A health‐economic analysis of porcine islet xenotransplantation

Beckwith J, Nyman JA, Flanagan B, Schrover R, Schuurman H‐J. A health‐economic analysis of porcine islet xenotransplantation. Xenotransplantation 2010; 17: 233–242. © 2010 John Wiley & Sons A/S. Abstract: Background: Islet cell transplantation is a promising treatment for type 1 diabetes. To overcome the shortage of deceased human pancreas donors, porcine islet cell xenotransplantation is being developed as an alternative to allotransplantation. The objective of this study was to perform a cost‐effectiveness analysis of porcine islet transplantation in comparison with standard insulin therapy. The patient population for this study was young adults, ages 20 to 40, for whom standard medical care is inadequate in controlling blood glucose levels (hypoglycemia unawareness). Since trial data were lacking, estimates used extrapolations from data found in the literature and ongoing trials in clinical allotransplantation. Cost estimates were based on the data available in the USA. Methods: Markov modeling and Monte Carlo simulations using software specifically developed for health‐economic evaluations were used. Outcomes data for ongoing clinical islet allotransplantation from the University of Minnesota were used, along with probabilities of complications from the Diabetes Control and Complications Trial. Quality‐adjusted life years (QALYs) were the effectiveness measure. The upper limit of being cost‐effective is $100 000 per QALY. Cost data from the literature were used and adjusted to 2007 US dollars using the medical care portion of the Consumer Price Index. Results: In both Markov modeling and Monte Carlo simulations, porcine islet xenotransplantation was both more effective and less costly over the course of the 20‐yr model. For standard insulin therapy, cumulative cost per patient was $661 000, while cumulative effectiveness was 9.4 QALYs, for a cost of $71 100 per QALY. Transplantation had a cumulative cost of $659 000 per patient, a cumulative effectiveness of 10.9 QALYs, and a cost per QALY of $60 700. Islet transplantation became cost‐effective at 4 yr after transplantation, and was more cost‐effective than standard insulin treatment at 14 yr. These findings are related to relative high costs in the transplantation arm of the evaluation during the first years while those in the insulin arm became higher later in follow‐up. Throughout the follow‐up period, effectiveness of transplantation was higher than that of insulin treatment. In sensitivity analysis, duplication or triplication of one‐time initial costs such as costs of donor animal, islet manufacturing and transplantation had no effect on long‐term outcome in terms of cost‐saving or cost‐effectiveness, but the outcome of transplantation in terms of diabetes complications in cases with partial graft function could affect cost‐saving and cost‐effectiveness conclusions. Conclusion: Despite limitations in the model and lack of trial data, and under the assumption that islet transplantation outcomes for young adult type 1 diabetes patients are not dependent on the source of islet cells, this health‐economic evaluation suggests that porcine islet cell xenotransplantation may prove to be a cost‐effective and possibly cost‐saving procedure for type 1 diabetes compared to standard management.     

CD40‐Specific Costimulation Blockade Enhances Neonatal Porcine Islet Survival in Nonhuman Primates

The widespread clinical implementation of alloislet transplantation as therapy for type 1 diabetes has been hindered by the lack of suitable islet donors. Pig‐to‐human islet xenotransplantation is one strategy with potential to alleviate this shortage. Long‐term survival of porcine islets has been achieved using CD154‐specific antibodies to interrupt the CD40/CD154 costimulation pathway; however, CD154‐specific antibodies seem unlikely candidates for clinical translation. An alternative strategy for CD40/CD154 pathway interruption is use of CD40‐specific antibodies. Herein, we evaluate the ability of a chimeric CD40‐specific monoclonal antibody (Chi220) to protect islet xenografts. Neonatal porcine islets (～50 000 IEQ/kg) were transplanted intraportally into pancreatectomized diabetic macaques. Immunosuppression consisted of induction therapy with Chi220 and the IL‐2 receptor‐specific antibody basiliximab, and maintenance therapy with sirolimus and the B7‐specific fusion protein belatacept. Chi220 effectively promoted xenoislet engraftment and survival, with five of six treated recipients achieving insulin‐independent normoglycemia (median rejection‐free survival 59 days; mean 90.8 days, maximum 203 days). No thromboembolic phenomena were observed. CD40 represents a promising alternative to CD154 as a therapeutic target, and the efficacy of CD40‐specific antibodies in islet xenotransplantation warrants further investigation.     

Enhanced effect of human mesenchymal stem cells expressing human TNF‐αR‐Fc and HO‐1 gene on porcine islet xenotransplantation in humanized mice

Background

Porcine islet xenotransplantation is considered an attractive alternative treatment for type 1 diabetes mellitus. However, it is largely limited because of initial rejection due to Instant Blood‐Mediated Inflammatory Reaction (IBMIR), oxidative stress, and inflammatory responses. Recently, soluble tumor necrosis factor‐ɑ receptor type I (sTNF‐αR) and heme oxygenase (HO)‐1 genes (HO‐1/sTNF‐αR) have been shown to improve the viability and functionality of porcine islets after transplantation.

Methods

In this study, genetically modified mesenchymal stem cells (MSCs) expressing the HO‐1/sTNF‐αR genes (HO‐1/sTNF‐αR‐MSC) were developed using an adenoviral system, and porcine islet viability and function were confirmed by in vitro tests such as GSIS, AO/PI, and the ADP/ATP ratio after coculturing with HO‐1/sTNF‐αR‐MSCs. Subsequently, isolated porcine islets were transplanted underneath the kidney capsule of diabetic humanized mice without MSCs, with MSCs or with HO‐1/sTNF‐αR‐MSCs.

Results

According to the results, the HO‐1/sTNF‐αR‐MSC‐treated group exhibited improved survival of porcine islets and could reverse hyperglycemia more than porcine islets not treated with MSCs or islets cotransplanted with MSCs. Moreover, the HO‐1/sTNF‐αR‐MSC group maintained its morphological characteristics and the insulin secretion pattern of transplanted porcine islets similar to endogenous islets in immunocompetent humanized mice.

Conclusions

Our results suggest that HO‐1/sTNF‐αR‐MSCs are efficient tools for porcine islet xenotransplantation, and this study may provide basic information for pre‐clinical animal models and future clinical trials of porcine islet xenotransplantation.     

The Clinical Impact of Islet Transplantation

Islet cell transplantation has recently emerged as one of the most promising therapeutic approaches to improving glycometabolic control in diabetic patients and, in many cases, achieving insulin independence. Unfortunately, many persistent flaws still prevent islet transplantation from becoming the gold standard treatment for type 1 diabetic patients. We review the state of the art of islet transplantation, outcomes, immunosuppression and—most important—the impact on patients' survival and long‐term diabetic complications and eventual alternative options. Finally, we review the many problems in the field and the challenges to islet survival after transplantation. The rate of insulin independence 1 year after islet cell transplantation has significantly improved in recent years (60% at 1 year posttransplantation compared with 15% previously). Recent data indicate that restoration of insulin secretion after islet cell transplantation is associated with an improvement in quality of life, with a reduction in hypoglycemic episodes and potentially with a reduction in long‐term diabetic complications. Once clinical islet transplantation has been successfully established, this treatment could even be offered to diabetic patients long before the onset of diabetic complications.     

Native pancreatic α-cell adaptation in streptozotocin-induced diabetic primates: importance for pig islet xenotransplantation

Abstract: Background: Metabolic compatibility between donor and recipient species is an important matter for pig islet xenotransplantation. Glucagon is a key hormone for the function of pig islets as well as control of hypoglycemia in the recipients of the islets. Because a discrepancy exists in the composition of glucagon cells of pig and human/primate islets, the present study was designed to determine the role of native recipient glucagon cells in the treatment of diabetes by islet transplantation in a “pig‐to‐primate” model. Methods: Streptozotocin‐treated (50 mg/kg) monkeys (n = 12, follow‐up of 6 to 231 days) were compared with non‐diabetic animals (n = 5; follow‐up, 180 days). Metabolic [fasting and intravenous glucose tolerance tests (IVGTTs) for serum levels of glucose, insulin, glucagon] and morphologic (endocrine volume density and cell mass for insulin and glucagon) were compared between non‐diabetic and diabetic animals. Six additional diabetic primates were given transplants of 15 000 adult pig islet equivalents without immunosuppression to monitor glucose, glucagon, insulin, and porcine C‐peptide levels until 48 h after transplantation. Results: Elevated fasting blood glucose, pathologic IVGTT, destruction of 95% of β‐cell mass, and glycosylated hemoglobin (>13%) were assessed in diabetic monkeys. The serum glucagon levels and glucagon cell mass correlated significantly with diabetes time course of diabetes (R = 0.940, p = 0.005; R = 0.663, p = 0.019, respectively). A mean increase of 89% in glucagon cell mass was observed for primates suffering from diabetes >53 days. No response of glucagon secretion was observed for diabetic animals during IVGTT, because no increase of serum insulin levels followed glucose loading. Blood glucose levels dropped after pig islet xenografts in diabetic primates. This reduction was maintained by an insulin level >20 μU/ml over the period of time of xenograft function (porcine C‐peptide >0.1 ng/ml). A total restoration of native primate glucagon sensitivity to insulin was found after pig islets xenotransplantation as revealed by a reduction of 80% of the glucagon level. When graft dysfunction (>24 h post‐transplantation), the insulin level dropped and glucagon levels rose again (>50 pg/ml). Conclusions: Native glucagon cells provide morphologic and functional plasticity to diabetes. Adult pig islet xenotransplantation can restore the sensitivity of primate glucagon to insulin but cannot protect the diabetic recipient against hypoglycemia.     

Three-yr follow-up of a type 1 diabetes mellitus patient with an islet xenotransplant

In order to alleviate the shortage of human donors, the use of porcine islets of Langerhans for xenotransplantation in diabetic patients has been proposed as a solution. To overcome rejection, we have developed a procedure for protecting the islets by combining them with Sertoli cells and placing them in a novel subcutaneous device, that generates an autologous collagen covering. A type 1 diabetic woman was closely monitored for 10 months, and then transplanted in two devices with two months of difference and a third time after 22 months. Here we present a three-yr follow-up. The close monitoring induced a rapid decrease in exogenous insulin requirements, which stabilized between 19 and 28 IU/d for nine months. After transplantation, the requirements reduced further to below 6 IU/d and for some weeks she was insulin free. Glycosylated hemoglobin levels decreased concomitantly. Porcine insulin could be detected in the serum after a glucose challenge and insulin positive cells inside a removed device after two yr. No complications have arisen and no porcine endogenous retrovirus infection has been detected through PCR and RT-PCR. This case demonstrates the feasibility of using the xenotransplantation of porcine cells to alleviate metabolic complications and insulin requirements in type 1 diabetic patients.     

Islet cell xenotransplantation: a serious look toward the clinic

Type I diabetes remains a significant clinical problem in need of a reliable, generally applicable solution. Both whole organ pancreas and islet allotransplantation have been shown to grant patients insulin independence, but organ availability has restricted these procedures to an exceptionally small subset of the diabetic population. Porcine islet xenotransplantation has been pursued as a potential means of overcoming the limits of allotransplantation, and several preclinical studies have achieved near‐physiologic function and year‐long survival in clinically relevant pig‐to‐primate model systems. These proof‐of‐concept studies have suggested that xenogeneic islets may be poised for use in clinical trials. In this review, we examine recent progress in islet xenotransplantation, with a critical eye toward the gaps between the current state of the art and the state required for appropriate clinical investigation.     

A review of piscine islet xenotransplantation using wild‐type tilapia donors and the production of transgenic tilapia expressing a “humanized” tilapia insulin

Most islet xenotransplantation laboratories have focused on porcine islets, which are both costly and difficult to isolate. Teleost (bony) fish, such as tilapia, possess macroscopically visible distinct islet organs called Brockmann bodies which can be inexpensively harvested. When transplanted into diabetic nude mice, tilapia islets maintain long‐term normoglycemia and provide human‐like glucose tolerance profiles. Like porcine islets, when transplanted into euthymic mice, they are rejected in a CD4 T‐cell‐dependent manner. However, unlike pigs, tilapia are so phylogenetically primitive that their cells do not express α(1,3)Gal and, because tilapia are highly evolved to live in warm stagnant waters nearly devoid of dissolved oxygen, their islet cells are exceedingly resistant to hypoxia, making them ideal for transplantation within encapsulation devices. Encapsulation, especially when combined with co‐stimulatory blockade, markedly prolongs tilapia islet xenograft survival in small animal recipients, and a collaborator has shown function in diabetic cynomolgus monkeys. In anticipation of preclinical xenotransplantation studies, we have extensively characterized tilapia islets (morphology, embryologic development, cell biology, peptides, etc.) and their regulation of glucose homeostasis. Because tilapia insulin differs structurally from human insulin by 17 amino acids, we have produced transgenic tilapia whose islets stably express physiological levels of humanized insulin and have now bred these to homozygosity. These transgenic fish can serve as a platform for further development into a cell therapy product for diabetes.     

Long‐Term Controlled Normoglycemia in Diabetic Non‐Human Primates After Transplantation with hCD46 Transgenic Porcine Islets

Xenotransplantation of porcine islets into diabetic non‐human primates is characterized by (i) an initial massive graft loss possibly due to the instant blood‐mediated inflammatory reaction and (ii) the requirement of intensive, clinically unfriendly immunosuppressive therapy. We investigated whether the transgenic expression of a human complement‐regulatory protein (hCD46) on porcine islets would improve the outcome of islet xenotransplantation in streptozotocin‐induced diabetic Cynomolgus monkeys. Immunosuppression consisted of thymoglobulin, anti‐CD154 mAb for costimulation blockade, and mycophenolate mofetil. Following the transplantation of islets from wild‐type pigs (n = 2) or from 1,3‐galactosyltransferase gene‐knockout pigs (n = 2), islets survived for a maximum of only 46 days, as evidenced by return to hyperglycemia and the need for exogenous insulin therapy. The transplantation of islets from hCD46 pigs resulted in graft survival and insulin‐independent normoglycemia in four of five monkeys for the 3 months follow‐up of the experiment. One normalized recipient, selected at random, was followed for >12 months. Inhibition of complement activation by the expression of hCD46 on the pig islets did not substantially reduce the initial loss of islet mass, rather was effective in limiting antibody‐mediated rejection. This resulted in a reduced need for immunosuppression to preserve a sufficient islet mass to maintain normoglycemia long‐term.     

Chapter 1: Key ethical requirements and progress toward the definition of an international regulatory framework

Abstract:  The outstanding results recently obtained in islet xenotransplantation suggest that porcine islet clinical trials may soon be scientifically appropriate. Before the initiation of such clinical studies, however, it is essential that a series of key ethical and regulatory conditions are satisfied. As far as ethics is concerned, the fundamental requirements have been previously reported in a position paper of the Ethics Committee of the International Xenotransplantation Association. These include aspects related to the selection of adequately informed, appropriate recipients; animal breeding and welfare; safety issues and the need for a favorable risk/benefit assessment based on strong efficacy data in relevant xenotransplantation studies in the primate. As most diabetic patients are not at risk of short-term mortality without islet transplantation, only a small subset of patients could currently be considered for any type of islet transplant. However, there are potential advantages to xenotransplantation that could result in a favorable benefit-over-harm determination for islet xenotransplantation in this subpopulation and ultimately in a broader population of diabetic patients. With regard to regulatory aspects, the key concepts underlying the development of the regulatory models in existence in the United States, Europe and New Zealand are discussed. Each of these models provides an example of a well-defined regulatory approach to ensure the initiation of well-regulated and ethically acceptable clinical islet xenotransplantation trials. At this stage, it becomes apparent that only a well-coordinated international effort such as that initiated by the World Health Organization, aimed at harmonizing xenotransplantation procedures according to the highest ethical and regulatory standards on a global scale, will enable the initiation of clinical xenotransplantation trials under the best auspices for its success and minimize any risk of failure.     

Reluctance of French patients with type 1 diabetes to undergo pig pancreatic islet xenotransplantation

INTRODUCTION: Type 1 diabetes could possibly be treated by transplantation of pig pancreatic islets. In addition to medical difficulties and ethical problems, social hurdles may need to be overcome. We have evaluated the attitude of patients with type 1 diabetes to the xenotransplantation of pig pancreatic islets and to the potential risks associated with such treatment. METHODS: A survey of 214 patients with type 1 diabetes was carried out in France based on a multiple-choice questionnaire. RESULTS: At first, 52.0% of these patients indicated that they would agree to receive pig islet xenografts. The main sources of reluctance were the 'risk of disease transmission' (55.5%) and 'risks not yet identified' (48.7%). After they were told of the risk of cancer or infection associated with immunosuppression, 74.9% of the respondents chose to refuse the transplant, compared with 48.0% before they heard of such risks. A 68.1% would refuse the xenotransplant if it would not exempt them completely from being treated by insulin injections. Discontinuing insulin injections was the most important priority for diabetic patients (73.5%), rather than limitation of diabetes-related complications (52.5%) or increase in life expectancy (44.0%). After they were informed of all of the risks associated with the procedure, 70.5% of the respondents decided they would rather not take any risks, and said they would refuse pig islet transplantation. CONCLUSION: When diabetic patients learned about potential infectious risks and other risks associated with immunosuppression, reluctance to undergo xenotransplantation gained in significance or even led to refusal of the procedure.     

Pre-clinical model of composite foetal pig pancreas fragment/renal xenotransplantation to treat renal failure and diabetes

Hawthorne WJ, Simond DM, Stokes R, Patel AT, Walters S, Burgess J, O’Connell PJ. Pre‐clinical model of composite foetal pig pancreas fragment/renal xenotransplantation to treat renal failure and diabetes. Xenotransplantation 2011; 18: 390–399. © 2011 John Wiley & Sons A/S. Abstract: Background: Development of a limitless source of β cells for xenotransplantation into patients suffering type 1 diabetes and renal failure that can control their diabetes and provide normal renal function in one procedure would be a major achievement. For the islet tissue to survive transplantation, as an islet‐kidney composite graft this would have significant advantages. It would simplify the surgical procedure; remove the complications caused by the exocrine pancreas whilst reversing diabetes and uraemia. It was our hypothesis that a composite foetal porcine pancreas fragment (FPPF)/renal graft could achieve these objectives in a large pre‐clinical animal model as a means to establish whether this would be feasible before moving to the clinic. Methods: Inbred ‘Westran’ pig FPPF were transplanted under the kidney capsule of syngeneic Westran pig recipients without immunosuppression. Following maturation of the FPPF under the renal subcapsular space of this recipient, this kidney bearing the composite FPPF piggyback graft was removed and transplanted into another nephrectomized and pancreatectomized recipient to demonstrate function. Results: Under the kidney capsule of the first transplant group (n = 6), the FPPF‐transplanted tissue developed and matured to form islet cell nests. These composite FPPF/renal grafts were then successfully removed and transplanted into the second functional assessment recipient group. This second group of six composite FPPF/renal‐grafted pigs had normal renal function for more than 44 days and normal glucose homoeostasis without exogenous insulin as assessed by normal glucose tolerance tests, K values and normal glucagon secretion. Histological analysis showed despite the ischaemic insult during the composite kidney transplant procedure, there was appropriate development of islet‐like structures up to and beyond 224 days after the original transplantation under the kidney capsule. Conclusions: This study shows that the use of composite FPPF/renal grafts can cure both diabetes and renal failure with a single‐transplant procedure. Using such composite grafts for xenotransplantation would simplify the surgical procedure and protect the islet graft from the immediate innate immune response.     

Islet transplantation in type 1 diabetic patients

Islet transplantation has been shown to improve overall glucose homeostasis and retard the progression of complications in type I diabetic patients. Also the percentage of recipients achieving complete insulin independence has progressively increased over recent years. An unsolved problem is whether the short-term graft function is secondary to progressive islet exhaustion or to recurrent autoimmunity despite the immunosuppressive therapy. The indications for this procedure remain limited to selected type I diabetic patients. The risks of the immunosuppressive therapy are only proposed to type I diabetic recipients with uncontrolled disease, despite all efforts of the diabetologist and the patient (brittle diabetes), or with a poor quality of life due to unawareness hypoglycemia or severe chronic and progressive complications.     

Islet transplantation

Recently, significant advances have been made in the number and purity of islets that can be retrieved from the human pancreas, thus enabling several centers to initiate or resume clinical trials of islet transplantation in type I diabetic patients. Although the success rate of islet transplantation is lower than that of pancreas transplantation in terms of achievement of insulin-independence, islet transplantation has significant potential advantages over vascularized pancreas transplantation: it is a simple and safe procedure; it has the potential to be performed on an outpatient basis; it offers access to cell banking after cryopreservation; it offers the potential advantages of pre-transplant reduction of im-munogenecity; and it even offers the future feasibility of xenotransplantation. In this article, the current status of clinical trials and future perspectives of islet transplantation, including immunomodulation, immunotolerance, immunoisolation, and xenotransplantation, are reviewed. Received for publication on Feb. 24, 1999; accepted on March 28, 1999     

Attitude toward xenotransplantation of patients prior and after human organ transplantation

Stadlbauer V, Stiegler P, Müller S, Schweiger M, Sereingg M, Tscheliessnigg KH, Freidl W. Attitude toward xenotransplantation of patients prior and after human organ transplantation.
Clin Transplant 2011: 25: 495–503. © 2010 John Wiley & Sons A/S. Abstract: Xenotransplantation is a potential strategy to overcome the shortage of human donor organs. As this technique has a major medical and psychological impact on patients and their family and friends, the attitude of patients currently waiting for organ transplantation is important. Therefore, we conducted a survey on the attitude toward xenotransplantation of patients on the waiting list and already transplanted patients. Patients received detailed information before being asked to fill in the questionnaire. We found that 65% would accept xenotransplantation, irrespective of gender, education level or if the patients were on the waiting list or already transplanted. The most common concern was transmission of diseases or genetic material, followed by psychological concerns and ethical issues. More patients had a positive attitude toward accepting cell or tissue transplantation when compared to whole organs. Pig pancreas islet cell transplantation is generally well accepted, patients with diabetes mellitus show even higher acceptance rates than patients without diabetes. In conclusion, xenotransplantation seems to be well accepted in patients who are potential future candidates for organ transplantation. Informing patients about the current status of research tended to decrease acceptance rates slightly.     

Diabetic rats and mice are resistant to porcine and human insulin: flawed experimental models for testing islet xenografts

Pepper AR, Gall C, Mazzuca DM, Melling CWJ, White DJG. Diabetic rats and mice are resistant to porcine and human insulin: flawed experimental models for testing islet xenografts.
Xenotransplantation 2009; 16: 502–510. © 2009 John Wiley & Sons A/S. Abstract: Background: Islet transplantation is potentially a promising therapy for the restoration of carbohydrate control to diabetic patients. However, the global application of islet transplantation requires a ubiquitous source of β cells. The xenotransplantation of porcine islets would provide such a source. Success in porcine islet xenografting has been achieved in diabetic primates. However, there are few reports of reversal of diabetes with porcine islet xenografts in rodent models of diabetes, relative to the number of successful rodent experiments performed as allografts. Here we report for the first time the inability of porcine (and human) insulin to control blood glucose levels in diabetic rodents determined by a series of dose escalating studies. Methods: Insulin was administered intravenously to streptozotocin induced diabetic Lewis rats, Balb/c and athymic Balb/c mice (n = 5 per group) at the following doses: Group I “physiological dose” (pd) of 0.16 U/kg for a total dose of 40 mU to a 250 g rat. Group II received 0.64 U/kg (4xpd), group III 1.6 U/kg (10xpd) and group IV 6.4 U/kg (40xpd). Blood glucose levels were monitored in each animal at seven time points: 0 (pre‐injection), 10 min, 20 min, 30 min, 45 min, 1 h, 1.5 h, 2 h and 3 h post‐injection. Serum insulin levels were also determined. Results: Diabetic Lewis rats achieved a maximum reduction in blood glucose from 22.1 ± 1.8mmol/l to 8.0 ± 3.1 mmol/l (a 63.7% reduction), 90 minutes post‐injection of 6.4 U/kg dose of porcine insulin (40xpd). Human insulin was less effective at reducing blood glucose levels in rats than porcine insulin (P < 0.001). Porcine insulin reduced blood glucose levels in Balb/c mice from a mean of 18.2 ± 2.1 mmol/l to a hypoglycemic minimum of 1.26 ± 0.18 mmol/l a reduction of 93.0%, 60 min post‐injection of the maximum dose of 6.4 U/kg. Balb/c mice were significantly more responsive to porcine insulin than Lewis rats at doses of 0.64 U/kg (P < 0.001), 1.6 U/kg (P < 0.05) and 6.4 U/kg (P < 0.001). Athymic Balb/c nude mice reached a maximum reduction in blood glucose from 21.6 ± 1.8 mmol/l to 3.6 ± 0.9 mmol/l (a 83.4% reduction) 120 min post‐injection at a dose of 6.4 U/kg. Overall, athymic Balb/c nude mice were more resistant to porcine insulin than immunocompetent Balb/c mice at doses of 0.64 U/kg (P < 0.001), 1.6 U/kg (P < 0.001) and 6.4 U/kg (P < 0.05). Insulin diluent alone marginally increased blood glucose levels in all animals tested. Conclusions: Our results suggest that restoration of normoglycemia in diabetic rodents is not ideal for testing porcine islets xenografts since the reversals of diabetes in these species requires 20 to 40 times the dose of porcine insulin used in humans.     

Experimental and clinical islets transplantation. Current status]

25 years have passed since the first enzymatic isolation of islets of Langerhans from the rat pancreas. During this period of time, it could be demonstrated that transplantation of syngeneic islets intraportally into streptozoticin-treated diabetic recipients (rat, mouse) does not only guarantee long term normoglycemia but inhibits also typical late complications of the disease. Allogeneic islets, however, exhibit strong immunogenicity (rejection within a few days) which can be overcome by various immunomodulating in vitro measures of the islets before transplantation. Isolated islets have been successfully transplanted also in larger animals as dogs and pigs, when transplanted in an autologous or allogeneic system. In human diabetes the success rate of islet transplantation up to now is low and cannot be compared with the results in experimental diabetes. The reasons are manyfold: islet damage due to long ischemia time, low number of islets, low purity, lack of diagnostic markers which indicate rejection, autoimmune destruction. The fact that in the meantime a few patients remain insulin independent after a single islet transplant with the maximum of 2 years indicates however that this method in principle may serve as a tool for the treatment of diabetes. This is underlined by several advantages compared to pancreatic organ transplantation as low risk of the procedure for the recipient and the possibility of repeated transplantation. In addition, in the future xenotransplantation of (porcine) islets might be feasible.     

Engraftment of Adult Porcine Islet Xenografts in Diabetic Nonhuman Primates Through Targeting of Costimulation Pathways

Recent advances in human allogeneic islet transplantation have established beta-cell replacement therapy as a potentially viable treatment option for individuals afflicted with Type 1 diabetes. Two recent successes, one involving neonatal porcine islet xenografts transplanted into diabetic rhesus macaques treated with a costimulation blockade-based regimen and the other involving diabetic cynomolgus monkeys transplanted with adult porcine islet xenografts treated with an alternative multidrug immunosuppressive regimen have demonstrated the feasibility of porcine islet xenotransplantation in nonhuman primate models. In the current study, we assessed whether transplantation of adult porcine islet xenografts into pancreatectomized macaques, under the cover of a costimulation blockade-based immunosuppressive regimen (CD28 and CD154 blockade), could correct hyperglycemia. Our findings suggest that the adult porcine islets transplanted into rhesus macaques receiving a costimulation blockade-based regimen are not uniformly subject to hyperacute rejection, can engraft (2/5 recipients), and have the potential to provide sustained normoglycemia. These results provide further evidence to suggest that porcine islet xenotransplantation may be an attainable strategy to alleviate the islet supply crisis that is one of the principal obstacles to large-scale application of islet replacement therapy in the treatment of Type 1 diabetes.     

腹腔镜微囊化猪胰岛小网膜腔内异种移植的临床研究

目的 探讨腹腔镜技术应用于海藻酸钠－聚赖氨酸－海藻酸钠（APA）微囊包裹猪胰岛小网膜腔内异种移植术的可行性。方法 采用腹腔镜技术对5例6人次I型糖尿病病人进行了APA微囊新生猪胰岛小网膜腔内异种移植治疗，观察病人移植前后空腹血糖，C肽和胰岛素用量变化。结果 全部病例均未出现手术并发症。术后受体C肽较术前升高3－23倍，胰岛素用量明显减少，其中1例完全停用胰岛素，成为胰岛素不依赖者达31个月。结论 腹腔镜技术用于临床微囊化新生猪胰岛小网膜腔移植术治疗I型糖尿病安全可行，有较高的临床应用价值。