Porcine Islet Transplantation Research Articles

Clinical Trial Protocol for Porcine Islet Xenotransplantation in South Korea.

Islet transplantation holds promise for treating selected type 1 diabetes mellitus patients, yet the scarcity of human donor organs impedes widespread adoption. Porcine islets, deemed a viable alternative, recently demonstrated successful longterm survival without zoonotic risks in a clinically relevant pig-to-non-human primate islet transplantation model. This success prompted the development of a clinical trial protocol for porcine islet xenotransplantation in humans. A single-center, open-label clinical trial initiated by the sponsor will assess the safety and efficacy of porcine islet transplantation for diabetes patients at Gachon Hospital. The protocol received approval from the Gachon Hospital Institutional Review Board (IRB) and the Korean Ministry of Food and Drug Safety (MFDS) under the Investigational New Drug (IND) process. Two diabetic patients, experiencing inadequate glycemic control despite intensive insulin treatment and frequent hypoglycemic unawareness, will be enrolled. Participants and their family members will engage in deliberation before xenotransplantation during the screening period. Each patient will receive islets isolated from designated pathogen-free pigs. Immunosuppressants and systemic infection prophylaxis will follow the program schedule. The primary endpoint is to confirm the safety of porcine islets in patients, and the secondary endpoint is to assess whether porcine islets can reduce insulin dose and the frequency of hypoglycemic unawareness. A clinical trial protocol adhering to global consensus guidelines for porcine islet xenotransplantation is presented, facilitating streamlined implementation of comparable human trials worldwide.

Combined islet and kidney xenotransplantation for diabetic nephropathy: an update in ongoing research for a clinically relevant application of porcine islet transplantation.

Combined islet and kidney xenotransplantation for the treatment of diabetic nephropathy represents a compelling and increasingly relevant therapeutic possibility for an ever-growing number of patients who would benefit from both durable renal replacement and cure of the underlying cause of their renal insufficiency: diabetes. Here we briefly review immune barriers to islet transplantation, highlight preclinical progress in the field, and summarize our experience with combined islet and kidney xenotransplantation, including both challenges with islet-kidney composite grafts as well as our recent success with sequential kidney followed by islet xenotransplantation in a pig-to-baboon model.

Development and characterization of islet-derived mesenchymal stem cells from clinical grade neonatal porcine cryopreserved islets.

Porcine tissues display a great potential as donor tissues in xenotransplantation, including cell therapy. Cryopreserving clinical grade porcine tissue and using it as a source for establishing therapeutic cells should be advantageous for transportation and scheduled manufacturing of MSCs. Of note, we previously performed encapsulated porcine islet transplantation for the treatment of unstable type 1 diabetes mellitus in the clinical setting. It has been reported that co-transplantation of islets and Mesenchymal stem cells (MSCs) enhanced efficacy. We assume that co-transplantation of porcine islets and porcine islet-derived MSCs could improve the efficacy of clinical islet xenotransplantation. MSCs were established from fresh and cryopreserved non-clinical grade neonatal porcine islets and bone marrow (termed non-clinical grade npISLET-MSCs and npBM-MSCs, respectively), as well as from cryopreserved clinical grade neonatal porcine islets (termed clinical grade npISLET-MSCs). Subsequently, the cell proliferation rate and diameter, surface marker expression, adipogenesis, osteogenesis, and colony-forming efficiency of the MSCs were assessed. Cell proliferation rate and diameter did not differ between clinical grade and non-clinical grade npISLET-MSCs. However, non-clinical grade npBM-MSCs were significantly shorter and smaller than both npISLET-MSCs (p<0.05). MSC markers (CD29, CD44, and CD90) were strongly expressed in clinical grade npISLET-MSCs and non-clinical grade npISLET-MSCs and npBM-MSCs. The expression of MSC-negative markers CD31, CD34, and SLA-DR was low in all MSCs. Clinical grade npISLET-MSCs derived from adipose and osteoid tissues were positive for Oil Red and alkaline phosphatase staining. The results of colony-forming assay were not significantly different between clinical grade npISLET-MSCs and non-clinical grade npBM-MSCs. The method described herein was successful in of developing clinical grade npISLET-MSCs from cryopreserved islets. Cryopreserved clinical grade porcine islets could be an excellent stable source of MSCs for cell therapy.

P.18: No tumorigenicity after 26 weeks of follow-up after subcutaneous transplantation of porcine islets in immunodeficient mice

P.18: No tumorigenicity after 26 weeks of follow-up after subcutaneous transplantation of porcine islets in immunodeficient mice

Neonatal islets from human PD-L1 transgenic pigs reduce immune cell activation and cellular rejection in humanized nonobese diabetic-scid IL2rγnull mice

Strong xenorejection limits the clinical application of porcine islet transplantation in type 1 diabetes. Targeting T cell-mediated rejection is one of the main approaches to improve long-term graft survival. Here we study engraftment and survival of porcine islet cells expressing human programmed cell death ligand-1 (hPD-L1) in a humanized mouse model. Neonatal islet-like clusters (NPICCs) from transgenic hPD-L1 (hPD-L1-Tg) and wild-type (Wt) pigs were transplanted into nonobese diabetic-scid IL2rγnull mice stably reconstituted with human immune cells (hPD-L1 n = 10; Wt n = 6). Primary endpoint was development of normoglycemia during a 16-week observation period after transplantation. Secondary endpoints were porcine C-peptide levels and immune cell infiltration. Animals transplanted with hPD-L1-Tg neonatal islet-like clusters achieved a superior normoglycemic rate (50% versus 0%) and significantly higher plasma C-peptide levels as compared to the Wt group, indicating long-term beta cell function. Intracytoplasmic fluorescence-activated cell sorting analysis and immunohistochemistry revealed significantly decreased frequencies of interferonγ-expressing splenic hCD8-positive T cells and reduced intragraft-infiltrating immune cells. We here demonstrate that expression of hPD-L1 provides strong islet xenograft protection without administration of immunosuppressive drugs. These findings support the hypothesis that hPD-L1 has the capacity to control cellular rejection and therefore represents a very promising transgene candidate for clinical porcine islet xenotransplantation.

Patients' opinions 10 years after receiving encapsulated porcine islet xenotransplantation without immunosuppression.

Previously we performed clinical encapsulated neonatal porcine islet transplantation under comprehensive regulation, and demonstrated the efficacy and safety. To analyze the patients' quality of life (QOL), we assessed patients' opinions 10 years after islet xenotransplantation. Twenty-one type 1 diabetic patients received microencapsulated neonatal porcine islet transplants in Argentina were enrolled. Seven patients were enrolled in efficacy and safety study and 14 patients were enrolled in safety studies. Patients' opinions related to the current and pre-transplant status of diabetes control, blood glucose levels, severe hypoglycemia, and hyperglycemia required hospitalization were analyzed. In addition, opinions related to islet xenotransplantation were assessed. At the time of this survey, average HbA1c was still significantly lower compared to pre-transplantation (8.5±0.9 (%) at pre-transplant and 7.4±0.5(%) at the survey, p<.05) and average insulin dose were also lower (0.95±0.32 (IU/kg) at pre-transplant and 0.73±0.27 (IU) at the survey). The majority of patients improved diabetes control (71%), blood glucose levels (76%), severe hypoglycemia (86%) and hyperglycemia required hospitalization (76%), and no patients deteriorated in all of the categories when compared with pre-transplantation. No patients had cancer, or psychological problem, and one patient had a serious adverse event. The majority of patients wanted to recommend this treatment to other patients (76%) and receive booster transplantation (85.7%). The majority of patients had positive opinions related to the encapsulated porcine islet xenotransplantation 10 years after transplantation.

Pancreas Preservation with a Neutrophil Elastase Inhibitor, Alvelestat, Contributes to Improvement of Porcine Islet Isolation and Transplantation.

For pancreatic islet transplantation, pancreas procurement, preservation, and islet isolation destroy cellular and non-cellular components and activate components such as resident neutrophils, which play an important role in the impairment of islet survival. It has been reported that inhibitors of neutrophil elastase (NE), such as sivelestat and α1-antitrypsin, could contribute to improvement of islet isolation and transplantation. In this study, we investigated whether pancreatic preservation with alvelestat, a novel NE inhibitor, improves porcine islet yield and function. Porcine pancreata were preserved with or without 5 μM alvelestat for 18 h, and islet isolation was performed. The islet yields before and after purification were significantly higher in the alvelestat (+) group than in the alvelestat (−) group. After islet transplantation into streptozotocin-induced diabetic mice, blood glucose levels reached the normoglycemic range in 55% and 5% of diabetic mice in the alvelestat (+) and alvelestat (−) groups, respectively. These results suggest that pancreas preservation with alvelestat improves islet yield and graft function and could thus serve as a novel clinical strategy for improving the outcome of islet transplantation.

Long-term control of diabetes in a nonhuman primate by two separate transplantations of porcine adult islets under immunosuppression

Porcine islet transplantation is an alternative to allo-islet transplantation. Retransplantation of islets is a routine clinical practice in islet allotransplantation in immunosuppressed recipients and will most likely be required in islet xenotransplantation in immunosuppressed recipients. We examined whether a second infusion of porcine islets could restore normoglycemia and further evaluated the efficacy of a clinically available immunosuppression regimen including anti-thymocyte globulin for induction; belimumab, sirolimus, and tofacitinib for maintenance and adalimumab, anakinra, IVIg, and tocilizumab for inflammation control in a pig to nonhuman primate transplantation setting. Of note, all nonhuman primates were normoglycemic after the retransplantation of porcine islets without induction therapy. Graft survival was >100days for all 3 recipients, and 1 of the 3 monkeys showed insulin independence for >237days. Serious lymphodepletion was not observed, and rhesus cytomegalovirus reactivation was controlled without any serious adverse effects throughout the observation period in all recipients. These results support the clinical applicability of additional infusions of porcine islets. The maintenance immunosuppression regimen we used could protect the reinfused islets from acute rejection.

Long‐term porcine islet graft survival in diabetic non‐human primates treated with clinically available immunosuppressants

Although pancreatic islet transplantation is becoming an effective therapeutic option for patients with type 1 diabetes (T1D) who suffer from a substantially impaired awareness of hypoglycemia, its application is limited due to the lack of donors. Thus, pig-to-human islet xenotransplantation has been regarded as a promising alternative due to the unlimited number of "donor organs." Long-term xenogeneic islet graft survival in pig-to-non-human primate (NHP) models has mainly been achieved by administering the anti-CD154 mAb-based immunosuppressant regimen. Since the anti-CD154 mAb treatment has been associated with unexpected fatal thromboembolic complications in clinical trials, the establishment of a new immunosuppressant regimen that is able to be directly applied in clinical trials is an urgent need. We assessed an immunosuppressant regimen composed of clinically available agents at porcine islet transplantation in consecutive diabetic NHPs. Porcine islet graft survival in consecutive diabetic NHPs (n=7; >222, >200, 181, 89, 62, 55, and 34 days) without severe adverse events. We believe that our study could contribute greatly to the initiation of islet xenotransplantation clinical trials.

Rejection of xenogeneic porcine islets in humanized mice is characterized by graft-infiltrating Th17 cells and activated B cells.

Xenogeneic porcine islet transplantation is a promising potential therapy for type 1 diabetes (T1D). Understanding human immune responses against porcine islets is crucial for the design of optimal immunomodulatory regimens for effective control of xenogeneic rejection of porcine islets in humans. Humanized mice are a valuable tool for studying human immune responses and therefore present an attractive alternative to human subject research. Here, by using a pig-to-humanized mouse model of xenogeneic islet transplantation, we described the human immune response to transplanted porcine islets, a process characterized by dense islet xenograft infiltration of human CD45+ cells comprising activated human B cells, CD4+ CD44+ IL-17+ Th17 cells, and CD68+ macrophages. In addition, we tested an experimental immunomodulatory regimen in promoting long-term islet xenograft survival, a triple therapy consisting of donor splenocytes treated with ethylcarbodiimide (ECDI-SP), and peri-transplant rituximab and rapamycin. We observed that the triple therapy effectively inhibited graft infiltration of T and B cells as well as macrophages, promoted transitional B cells both in the periphery and in the islet xenografts, and provided a superior islet xenograft protection. Our study therefore indicates an advantage of donor ECDI-SP treatment in controlling human immune cells in promoting long-term islet xenograft survival.

Fibrin supports subcutaneous neonatal porcine islet transplantation without the need for pre-vascularization.

Neonatal porcine islets (NPIs) are a promising tissue source for clinical islet xenotransplantation. To facilitate graft monitoring and recovery if needed, an extra-hepatic transplant site would be optimal. In addition, islet transplantation into the portal vein has been associated with life-threatening intraperitoneal bleeding, portal vein thrombosis, hepatic steatosis, and loss of islet graft function. Although it is hypoxic, the subcutaneous space is a potential extra-hepatic location for clinical islet transplantation. In this study, we explore the benefits of fibrin scaffolds in enhancing the engraftment and long-term function of NPI grafts in this ectopic site. Diabetic immune-compromised mice were transplanted with 5000 NPIs under the kidney capsule (KC), and subcutaneously with or without fibrin (SC+F, SC, respectively). All mice were monitored for reversal of hyperglycemia and long-term metabolic function. All mice transplanted with NPI under the KC or SC+F (12/12 and 17/17, respectively) achieved normal fasting blood glucose levels between 5 and 22weeks post-transplantation and displayed normal glucose tolerance during an intraperitoneal glucose tolerance test. In contrast, NPIs transplanted SC with no fibrin (n=7) failed to obtain normoglycemia. Fibrin matrix facilitates engraftment of NPIs in the subcutaneous site of diabetic mice. These data support further investigation of the subcutaneous site for clinical islet xenotransplantation.

Is the renal subcapsular space the preferred site for clinical porcine islet xenotransplantation? Review article

It can reasonably be anticipated that, within 5-10 years, islet allotransplantation or pig islet xenotransplantation may be the preferred options for β-cell replacement therapy. The portal vein/liver is currently the preferred clinical site for free islet transplantation, constituting 90% of clinical islet transplants. Despite being the site of choice for rodent and some large animal studies, the renal subcapsular space is rarely used clinically, even though the introduction of islets intraportally is not entirely satisfactory (particularly for pig islet xenotransplantation). We questioned why this might be so. Is it perhaps based on prior clinical evidence, or from experience in nonhuman primates? When we have questioned experts in the field, no definitive answers have been forthcoming. We have therefore reviewed the relevant literature, and still cannot find a convincing reason why the renal subcapsular space has been so relatively abandoned as a site for clinical islet transplantation. Owing to its sequestered environment, subcapsular transplantation might avoid some of the remaining challenges of intraportal transplantation. This may be particularly true when using pig islets for xenotransplantation, which are exceptionally pure in comparison to human islets used in auto- or allo-transplantation. With evidence from the literature, we question the notion that the subcapsular space is inhospitable to islet transplantation and suggest that, when porcine islet transplantation is introduced, this site should perhaps be reconsidered.

Overcoming Immunobiological Barriers Against Porcine Islet Xenografts: What Should Be Done?

Porcine islets might represent an ideal solution to the severe shortage of living donor islets available for transplantation and thus have great potential for the treatment of diabetes. Although tremendous progress has been achieved through recent experiments, the immune response remains a major obstacle. This review first describes the 3 major pathways of rejection: hyperacute rejection mediated by preformed natural antibodies and complement, instant blood-mediated inflammatory reactions, and acute cell-mediated rejection. Furthermore, this review examines immune-related strategies, including major advances, which have been shown to extend the life and/or function of porcine islets in vitro and in vivo: (1) genetic modification to make porcine islets more compatible with the recipient, (2) optimization of the newly defined biological agents that have been shown to promote long-term survival of xenografts in nonhuman primates, and (3) development of novel immunoisolation technologies that maintain the long-term survival of islet xenografts without the use of systemic immunosuppressive drugs. Finally, the clinical application of porcine islet transplantation is presented. Even though less clinical information is available, experimental data indicate that porcine islet xenografts are likely to become a standard treatment for patients with type 1 diabetes in the future.

Absence of spontaneous regeneration of endogenous pancreatic β-cells after chemical-induced diabetes and no effect of GABA on α-to-β cell transdifferentiation in rhesus monkeys

β-cell deficiency is common feature of type 1 and late-stage of type 2 diabetes mellitus. Thus, β−cell replacement therapy has been the focus of regenerative medicine past several decades. Particularly, evidences suggest that β−cell regeneration via transdifferentiation from sources including α-cells is promising. However, data using higher mammals besides rodents are scarce. Here, we examined whether endogenous pancreatic β-cells could regenerate spontaneously or under normoglycemia following porcine islet transplantation for varied periods up to 1197 days after streptozotocin-induced diabetes, and remaining α-cells transdifferentiate into β-cells by GABA treatment in vivo and in vitro. The results showed that endogenous β-cells rarely regenerate in both conditions as evidenced by stagnant serum C-peptide levels and β-cell number in the pancreas, and the remaining α-cells did not transdifferentiate into β-cells by GABA treatment. Collectively, we concluded that monkey β-cells had relatively low regenerative potential compared with rodent counterpart and GABA treatment could not induce α-to-β-cell transdifferentitation.

The Value of Glycated Albumin for Monitoring Graft Function in the Non-Human Primate Porcine Islet Transplantation Model

Background The development of a precise and simple-to-use monitoring tool for islet graft function is important in clarifying the causes of graft loss, identifying appropriate therapy, and ensuring graft survival in the nonhuman primate (NHP) model of porcine islet transplantation (PITx). Glycated albumin (GA) is an indicator of intermediate-term changes in blood glucose control and is useful in clinical diabetes management. The validity of GA for monitoring graft function in NHP recipients of PITx was evaluated using a retrospective analysis of cohort samples. Methods Data from a total of 23 PITxs performed in 20 recipients (3 were re-transplanted) were included in this study. Islet clusters purified from adult wild-type pigs were transplanted via the intraportal route into streptozotocin-induced diabetic rhesus monkeys with immune suppression. Blood samples were obtained once per week from the recipients until they lost insulin-independence (Ins-Ind). Blood was also obtained from 69 non-diabetic monkeys that served as a control group. The levels of GA and albumin in stored plasma aliquots were measured using each enzymatic method, and the GA result was expressed as the percentage of GA level to the total albumin level. Results The median level of GA in the recipients on the day of PITx (median 18.6%, 95% confidence interval [CI] 16.7-20.4%) was significantly higher than that of healthy controls (median 9.14%, 95% CI 9.0-9.3%, P < 0.0001). However, the level decreased after PITx and remained low or increased depending on the extent of residual graft function. The GA level at a nadir (median 11.6%, 95% CI 10.8-13.0%) and the time to reach a nadir (median 43 days, 95% CI 21.7-69.3 days) correlated with Ins-Ind duration (rho [ρ] = -0.605, P = 0.0028 and ρ = 0.662, P = 0.0008, respectively]. The GA level strongly correlated with KG, the glucose disappearance rate during intravenous glucose tolerance testing (ρ = -0.76, P < 0.0001). The GA levels at post-transplant week (PTW) 3 and at PTW 4 in recipients with long-term Ins-Ind (>90 days) were significantly lower than those with short-term Ins-Ind, revealing excellent performance for prediction of long-term Ins-Ind, similar to that of porcine C-peptide (historic data). Conclusions As a surrogate indicator for graft function, serial measurement of GA may provide supplemental information to conventional monitoring techniques for graft function in assessing porcine islet grafts in NHP models.

Construction of EMSC-Islet Co-Localizing Composites for Xenogeneic Porcine Islet Transplantation

Construction of EMSC-Islet Co-Localizing Composites for Xenogeneic Porcine Islet Transplantation

Correlation between Islet Number in the Small Biopsy Liver and Blood Glucose Level after Pig to Non-Human Primate Islet Xenotransplantation Model

Introduction Pig to non-human primate (NHP) islet xenotransplantation is currently being explored as a pre-clinical model for treatment of type 1 diabetes patients with hypoglycemia unawareness. Pig islet has been shown to regulate blood glucose control in diabetic NHPs. However, due to initial immune responses including IBMIR etc., a large number of islets are destroyed and subsequently the remaining islets can engraft and regulate blood glucose level in the recipients. Among these pre-clinical studies, the proper number of islets required for blood glucose level control in diabetic NHPs has not been reported. Here, we measure the number of islets present in small biopsy liver samples from NHPs underwent porcine islet transplantation and correlate its number with blood glucose levels during follow-up periods. Method Pig islets were isolated from designated pathogen-free SNU miniature pigs and transplanted via a portal vein into streptozotocin-induced diabetic monkeys (Rhesus macaque). After transplantation, 42 biopsies were performed from 29 NHPs. The experimental group was divided into three groups; normoglycemia (about 100-150 mg/dl), intermediate hyperglycemia (150-250 mg/dl) and hyperglycemia (more than 250 mg/dl) according to blood glucose levels. To measure the number of transplanted islets, a biopsy of the distal portion of the liver was performed and the biopsied samples were stained with anti-insulin antibodies. Also, semi-quantitative histological and statistical analyses were conducted. Result Pig islets were positively stained with anti-insulin antibody in the liver samples from the recipient NHPs. The number of stained islets per cm2 was measured in liver section, with its number ranging from 0 to 26.6. The values was 3.89-26.6, 1.18-3.77, and 0-2.53 in the normoglycemia, intermediate hyperglycemia, and hyperglycemia group, respectively. Importantly, islet number in the liver section was negatively correlated to the level of fasting blood glucose at the day of biopsy and this relationship is highly significant (Figure 1). Conclusion The number of islets present in small biopsy liver samples is significantly correlated with blood glucose level in islet recipient NHPs. This finding suggests that islet number in the small liver biopsy samples can represent engrafted islet mass and thus be potentially one of parameters to predict the outcome of islet transplantation.This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare, Republic of Korea (Project No. HI13C0954) and the National Research Foundation of Korea (Project No. NRF-2017R1D1A1B03030897). Anti-CD40 antibody used in these studies was provided by the Nonhuman Primate Reagent Resource supported by the NIH Nonhuman Primate Reagent Resource (U24 AI126683 and R24 OD10976).

Construction of EMSC-islet co-localizing composites for xenogeneic porcine islet transplantation

Pancreatic islet transplantation is an ultimate solution for treating patients with type 1 diabetes (T1D). The pig is an ideal donor of islets for replacing scarce human islets. Besides immunological hurdles, non-immunological hurdles including fragmentation and delayed engraftment of porcine islets need solutions to succeed in porcine islet xenotransplantation. In this study, we suggest a simple but effective modality, a cell/islet co-localizing composite, to overcome these challenges. Endothelial-like mesenchymal stem cells (EMSCs), differentiated from bone-marrow derived mouse mesenchymal stem cells (MSCs), and MSCs evenly coated the surface of porcine islets (>85%) through optimized culture conditions. Both MSCs and EMSCs significantly reduced the fragmentation of porcine islets and increased the islet masses, designated as islet equivalents (IEQs). In fibrin in vitro and in vivo angiogenesis analysis, constructed EMSC-islet composites showed higher angiogenic potentials than naked islets, MSC-islet composites, or human endothelial cell-islet composites. This novel delivery method of porcine islets may have beneficial effects on the engraftment of transplanted islets by prevention of fragmentation and enhancement of revascularization.

The value of glycated albumin for the prediction of graft outcome in the non-human primate porcine islet transplantation model.

The development of a precise and easy-to-use tool for monitoring islet graft function is important in clarifying the causes of graft loss, identifying appropriate therapy, and ensuring graft survival in the nonhuman primate (NHP) model of porcine islet transplantation (PITx). Glycated albumin (GA) is an indicator of intermediate-term changes in blood glucose control and is useful in clinical diabetes management. The validity of GA for monitoring graft function in NHP recipients of PITx was evaluated using a retrospective analysis of cohort samples. Data from a total of 23 PITxs performed in 20 recipients (3 were retransplanted) were included in this study. Islet clusters purified from adult wild-type pigs were transplanted via the intraportal route into streptozotocin-induced diabetic rhesus monkeys with immune suppression. Blood samples were obtained once per week from the recipients until they lost insulin-independence. Blood samples were also obtained from 69 non-diabetic monkeys that served as a control group. The levels of GA and albumin in stored plasma aliquots were measured using each enzymatic method, and the GA result was expressed as the percentage of GA level to the total albumin level. The median level of GA in the recipients on the day of PITx (median 18.6%, 95% confidence interval [CI] 16.7%-20.4%) was significantly higher than that of healthy controls (median 9.14%, 95% CI 9.0%-9.3%, P<.0001). However, the level decreased after PITx and remained low or increased depending on the extent of residual graft function. The GA level at a nadir (median 11.6%, 95% CI 10.8%-13.0%) and the time to reach a nadir (median 43days, 95% CI 21.7-69.3days) both correlated with the duration of insulin-independence (rho [ρ]=-.605, P=.0028 and ρ=.662, P=.0008, respectively). The GA level strongly correlated with KG , the glucose disappearance rate during intravenous glucose tolerance testing (ρ=-.76, P<.0001). At post-transplant week (PTW) 3 and at PTW 4, the GA levels in recipients with long-term insulin-independence (>90days) were significantly lower than those with short-term insulin-independence, which revealed the excellent performance for the prediction of long-term insulin-independence that is comparable to that of porcine C-peptide (historic data). As a surrogate indicator for graft function, serial measurement of GA may provide Supporting Information to that obtained from conventional monitoring techniques of graft function for assessing porcine islet grafts in NHP models.

Xenoislets: porcine pancreatic islets for the treatment of type I diabetes.

Porcine islets are being extensively investigated as alternative sources of insulin-secreting cells for transplantation in insulin-dependent diabetic patients. The present review focuses on recent advances in porcine islet transplantation with particular emphasis on new transgenic pig models, islet encapsulation, and biosafety considerations. Genetic modifications aimed to reduce islet cell immunogenicity, to prolong their survival, and to improve their secretory function have been reported. Micro- and macroencapsulation of porcine islets should allow their use in the clinic with no or minimal immunosuppression. The risk of porcine endogenous retrovirus transmission is being re-evaluated since no evidence for infection was found in several clinical and preclinical studies. Pig islet xenotransplantation is still a serious contestant in the race for novel treatments for type I diabetes. Adequate pathogen screening, animal selection, and the establishment of microbiological, genetic, and potency release quality controls should increase safety and efficacy of future porcine islets transplantation clinical trials.