Pancreatic islet transplantation for treating diabetes - CiteSeerX

Review Cell- & Tissue-based Therapy

Pancreatic islet transplantation for treating diabetes 1. Introduction 2. The Edmonton protocol 3. Progress after the Edmonton protocol 4. Research focuses 5. Expert opinion and future prospects

Shinichi Matsumoto†, Hirofumi Noguchi, Yukihide Yonekawa, Teru Okitsu, Yasuhiro Iwanaga, Xiaoling Liu, Hideo Nagata, Naoya Kobayashi & Camillo Ricordi †Kyoto

University Hospital Transplantation Unit, Diabetes Research Institute Kyoto, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan

Pancreatic islet transplantation is one of the options for treating diabetes and has been shown to improve the quality of life of severe diabetic patients. Since the Edmonton protocol was announced, islet transplantation have advanced considerably, including islet after kidney transplantation, utilisation of non-heart-beating donors, single-donor islet transplantation and living-donor islet transplantation. These advances were based on revised immunosuppression protocols, improved pancreas procurement and islet isolation methods, and enhanced islet engraftment. Further improvements are necessary to make islet transplantation a routine clinical treatment. To synergise efforts towards a cure for type 1 diabetes, a Diabetes Research Institute (DRI) Federation is currently being established to include leading diabetes research centres worldwide, including DRIs in Miami, Edmonton and Kyoto among others. Keywords: Diabetes Research Institute Federation, islet transplantation, Kyoto Islet Isolation Method, living donor islet, non-heart-beating donor, transplantation, type 1 diabetes Expert Opin. Biol. Ther. (2006) 6(1):23-37

1.

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Diabetes is a major burden, with > 200 million people affected worldwide [1]. Among diabetes, type 1 diabetes represents a therapeutic challenge and remains a substantial burden for patients and their families. The Diabetes Control and Complication Trial (DCCT) showed that intensive insulin therapy improved glycated haemoglobin (HbA1c) and protected against diabetic triopathy [2], but the penalty was a thrice-increased risk of serious hypoglycaemic events, including recurrent seizures and coma [3]. Whole pancreas transplantation can cure type 1 diabetes, but remains too morbid to advocate for most patients [4]. An attractive alternative is islet transplantation, as it can avoid major surgery, general anaesthesia and complications related to exocrine enzymes. Since the first human islet allograft transplant in 1974 [5], > 750 diabetic patients have received allogeneic islet transplants. Until 2000, clinical success rates were not excellent [6,7], but a dramatic improvement was achieved with the Edmonton Protocol [8]. Still, islet transplantation efforts have limitations, including supplies of donor pancreata, experienced islet isolation teams, side effects of immunosuppressants and long-term results [9]. In this manuscript, current advances in islet transplantation and research focuses are described. 2.

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Introduction

The Edmonton protocol

A protocol introduced by the Edmonton group in 2000 led to dramatic improvements in islet allograft survival [8]. Seven out of seven pre-uraemic type 1 diabetic 10.1517/14712598.6.1.23 © 2006 Ashley Publications ISSN 1471-2598

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Pancreatic islet transplantation for treating diabetes

patients who received islet transplants became insulin-independent at 1 year post-transplantation. In addition, HbA1c levels became normal and a dramatic decrease was seen in the frequency of hypoglycaemic unawareness. Key elements of this protocol lay in avoidance of corticosteroids with combined sirolimus, tacrolimus and anti-IL-2-receptor antibody to protect against rejection and autoimmunity, and the use of ≥ 2 fresh islet preparations (within 3 – 4 h after isolation) processed by the Edmonton islet isolation protocol. The Edmonton islet isolation protocol includes: • preserving donor pancreas from brain-dead donors in cold University of Wisconsin (UW) solution with a minimal storage period • collagenase infusion via the main pancreatic duct using a pressure-controlled method • pancreas digestion using the Ricordi system • islet purification by continuous density gradient using Ficoll with chilled COBE 2991 cell processor • removal of all the xenoprotein from the islet isolation process [8] At present, isolated islets are transplanted immediately by simple gravity infusion [10], and D-Stat™ is used to prevent bleeding following transhepatic intraportal islet transplantation [11]. The Edmonton protocol was replicated by advanced islet transplantation centres [12], but the results were more variable at the other centres [13]. Recently, there has been an exponential increase in clinical islet transplantation activity, with 471 patients transplanted at 43 international institutions [14]. The University of Alberta, University of Minnesota and University of Miami demonstrated that 82% of a total of 118 recipients of completion transplants were insulinindependent within the first year after transplantation [14]. The University of Alberta demonstrated progressive loss of insulin independence over time, leaving 50% of patients insulin-free at 3 years. In contrast, > 80% of patients continue to demonstrate persistent islet function at 5 years, with effective prevention of recurrent hypoglycaemia or severe lability combined with correction in HbA1c [14,15]. These effects of islet transplantation need to be balanced against the risk of lifelong immunosuppression [16,17]. However, the quality of life was significantly improved by islet transplantation despite high levels of immunosuppression [18,19]. Therefore, it should be reasonable to consider that islet transplantation could be an option for the treatment of unstable type 1 diabetes. 3.

Progress after the Edmonton protocol

Islet after kidney transplantation Pre-uraemia was thought to be one of the important factors for Edmonton’s success [8]. A case was reported in which the Edmonton-type steroid-free immunosuppression regimen worked well for kidney transplantation [20]. In this case, an islet transplantation was performed after the kidney transplantation and it worked better than islet transplantation 3.1

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alone [20]. In addition, the Edmonton-type immunosuppression regimen with minimum steroid (prednisone ≤ 5 mg) was shown to work for islet after kidney transplantation [21,22]. Furthermore, islet after kidney transplantation using a regular kidney immunosuppression regimen with daclizumab induction worked better than the Edmonton-type immunosuppression regimen [23]. Their regular kidney immunosuppression regimen included tacrolimus/sirolimus, tacrolimus/mycophenolate mofetil/prednisone, and cyclosporin/mycophenolate mofetil/prednisone. This group used a regular kidney immunosuppression protocol because they put priority on the transplanted kidney. The preimmunosuppressed state was thought to contribute to the improvement of early islet engraftment. Their experience demonstrated that sirolimus was not essential for the success of islet transplantation. As sirolimus is responsible for side effects, including high blood lipid concentration, oral ulcer and renal dysfunction when combined with tacrolimus, avoidance of sirolimus would enhance applications of islet transplantation [24]. 3.2 Islet transplantation using non-heart-beating donors

One of the strategies to alleviate donor shortage is to utilise marginal donors, including non-heart-beating donors (NHBDs). Islet isolation from NHBDs is feasible, but only one clinical islet transplant from a NHBD has been performed [25]. In Japan, it is illegal to use brain-dead heart-beating donors for islet isolation and transplantation; therefore, islet transplantation from NHBDs or living-donors must be pursued [26,27]. As successful islet isolation is the key for successful islet transplantation, the authors implemented several strategies to improve islet isolation using NHBDs [28] and named it the ‘Kyoto Islet Isolation Method’ [29]. First, a double balloon catheter was inserted before cessation of heart beating to chill the pancreas immediately after cardiac arrest [30]. This technique enabled the authors to minimise warm ischaemic time, and the average warm ischaemic time was 6.0 ± 0.9 min; this is shorter compared with published data (> 20 min) [25]. Corlett et al. demonstrated that islet yield and function deteriorated after 30 min warm ischaemia in rat and dog models [31]. Therefore, it is believed that warm ischaemic time should be minimised to isolate islets from NHBDs. Second, the authors introduced ductal injection immediately after procurement [32]. ET-Kyoto solution (Kyoto Biomedical, Kyoto, Japan) [33,34] was used instead of UW solution for ductal injection, as UW solution inhibited collagenase activity and had a negative effect on human islet isolation results [35]. The trypsin inhibitor ulinastatin (Mochida Pharmaceutical Company, Tokyo, Japan) was added in ET-Kyoto solution for this purpose [28]. Third, the two-layer method of pancreas preservation was modified [36-38]. It was shown that ET-Kyoto solution plus perfluorocarbon was better than UW solution plus perfluorocarbon [39]. Therefore, ET-Kyoto solution was introduced for

Expert Opin. Biol. Ther. (2006) 6(1)

Matsumoto, Noguchi, Yonekawa, Okitsu, Iwanaga, Liu, Nagata, Kobayashi & Ricordi

the component of the two-layer method. However, as the perfluorocarbon one-layer method was shown to be superior to the two-layer method [40], the authors currently completely immerse the pancreas into oxygenated perfluorocarbon [41]. In such cases, the authors put ET-Kyoto solution on the top of perfluorocarbon, as oxygen escapes from the surface of perfluorocarbon if the surface is not covered by another solution. Even using this new preservation method, cold preservation time was limited to < 5 h. Fourth, ulinastatin was used for trypsin inhibition during islet isolation [28]. Previously the authors have shown that trypsin inhibition during islet isolation using the simple open pan islet isolation method improved islet yield in non-human primate and human models [42]. The University of Alberta also demonstrated that human islet isolation was improved with trypsin inhibition when pancreata were preserved for extended time periods [43]. However, trypsin inhibition had no effect in improving islet isolation when pancreata were procured from brain-dead heart-beating donors with the Ricordi islet isolation method [44,45]. Trypsin inhibition during islet isolation may not be important where an optimal pancreas is processed with the Ricordi islet isolation method. However, as trypsin inhibition during islet isolation using damaged human or porcine pancreata [46,47] improved the islet isolation results, the authors believe trypsin inhibition should improve islet isolation from NHBDs. Finally, density measurement of exocrine tissue was used [28,42], as acinar tissue density could decrease during warm ischaemia [48]. In addition, iodixanol was used instead of Ficoll for islet purification as iodixanol has low levels of endotoxin and low viscosity, which should be less harmful for islets [49,50]. The first human islet transplant occurred on 7th April 2004 in Japan. This patient became insulin-independent after the second islet transplant, which was another first in Japan [28]. The authors have isolated 15 human pancreata from NHBDs using the Kyoto Islet Isolation Method. Double balloon catheters were inserted before cardiac arrest combined with kidney retrieval in 12 cases. In those 12 cases, average islet yields before purification were 664,756 ± 62,993 islet equivalent (IE) and after purification were 477,796 ± 42,834 IE. Recovery rate postpurification was 74.5 ± 4.9%. These numbers were higher than previously published data [25]. Eleven out of twelve islet preparations were transplanted into five type 1 diabetic patients. All five transplanted patients had better glycaemic control after islet transplantation with positive C-peptide and a reduction of insulin requirement. HbA1c levels reduced to a normal range in all cases [28]. The Kyoto Islet Isolation Method should be useful for islet isolation from brain-dead donors. Islet transplantation using single donors Recently, the University of Minnesota demonstrated that singledonor islet transplantation reversed type 1 diabetes [51-53]. Compared with the Edmonton protocol, their protocol: 3.3

• excluded older donors (≥ 50 years old) • avoided islet-toxic reagents during islet processing • cultured islets for 2 days, initiated potent immunosuppressive and anti-inflammatory treatment pretransplant • applied aggressive insulin therapy peri-transplant and minimised exposure to calcineurin inhibitors In terms of donor age, islets from older donors had inferior functionality compared with those from younger donors, but islet isolation from younger donors is usually difficult [54]. Therefore, if enough islets are isolated, younger donors could provide high-quality islets. Avoiding islet toxic solution is the same concept as the authors’ Kyoto Islet Isolation Method. In particular, the utilisation of iodixanol for purification contributed to this concept. It still remains controversial whether culturing would help to improve the result of islet transplantation. The authors’ data suggested that cultured islets from NHBDs significantly reduced the mass of engrafted islets [55]. However, as the Minnesota group mentioned, during the culture period a recipient could receive immunosuppressants and anti-inflammatory reagents before transplantation, and this advantage might overcome the disadvantages such as reduction of islet yield during culture. Aggressive insulin therapy and minimising exposure to calcineurin inhibitors are reasonable strategies, and these are implemented in other centres, including the authors’. Achieving insulin independence with islets prepared from a single donor pancreas will have profound implications on the transition of islet transplants from clinical research to clinical care [53,56]. Single-donor islet transplants increase safety, reduce costs and promote donor pancreas allocation to islet recipients. Living-donor islet transplantation The authors performed the first successful living-donor islet transplantation for the treatment of brittle diabetes [57]. Living-donor islet transplantation includes distal pancreatectomy from healthy donors, islet isolation from the tail section of resected pancreas and infusion of isolated islets into a diabetic patient (Figure 1). Living-donor islet transplantation has both advantages and disadvantages. In terms of advantages, a pancreas from a living-donor has not suffered injuries by cytokine storms, which occur during brain-dead status [58]. Contreras et al. demonstrated that brain-death significantly reduced islet yields and functionality in vitro and in vivo after transplantation in rats [59]. Therefore, avoidance of brain-dead status is a clear advantage. In addition, the pancreas could have no warm ischaemic time and minimum cold ischaemic time. Living-donors could be examined for insulin secretory ability beforehand; therefore, it is possible to estimate the quality of islets. From the recipient’s point of view, immunosuppression could be initiated before transplantation and ideal blood levels could be achieved at the time of transplantation. Tight blood glucose control before transplantation should help to improve the efficacy of 3.4


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Pancreas donor

Diabetic patient

Distal pancreatectomy Islet transplantation Islet isolation

Figure 1. A schema of living-donor islet transplantation. Distal pancreatectomy from a healthy donor was followed by islet isolation from the tail section of a resected pancreas and infusion of isolated islets into a diabetic patient.

islet engraftment. In terms of disadvantages, obviously the healthy donor would need an operation to provide the pancreas, and donor safety is of great concern. The University of Minnesota reported a complication rate of 3 – 5% in living-donors for segmental pancreas transplantation [60]. Complications included pancreatic fistula, pancreatitis, wound infection and bleeding. Although no deaths and life-threatening complications occurred in these 130 living pancreas donors, donation of half the pancreas has the potential to induce new diabetes. The risk of diabetes can be reduced substantially if the donor is not obese, the donor islet autoantibody status is negative, and the donor oral glucose tolerance test (OGTT) result is healthy, but these precautions might not eliminate the risk entirely. Complete informed consent, especially in regard to donor risks, is essential. NHBDs and living donors are the only pancreas resources available at present in Japan for islet transplants [26,27]. At the authors’ institute, an average of ∼ 10 NHBDs are available per year, and > 10 type 1 diabetic patients per month come to the institute for islet transplantation; hence, there exists already a huge discrepancy between recipient and donor numbers. With this unique situation in Japan, the authors were able to perform the living-donor islet transplantation. It might be difficult to justify the living-donor 26

islet transplantation where cadaveric donors could provide enough islets [61]; however, apparent donor shortages would necessitate this treatment all over the world [62]. In the first case, the recipient had brittle diabetes and hypoglycaemic unawareness occurred with intensive insulin therapy [57]. The recipient was enrolled for cadaveric islet transplantation, but ∼ 40 other patients had previously been enrolled. Therefore, the recipient needed to wait for a minimum of 5 years. The donor in this case was the mother of the recipient. The donor was examined for OGTT in both blood glucose levels and insulin levels, HbA1c, body mass index, surveillance of diabetes in relatives, and abdominal computed tomography (CT) scan. Glucose concentrations and insulinogenic index during OGTT was normal. HbA1c was 5% and there were no diabetic relatives except for the recipient. Abdominal CT demonstrated that her pancreas showed normal anatomy, and the cutting line of the pancreas was determined to be at the left side of the portal vein. In order to have effective blood concentrations of immunosuppressants at the time of transplantation, the recipient initiated sirolimus and tacrolimus 1 week prior to transplantation. Basiliximab was administered 4 days before transplantation and on the day of transplantation. Infliximab (5 mg/kg) was also administered 1 day before transplantation [57].



Distal pancreatectomy with splenectomy was performed using open laparotomy. The resected pancreas was perfused via the splenic artery and ductal injection was also performed. The pancreas graft was brought to a cell processing facility and cold ischaemic time was 44 min. More than 400,000 IE islets were isolated and these islets were transplanted immediately. The recipient had been insulin-independent post-transplant for > 5 months at this time point. HbA1c levels before transplantation were 9.9% and had been reduced to 6.2%. No hypoglycaemic unawareness was suffered post-transplantation. Basal C-peptide levels for the recent 1-month follow-up were between 1.0 and 1.7 ng/ml. The recipient experienced an oral ulcer and leukocytopenia, which required filgrastim. Both side effects were cured within a few days. The donor’s clinical course was uneventful, with discharge 18 days post-operation without complications. The donor returned to work within 1 month. Donor HbA1c levels have been between 5.1 and 5.4%. Both the recipient’s and donor’s OGTT at 37 post-operative days were normal [57]. This first successful living-donor islet transplantation showed important facts. Half of a living-donor pancreas could provide enough islets to cure diabetes. In this case, ∼ 400,000 IE islets were transplanted, and this islet yield was similar to current islet yields from brain-dead donors or NHBDs. As islet transplantation usually requires two or more cadaveric donors to cure one recipient, islets from a living-donor should have high efficacy of engraftment. The authors’ group created the Secretory Units of Islet Transplant Object index (SUITO index) to estimate engrafted islet numbers (Yamada et al., manuscript submitted). The SUITO index is calculated by the formula: 1500 × fasting C-peptide [ng/dl]/(fasting blood glucose [mg/dl]-63) [55]. For example, if C-peptide is 0.8 ng/ml and blood glucose is 103 mg/dl, the SUITO index is 1500 × 0.8/(103-63) = 30. This indicates that the recipient has 30% of functional islets in comparison to a normal healthy person (a healthy person was estimated to have 100% functional islets and, therefore, a SUITO index of 100). The SUITO index of the authors’ living-donor islet recipient was ∼ 40 and that of the NHBD recipient after two transplants was ∼ 30. Both cases became insulin-independent; however, the single living-donor islet transplant recipient showed a better SUITO index compared with multiple NHBD islet transplant recipients [55]. As the SUITO index represents engrafted islet numbers, this index might be useful to trace the number of engrafted islets. A limited number of the islet recipients maintained insulin independence after 5 years with the Edmonton protocol [14,15]; hence, it is important to evaluate whether the living-donor islet transplant recipients could maintain insulin independence for 5 years. As islets from a living donor should have high quality and viability, it might be possible to maintain insulin independence for a relatively long period. If a safe immunosuppression regimen is established, living-donor islet transplantation could become an option for the treatment of diabetic children (in particular, when a

type 1 diabetic child enters school, the stress of being separated from parents often causes hypoglycaemic or hyperglycaemic episodes). The other option might be for diabetic gravida to have a healthy pregnancy and delivery. 4.

Research focuses

To apply islet transplantation for a larger number of patients with type 1 diabetes and eventually for patients with insulin requiring diabetes, including type 2, further research is mandatory. Research areas include donor management, pancreas procurement, pancreas preservation, islet isolation, pretransplant management, transplant technique, engraftment, immune monitoring, immunosuppression and tolerance [63]. The aforementioned research areas were categorised into: • isolation technique • islet engraftment • control of immunological event Islet isolation technique The current method of islet isolation was established by Ricordi [64], and this is the gold standard. Donor factors are important for successful islet isolation [65-69]. Careful donor selection is one strategy to improve the success rate of islet isolation; however, this strategy reduces donor pools. Intensive management of donors could expand donor pools, and the authors’ experiences of islet transplantation with NHBDs proved this concept [28]. Ductal injection seems to be one of the most important factors for successful islet isolation from NHBDs. Sawada et al. demonstrated that ductal injection is important to protect the main pancreatic duct and they limited the solution volume to prevent pancreas distention [32]. In contrast, the authors used ductal injection to prevent autolysis of the pancreas, as this technique effectively delivers the solution and drugs into the exocrine tissue; therefore, the authors infused a large volume of solution. Ulinastatin is used in the ET-Kyoto solution for ductal injection as ulinastatin inhibits trypsin activity at normal pH. With this technique, clumping or DNA release were rarely obsereved, even using NHBDs, and DNase was never used. The authors think this is due to the protective effect of ulinastatin for exocrine tissue, as it was shown that ulinastatin significantly reduced blood amylase and lipase concentrations after endoscopic retrograde cholangiopancreatograpy [70]. Other reagents, such as glutamine [71,72], for ductal injection might further improve the efficacy of islet isolation. Perfusion into pancreas via artery is another important factor; UW solution is used universally for this purpose. However, the authors used massive (usually > 50 l) volumes of chilled Hanks’ solution for complete and immediate perfusion. UW solution has high viscosity and high potassium that causes vasospasm. Both high viscosity and vasospasms would interfere with the sufficient perfusion of small vessels. Islet-specific perfusion solution should be explored, and the authors used ET-Kyoto solution with ulinastatin for the acquisition of the living-donor pancreas. 4.1


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Pancreas preservation period should be minimised. Even for a short duration, oxygenated perfluorocarbon provides the best method for pancreas storage. Perfluorocarbons store and release high levels of oxygen have been examined as oxygen carriers [37,38,73]. Perfluorocarbon was first used for organ preservation as a component of the two-layer method of pancreas preservation in both experimental and clinical settings [37,38,74]. During two-layer method preservation, pancreas grafts continuously generate ATP [75]. ATP is used to drive the sodium/potassium pump to maintain cellular integrity [76] and generate proteins, including heat-shock protein-32 (haemoxygenase-1) and heat-shock protein-70 [77]. The two-layer method also maintains the viability of endothelium cells [78,79]. With these effects, oxygenated perfluorocarbon seems to be the most suitable substance for preservation before pancreas transplantation and islet isolation. With ductal injection and arterial perfusion, complete immersion of the pancreas into oxygenated perfluorocarbon (one-layer method) seems to be the best method [40], as the two-layer method is inadequate for pancreas oxygenation [80]. Collagenase delivery with pressure monitoring is the current standard [81]; however, a very limited study has been performed in terms of the method of collagenase delivery. This may be improved with further examinations. Selection of collagenase is important for successful islet isolation, and at present Liberase is exclusively used [82,83]. Liberase seems to be the best collagenase, but still has lot-tolot variation [84]. Hence, a more reliable collagenase needs to be sought out, and tailored collagenase combinations seem promising with further improvement [85,86]. Purification of islets from exocrine tissue is a critical step to maintain high islet yields. The common method of islet purification is density gradient centrifugation. Ficoll is widely used for density gradient centrifugation [87] with the COBE 2991 cell processor [88]. However, an iodixanol-based solution contributed to increase islet yield, especially for porcine islet isolation [49,50,89,90]. Iodixanol has low viscosity; therefore, it needs less force during centrifugation. Iodixanol-based purifications were clinically applied by others as well as the authors’ own group with promising results [28,51,52]. The authors diluted iodixanol with ET-Kyoto solution; however, other solutions, such as culture media or the other preservation solutions, could be examined. Islet engraftment In follow-up studies of the Edmonton protocol, ∼ 20 – 40% of the islets maintained their functional capacity [91,92]. The authors’ data suggested that survival rates of islets from NHBDs were similar when islets were transplanted without culture [55]. In contrast, the survival rate of islets from living donors is estimated to be more than double compared with islets from NHBDs without culture [55]. These facts indicated that the quality of islets has a significant impact on islet engraftment. To improve the efficacy of engraftment, many strategies were already published [93]. These strategies could be classified by: 4.2

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• • • • •

targeting inflammatory events maintaining euglycaemia manipulating islets for revascularisation administering antiapoptotic factors peritransplant selecting transplant site

Targeting inflammatory events Targeting inflammatory events, especially instant blood-mediated inflammatory reaction (IBMIR) is one of the most promising strategies [94]. IBMIR is a thrombotic/inflammatory reaction, which is elicited when islets come in direct contact with ABO-compatible blood [95-97]. A rapid binding to and activation of platelets on the islet surface, as well as activation of the coagulation and complement systems, characterise IBMIR. Clinically, IBMIR is triggered within minutes after islet infusion into the portal vein. Goto et al. clearly demonstrated that low molecular weight dextran sulfate prevented IBMIR [98]. Activated protein C was also shown to prevent IBMIR and improve the efficacy of islet transplantation [99]. Melagatran was shown to prevent IBMIR triggered by human islets using a tubing loop model [100]. Akima et al. demonstrated that dual therapy using clinical doses of tirofiban and human recombinant activated protein C synergistically inhibited islet destruction by IBMIR [101]. Overcoming IBMIR seems to be the next step towards significant improvement of engraftment. To suppress nonspecific inflammatory reactions, TNF-α blockers, infliximab [57] and etanercept [52] were used at the time of islet transplantation in clinical settings with positive results. The concept of blocking TNF-α to improve engraftment of islets was demonstrated by Farney et al. [102]. Many other anti-inflammatory reagents, including Silica [103], nicotinamide [104], desferrioxamine [104-106], IL-1 receptor antagonist [107], IL-4 combined with IL-10 [108], Lazaroid [109,110], pravastatin [111,112], lisofylline [113], gadolinium chloride [114], pyruvate [115], superoxide dismutase mimics [116] and MCI-186 [117] were also shown to be effective. 4.2.1

Maintaining euglycaemia peri-transplant period Maintaining euglycaemia is important for islet transplantation as hyperglycaemia induces islet dysfunction, insulin resistance [118] and poor blood perfusion of islets [119]. At present, avoiding hyperglycaemia is routine care after islet transplantation [52,53,57]. For this purpose, the authors use intravenous insulin injection during transplantation and a combination of recombinant insulin, insulin glargine and insulin lispro thereafter. In the authors’ experiences, glargine could be stopped early after transplantation, as basal insulin is supplied by transplanted islets. 4.2.2

Manipulating islet for revascularisation Pancreatic islets have a unique glomerular-like angioarchitecture (islet portal system) with a high blood perfusion rate of 5 – 7 ml/min/g tissue [120,121]. As engraftment is established by vascular anastomosis between the islet portal system and the 4.2.3



hepatic artery [122], improvement of vascularisation should improve engraftment. Investigators have noticed improvements in islet graft survival and function by means of basic fibroblast growth factor [123,124], endothelial cell growth factor [124] and vascular endothelial growth factor [125-127] exposure of the grafts. Recently, it was shown that prolactin stimulates islet production of endothelial cell growth factor and improves islet graft oxygen tension and blood perfusion [128]. Endothelium of transplanted islets expressed mRNA for both inhibitors and inducers of angiogenesis, and this expression differed with time [129]. Therefore, vascularisation of islets seems important for long-term results too. Antiapoptotic strategies It was shown that the islet isolation process induced apoptosis to isolated islets [130-133], and antiapoptotic reagents were shown to improve engraftment. Growth factors, including fibroblast growth factor [123], hepatocyte growth factor [134-136] and insulin-like growth factor-I [137], were shown to prevent apoptosis and beta cell dysfunction. Besides growth factors, haemoxygenase-1 [138-140], protoporphyrins [141], erythropoietin [142], 1,25-dihydroxy vitamin D3 [143], green tea polyphenol [144], caspase-3 inhibitor [145] and JNK-inhibitor [146] were shown to prevent apoptosis of islets. As apoptosis has several pathways, a combination of different reagents could effectively prevent apoptosis of islets [147]. 4.2.4

Transplant site The liver is exclusively selected as a transplant site in the clinical setting. However, intrahepatic islets could be exposed to toxic prescribed medication absorbed from the gastrointestinal tract and delivered into the portal vein [148]. In particular, the antiproliferative effects of sirolimus might hinder angiogenesis during engraftment and potential islet neogenesis from ductal stem cells [149]. In addition, the other standard immunosuppressant, tacrolimus, has adverse effect on pancreatic beta cells [150,151]. Besides the liver, the spleen, kidney capsule, pancreatic capsule, intestinal mucosa, testes, brain, peritoneal cavity and omentum have all been considered as potential sites of islet infusion [148]. As a relatively large amount of tissue is transplanted in the clinical setting, the peritoneal cavity or omentum pouch might be a realistic transplant site rather than the liver. Furthermore, those sites could provide enough space for unpurified islets or encapsulated islets. Improvement of oxygen and nutrition supply to transplanted islets should be the critical issues for these transplant sites. 4.2.5

Control immunological event A steroid-free immunosuppression regimen with anti-IL-2receptor antibody, sirolimus and low-dose tacrolimus is the key component of the Edmonton protocol. However, this regimen is still thought to be far from ideal, with side effects including mouth ulceration, peripheral oedema, ovarian cysts in females, proteinuria in some patients with underlying 4.3

pre-existing diabetic renal damage, hypertension and hypercholesterolemia [14]. Mycophenolate mofetil was introduced by several institutes, including the author’s centre, to reduce or eliminate the dosage of either sirolimus or tacrolimus [23,52,152]. Several promising protocols were published to minimise side effects or even to induce tolerance. New drugs include FTY720 [153,154], everolimus [154], LEA29Y [155,156], non-Fcbinding hOKT3, T cell-depleting antibody [51,157] and anti-CD40 receptor ligand [158-160] or antibody [156]. FTY720 shows no diabetogenic and nephrotoxic side effects [161], is effective against reperfusion injury [162,163], has a synergetic effect with calcineurin/TOR inhibitor [164,165], has remarkable efficacy with non-obese diabetic mice as a monotherapy [153], and is effective in clinical kidney transplantation [166,167]. Therefore, FTY720 is a particularly promising reagent for islet transplantation to cure type 1 diabetic patients. The authors developed a cell-permeable inhibitor of the nuclear factor of activated T cells using a protein transduction system [168,169]. This peptide provided efficient immunosuppression for islet allografts and did not affect insulin secretion, whereas tacrolimus caused a dose-dependent decrease in insulin secretion [170]. In addition, promising tolerance protocols, including diphtheria-conjugated anti-CD3 immunotoxin combined with deoxyspergualin [171], anti-CD40 ligand [172] and inducing mix chimerisms [173-176], were published. When tolerance becomes a clinical reality, it does not only eliminate side effects, but rather helps engraftment or even self duplication of islets. As islet autotransplantation for chronic pancreatitis only needs ∼ 300,000 IE to maintain insulin independence [177,178], elimination of immunological events should improve engraftment. In one case, a recipient of an islet autotransplant remained insulin-independent for > 18 years [178]; it seems reasonable that the islets have the ability to self-duplicate. Indeed, Melton et al. demonstrated that adult islets have stem cells and that the adult islets themselves have the ability to duplicate [179]. Recently, several promising substances, including glucagon-like peptide-1 with exendin-4 [180-184], hepatocyte growth factor [185] and INGAPS [186,187], were shown to promote beta cell duplication. Therefore, if immunological event can be controlled, transplanted islets might duplicate to maintain normoglycaemia with or without growth factors. 5.

Expert opinion and future prospects

Islet transplantation is the most promising method to cure diabetes with minimum risks at this time point. If more reliable methods of immunological tolerance, islet isolation and transplantation were established, the most important issue would be the shortage of donors. Living-donor islet transplantation could alleviate but not solve this issue. Xenogeneic islet transplantation using porcine islets seems to be promising, as islet xenografts are primarily avascular and become revascularised by host endothelium; furthermore, the


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gal-alfa1,3-gal (Gal) epitope is not expressed on adult pig islet endocrine cells [188,189]. In addition, there is a promising protocol for the treatment of diabetic non-human primates with porcine islets [190]. In fact, co-transplantation of neonatal porcine islets and Sertoli cells within the chamber improved glycaemic control of diabetic children [191]. Encapsulated neonatal pig islets were transplanted into the peritoneal cavity of a type 1 diabetic patient and the islets survived for 9 years with metabolic improvement [192]. Recently, the authors established an islet isolation method for extremely high islet yields (> 800,000 IE) that could be applied for single-donor islet xenotransplantation [193]. However, ethical issues including zoonosis and especially porcine endogenous retrovirus infection, must be addressed before clinical application can be expanded [194-198]. Even inherent ethical issues need to be addressed; generation of beta cells from stem cells, especially from embryonic stem (ES) cells can solve donor shortages [199,200]. Several studies show the potential of ES cells to generate insulinproducing cells, but there is still no reliable method to make beta cells from ES cells [201,202]. In contrast, insulin-producing cells have been generated in vitro from adult pancreatic stem cells in the pancreatic duct [203,204]. Pancreatic and duodenal homeobox factor-1 plays a main role in regulating pancreatic development, insulin gene transcription [205,206] and differentiation of insulin-producing cells from progenitor cells [207-209]. Other transcription factors, including neurogenin 3 [210], BETA2/NeuroD [211], Pax4 [212] and

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Acknowledgements This work was supported in part by the Ministry of Education, Science and Culture, the Ministry of Health, Labour and Welfare, and the 21st Century Center of Excellence Program, Japan. The authors thank Y Nakai, M Ueda, A Ishii and E Yabunaka for their technical support, and Y Tamura and L Upshaw for their careful review of this manuscript.

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Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers. 1.

NKX6 [213], as well as TAT-mediated neurogenin 3 [214] and gene Pax4 [212], also play important roles in beta cell generation. These findings should help to generate beta cells from ES cells. If autoimmunity could be controlled, regeneration of beta-cells from the naive pancreas of a diabetic patient might become a better treatment. Until a new paradigm shows up, improvement of safety and efficacy of islet transplantation seems the most realistic and wise way to cure diabetes. To synergise efforts toward a cure for type 1 diabetes, a Diabetes Research Institute (DRI) Federation is currently being established to include leading diabetes research centres worldwide, including DRIs in Miami, Edmonton and Kyoto among others. The DRI Federation will bring together scientists working at participating DRIs to catalyse new collaborative projects towards reaching the common goal of developing a cure for type 1 diabetes in the fastest, most efficient and safest way possible.

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Affiliation

Shinichi Matsumoto†1 MD, PhD, Hirofumi Noguchi2, Yukihide Yonekawa2, Teru Okitsu2, Yasuhiro Iwanaga2, Xiaoling Liu2, Hideo Nagata2,3, Naoya Kobayashi4 & Camillo Ricordi5 †Author for correspondence 1Kyoto University Hospital Transplantation Unit, Diabetes Research Institute Kyoto, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan Tel: +81 75 751 4699; Fax: +81 75 751 3896; E-mail: [email protected] 2Kyoto University Hospital Transplant Surgery, Diabetes Research Institute Kyoto, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan 3Fujita Health University, Second Department of Surgery, Toyoake, Aichi 470-11, Japan 4Okayama University Graduate School of Medicine and Dentistry, Department of Surgery, Okayama, Japan 5Diabetes Research Institute, University of Miami School of Medicine, Miami, Florida, USA

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