as a treatment for diabetes – a work in progress. N Engl J Med 2004;350:694–705. 63. Hering BJ, Matsumoto I, Sawada T, Nakano M, Sakai T, Kandaswamy R, Sutherland DE. Impact of two-layer pancreas preservation on islet isolation and transplantation. Transplantation 2002;74:1813–6. 64. Egidi MF, Lin A, Bratton CF, Baliga PK. Prevention and management of hyperglycemia after pancreas transplantation. Curr Opin Organ Transplant 2008;13:72–8.