Pig Islet Xenotransplantation Research Articles

A brief review of the current status of pig islet xenotransplantation.

An estimated 1.5 million Americans suffer from Type I diabetes mellitus, and its incidence is increasing worldwide. Islet allotransplantation offers a treatment, but the availability of deceased human donor pancreases is limited. The transplantation of islets from gene-edited pigs, if successful, would resolve this problem. Pigs are now available in which the expression of the three known xenoantigens against which humans have natural (preformed) antibodies has been deleted, and in which several human 'protective' genes have been introduced. The transplantation of neonatal pig islets has some advantages over that of adult pig islets. Transplantation into the portal vein of the recipient results in loss of many islets from the instant blood-mediated inflammatory reaction (IBMIR) and so the search for an alternative site continues. The adaptive immune response can be largely suppressed by an immunosuppressive regimen based on blockade of the CD40/CD154 T cell co-stimulation pathway, whereas conventional therapy (e.g., based on tacrolimus) is less successful. We suggest that, despite the need for effective immunosuppressive therapy, the transplantation of 'free' islets will prove more successful than that of encapsulated islets. There are data to suggest that, in the absence of rejection, the function of pig islets, though less efficient than human islets, will be sufficient to maintain normoglycemia in diabetic recipients. Pig islets transplanted into immunosuppressed nonhuman primates have maintained normoglycemia for periods extending more than two years, illustrating the potential of this novel form of therapy.

Characterisation of transgenic pigs expressing a human T cell-depleting anti-CD2 monoclonal antibody.

Pig islet xenotransplantation is a potential treatment for type 1 diabetes. We have shown that maintenance immunosuppression is required to protect genetically modified (GM) porcine islet xenografts from T cell-mediated rejection in baboons. Local expression of a depleting anti-CD2 monoclonal antibody (mAb) by the xenograft may provide an alternative solution. We have previously reported the generation of GGTA1 knock-in transgenic pigs expressing the chimeric anti-CD2 mAb diliximab under an MHC class I promoter (MHCIP). In this study, we generated GGTA1 knock-in pigs in which MHCIP was replaced by the β-cell-specific porcine insulin promoter (PIP), and compared the pattern of diliximab expression in the two lines. A PIP-diliximab knock-in construct was prepared and validated by transfection of NIT-1 mouse insulinoma cells. The construct was knocked into GGTA1 in wild type (WT) porcine fetal fibroblasts using CRISPR, and knock-in cells were used to generate pigs by somatic cell nuclear transfer (SCNT). Expression of the transgene in MHCIP-diliximab and PIP-diliximab knock-in pigs was characterised at the mRNA and protein levels using RT-qPCR, flow cytometry, ELISA and immunohistochemistry. Islets from MHCIP-diliximab and control GGTA1 KO neonatal pigs were transplanted under the kidney capsule of streptozotocin-diabetic SCID mice. NIT-1 cells stably transfected with the PIP-diliximab knock-in construct secreted diliximab into the culture supernatant, confirming correct expression and processing of the mAb in β cells. PIP-diliximab knock-in pigs showed a precise integration of the transgene within GGTA1. Diliximab mRNA was detected in all tissues tested (spleen, kidney, heart, liver, lung, pancreas) in MHCIP-diliximab pigs, but was not detectable in PIP-diliximab pigs. Likewise, diliximab was present in the serum of MHCIP-diliximab pigs, at a mean concentration of 1.8 μg/mL, but was not detected in PIP-diliximab pig serum. An immunohistochemical survey revealed staining for diliximab in all organs of MHCIP-diliximab pigs but not of PIP-diliximab pigs. Whole genome sequencing (WGS) of a PIP-diliximab pig identified a missense mutation in the coding region for the dixilimab light chain. This mutation was also found to be present in the fibroblast knock-in clone used to generate the PIP-diliximab pigs. Islet xenografts from neonatal MHCIP-diliximab pigs restored normoglycemia in diabetic immunodeficient mice, indicating no overt effect of the transgene on islet function, and demonstrated expression of diliximab in situ. Diliximab was widely expressed in MHCIP-diliximab pigs, including in islets, consistent with the endogenous expression pattern of MHC class I. Further investigation is required to determine whether the level of expression in islets from the MHCIP-diliximab pigs is sufficient to prevent T cell-mediated islet xenograft rejection. The unexpected absence of diliximab expression in the islets of PIP-diliximab pigs was probably due to a mutation in the transgene arising during the generation of the knock-in cells used for SCNT.

106.5: Comparison of open surgery and ultrasound-guided percutaneous injection on the cytokine response to pig islet xenotransplantation

106.5: Comparison of open surgery and ultrasound-guided percutaneous injection on the cytokine response to pig islet xenotransplantation

Current Topics of Relevance to the Xenotransplantation of Free Pig Islets.

Pig islet xenotransplantation is a potential treatment for patients with type 1 diabetes. Current efforts are focused on identifying the optimal pig islet source and overcoming the immunological barrier. The optimal age of the pig donors remains controversial since both adult and neonatal pig islets have advantages. Isolation of adult islets using GMP grade collagenase has significantly improved the quantity and quality of adult islets, but neonatal islets can be isolated at a much lower cost. Certain culture media and coculture with mesenchymal stromal cells facilitate neonatal islet maturation and function. Genetic modification in pigs affords a promising strategy to prevent rejection. Deletion of expression of the three known carbohydrate xenoantigens (Gal, Neu5Gc, Sda) will certainly be beneficial in pig organ transplantation in humans, but this is not yet proven in islet transplantation, though the challenge of the ‘4th xenoantigen’ may prove problematic in nonhuman primate models. Blockade of the CD40/CD154 costimulation pathway leads to long-term islet graft survival (of up to 965 days). Anti-CD40mAbs have already been applied in phase II clinical trials of islet allotransplantation. Fc region-modified anti-CD154mAbs successfully prevent the thrombotic complications reported previously. In this review, we discuss (I) the optimal age of the islet-source pig, (ii) progress in genetic modification of pigs, (iii) the immunosuppressive regimen for pig islet xenotransplantation, and (iv) the reduction in the instant blood-mediated inflammatory reaction.

P.167: Gene Expression and Function in Pig Islets From One-day-old Pigs

Introduction: Islet transplantation is a budding alternative treatment for type 1 diabetics. A potential solution to the limited number of human pancreas donors is pig islet xenotransplantation. Limited study has been performed on pig islet cell signaling pathways, which may differ from the mechanisms seen in humans. We have identified molecules involved in the insulin secretion pathway, including the glucose transporter GLUT2, GTPase RAC1, which is involved in F-actin remodeling in islet cells, and SNAP25, a protein involved in insulin release. We evaluated these molecules across different days of culture in neonatal pig islets. We also quantified the gene expression of common cadherins associated with cell-cell adhesion and islet function as determined by insulin secretion. Method: Islets from 1-day-old pigs (n=3) were isolated and samples collected on days 0, 3, 5 and 7 of culture to quantify GLUT2, SNAP25, RAC1, E-, N- and VE-cadherin gene expression by qRT-PCR. Immunofluorescence staining was performed to localize protein expression. Static glucose stimulation insulin secretion assays (GSIS) and ELISA were used to quantify the ability of these islets to secrete insulin under conditions containing low glucose, high glucose and high glucose with KCl. Kruskal-Wallis testing was completed with GraphPad Prism software. Results: Qualitatively, the islets developed visible membranes and had fewer contaminating exocrine cells as they moved from 0 to 7 days in culture. E-cadherin, SNAP25 and GLUT2 all peaked on day 5 of culture, correlating with when islets formed a distinct spherical structure in-vitro. N-cadherin consistently rose, peaking at day 7 of culture. VE-cadherin was highest at day 0 and decreased with a linear trend. RAC1 gene expression decreased from day 0, remaining stable between days 5 and 7. P-values are indicated in Figure 1. Preliminary immunofluorescence staining showed co-localization of SNAP25 and insulin at all-time points. The amount of insulin secreted in low vs high glucose settings was similar without KCl, and as expected, the amount of insulin secreted when islets were cultured in high glucose with KCl was greater. Kruskal-Wallis testing demonstrated significant differences amongst GSIS groups (Figure 2). Discussion/Conclusion: Our data demonstrates variation in the gene expression of our molecules of interest across 7 days of culture. Our immunofluorescence results demonstrate that SNAP25 colocalized with insulin, suggesting their proximity in islet cells. Our results also demonstrate the limited ability of glucose to stimulate islets from 1-day-old pigs at 7 days of culture. This is different than results seen previously in our lab suggesting islets from 7-day-old pigs at 7 days of culture secrete greater amounts of insulin when exposed to high glucose conditions. These findings may be important for the development of pig islets in vitro and warrant further investigation.Royal College of Physicians and Surgeons of Canada (RCPSC) - Clinician Investigator Program. Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant. Canadian Institutes of Health Research (CIHR) - Canadian Graduate Scholarships - Master’s Program. Walter H. John’s Graduate Fellowship (University of Alberta). Alberta Graduate Excellence Scholarship (AGES).

Challenges and practical realities of long-term patient follow-up in three xeno-islet clinical trials: The experience in pig islet xenotransplantation trials in New Zealand and Argentina.

XenotransplantationVolume 27, Issue 3 e12605 COMMENTARY Challenges and practical realities of long-term patient follow-up in three xeno-islet clinical trials: The experience in pig islet xenotransplantation trials in New Zealand and Argentina Shaun Wynyard, Corresponding Author Shaun Wynyard swynyard@dolglobal.com Diatranz Otsuka Limited, Auckland, New Zealand Correspondence Diatranz Otsuka Limited, Auckland, New Zealand. Email: swynyard@dolglobal.comSearch for more papers by this author Shaun Wynyard, Corresponding Author Shaun Wynyard swynyard@dolglobal.com Diatranz Otsuka Limited, Auckland, New Zealand Correspondence Diatranz Otsuka Limited, Auckland, New Zealand. Email: swynyard@dolglobal.comSearch for more papers by this author First published: 07 June 2020 https://doi.org/10.1111/xen.12605Citations: 5Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume27, Issue3May/June 2020e12605 RelatedInformation

The potential role of 3D-bioprinting in xenotransplantation.

To review the impact of a new technology, 3D-bioprinting, in xenotransplantation research. Genetically engineered pigs, beginning with human (h) CD55-transgenic and Gal-knockout pigs, have improved the outcomes of xenotransplantation research. Today, there are more than 30 different genetically engineered pigs either expressing human gene(s) or lacking pig gene(s). CRIPSR/cas9 technology has facilitated the production of multigene pigs (up to nine genes in a single pig), which lack multiple pig xenoantigens, and express human transgenes, such as hCD46, hCD55, hThrombomodulin, hCD39, etc. Although recent studies in nonhuman primates (NHPs) have demonstrated prolonged survival after life-supporting pig kidney, heart, and islet xenotransplantation, researchers have difficulty determining the best genetic combination to test in NHPs because of a potential greater than 100 000 genetic combinations. 3D-bioprinting of genetically engineered pig cells: is superior to 2D in-vitro testing, enables organ-specific testing, helps to understand differences in immunogenicity between organs, and is faster and cheaper than testing in NHPs. Moreover, 3D-bioprinted cells can be continuously perfused in a bioreactor, controlling for all variables, except the studied variable. 3D-bioprinting can help in the study of the impact of specific genes (human or pig) in xenotransplantation in a rapid, inexpensive, and reliable way.

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.

Will Genetic Engineering Carry Xenotransplantation of Pig Islets to the Clinic?

Porcine islets represent a potentially attractive beta-cell source for xenotransplantation into patients with type 1 diabetes, who are not eligible to islet allo-transplantation due to a lack of suitable human donor organs. Recent progress in genetic engineering/gene editing of donor pigs provides new opportunities to overcome rejection of xeno-islets, to improve their engraftment and insulin secretion capacity, and to reduce the risk for transmission of porcine endogenous retroviruses. This review summarizes the current issues and progress in islet xenotransplantation with special emphasis on genetically modified/gene edited donor pigs. Attempts to overcome acute rejection of xeno-islets, especially after intraportal transplantation into the liver, include the genetic elimination of specific carbohydrate antigens such as αGal, Neu5Gc, and Sd(a) for which humans and-in part-non-human primates have natural antibodies that bind to these targets leading to activation of complement and coagulation. A complementary approach is the expression of one or more human complement regulatory proteins (hCD46, hCD55, hCD59). Transgenic attempts to overcome cellular rejection of islet xenotransplants include the expression of proteins that inhibit co-stimulation of T cells. Expression of glucagon-like peptide-1 and M3 muscarinic receptors has been shown to increase the insulin secretion of virally transduced porcine islets in vitro and it will be interesting to see the effects of these modifications in transgenic pigs and islet products derived from them. Genome-wide inactivation of porcine endogenous retrovirus (PERV) integrants by mutating their pol genes using CRISPR/Cas9 is a recent approach to reduce the risk for PERV transmission by xeno-islets. Genetic engineering/gene editing of xeno-islet donor pigs facilitated major progress towards clinical islet xenotransplantation. The required set of genetic modifications will depend on the source of islets (fetal/neonatal vs. adult), the mode of delivery (encapsulated vs. free), and the transplantation site.

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.

The effect of epitope-based ligation of ICAM-1 on survival and retransplantation of pig islets in nonhuman primates.

Pig islet xenotransplantation is a promising alternative to allogeneic transplantation. However, the wide immunologic barrier between pigs and primates limits the long-term survival of the graft. MD-3, a novel monoclonal antibody (mAb) that recognizes a particular epitope of human ICAM-1, can render T cells tolerant to a xenograft by arresting dendritic cell maturation. We report the long-term survival of adult wild-type pig islets and successful retransplantation in nonhuman primates using a protocol comprising induction with MD-3 mAb and maintenance with anti-CD154 mAb and sirolimus. Eleven rhesus monkeys were assigned to three groups. Group 1 (n=4) involved treatment with MD-3 induction, short-term (<4months) administration of anti-CD154 mAb, and maintenance therapy with sirolimus. Group 2 (n=4) involved treatment with MD-3 induction and long-term maintenance therapy with anti-CD154 mAb and sirolimus. Group 3 (n=3) involved only maintenance therapy with anti-CD154 mAb and sirolimus. Diabetes was induced in monkeys by streptozotocin, and pig islets (61000-112000IEQ/kg for each transplant; up to 280000IEQ/kg per recipient) were infused through the portal vein. The in vivo functional potency of the isolated islets was tested by minimal model transplant in streptozotocin-induced diabetic NOD/SCID mice, and the mean AUC of blood glucose level divided by the number of follow-up days was calculated. The islet grafts survived more than 6months (between 225 and 727days) in nine of 12 transplants of MD-3-treated groups 1 and 2, whereas in the absence of MD-3 mAb, survival was <40days. In three transplants of the MD-3-treated Group 2, functional graft survival was only for 104, 125, and 154days. In these cases, a retrospective analysis suggested that the relatively short survival duration was associated with the relatively high AUC value in the NOD/SCID bioassay. Notably, when retransplantation was performed in Group 3, blood glucose control was extended up to 956days, which was supported by MD-3 mAb-based suppression of adaptive immunity. No replication of cytomegalovirus genes was observed. Long-term survival of pig islet xenografts and successful retransplantation were achieved with MD-3 mAb-based immunosuppression regimen in this pig-to-monkey transplantation model. It should be emphasized that these encouraging results were achieved following the transplantation of islets from pigs that had not been genetically modified. Considering that it is possible to further substantially reduce the destruction of grafted islet using genetically modified pig islet, the islet requirement could be reduced and much longer graft survival can be achieved.

Safe use of anti-CD154 monoclonal antibody in pig islet xenotransplantation in monkeys.

Anti-CD154mAb is a powerful co-stimulation blockade agent that is efficacious in preventing rejection, even in xenogeneic settings. It has been used in the majority of successful long-term pig-to-non-human primate islet transplantation models. However, its clinical use was halted as a result of thromboembolic complications that were also observed in preclinical and clinical organ transplantation models. An anti-CD154mAb was administered to 14 streptozotocin-induced diabetic cynomolgus monkey recipients of porcine islets, some of which received the agent for many months. Monkeys were monitored for complications, and blood monitoring was carried out frequently. After euthanasia, multiple biopsies of all organs were examined for histological features of thromboembolism. Anti-CD154mAb prevented rejection of genetically engineered pig islets in all monkeys. No significant complications were attributable specifically to anti-CD154mAb. There was no evidence of thromboembolism in multiple histological sections from all major organs, including the brain. Our data suggest that in diabetic monkeys with pig islet grafts, anti-CD154mAb would appear to be an effective and safe therapy, and is not associated with thromboembolic complications.

Progress in Clinical Encapsulated Islet Xenotransplantation.

At the 2015 combined congress of the Cell Transplant Society, International Pancreas and Islet Transplant Association, and International Xenotransplantation Association, a symposium was held to discuss recent progress in pig islet xenotransplantation. The presentations focused on 5 major topics - (1) the results of 2 recent clinical trials of encapsulated pig islet transplantation, (2) the inflammatory response to encapsulated pig islets, (3) methods to improve the secretion of insulin by pig islets, (4) genetic modifications to the islet-source pigs aimed to protect the islets from the primate immune and/or inflammatory responses, and (5) regulatory aspects of clinical pig islet xenotransplantation. Trials of microencapsulated porcine islet transplantation to treat unstable type 1 diabetic patients have been associated with encouraging preliminary results. Further advances to improve efficacy may include (1) transplantation into a site other than the peritoneal cavity, which might result in better access to blood, oxygen, and nutrients; (2) the development of a more biocompatible capsule and/or the minimization of a foreign body reaction; (3) pig genetic modification to induce a greater secretion of insulin by the islets, and/or to reduce the immune response to islets released from damaged capsules; and (4) reduction of the inflammatory response to the capsules/islets by improvements in the structure of the capsules and/or in genetic engineering of the pigs and/or in some form of drug therapy. Ethical and regulatory frameworks for islet xenotransplantation are already available in several countries, and there is now a wider international perception of the importance of developing an internationally harmonized ethical and regulatory framework.

Clinical Islet Xenotransplantation: A Step Forward

With the encouraging results of pancreatic islet allotransplantation, increasing attention is being directed towards pig islet xenotransplantation, which would resolve the problem of islet supply (Markmann et al., 2016, Ekser et al., 2012). Free (nonencapsulated) pig islets (either wild-type or genetically-engineered) have maintained normoglycemia in immunosuppressed diabetic nonhuman primates for > 1 year (Park et al., 2015). Immunoisolated (encapsulated) pig islets have maintained normoglycemia in non-immunosuppressed diabetic nonhuman primates for up to 6 months (Dufrane et al., 2006).

Engraftment and reversal of diabetes after intramuscular transplantation of neonatal porcine islet-like clusters.

Intraportal infusion is currently the method of choice for clinical islet cell transplantation but suffers from poor efficacy. As the liver may not represent an optimal transplantation site for Langerhans islets, we examined the potential of neonatal porcine islet-like clusters (NPICCs) to engraft in skeletal muscle as an alternative transplantation site. Neonatal porcine islet-like clusters were isolated from 2- to 5-day-old piglets and either transplanted under the kidney capsule (s.k.) or injected into the lower hindlimb muscle (i.m.) of streptozotocin-diabetic NOD-SCID IL2rγ(-/-) (NSG) mice. Survival, vascularization, maturation, and functional activity were analyzed by intraperitoneal glucose tolerance testing and immunohistochemical analyses. Intramuscular transplantation of NPICCs resulted in development of normoglycemia and restored glucose homeostasis. Time to reversal of diabetes and glucose tolerance (AUC glucose and AUC insulin) did not significantly differ as compared to s.k. transplantation. Intramuscular grafts exhibited rapid neovascularization and graft composition with cytokeratin-positive ductal cells and beta cells at post-transplant weeks 2 and 8 and after establishment of normoglycemia was comparable in both groups. Intramuscular injection represents a minimally invasive but efficient alternative for transplantation of NPICCs and, thus, offers an attractive alternative site for xenotransplantation approaches. These findings may have important implications for improving the outcome and the monitoring of pig islet xenotransplantation.

Microencapsulated Pig Islet Xenotransplantation as an Alternative Treatment of Diabetes.

Islet transplantation is emerging as an attractive option for the treatment of type 1 diabetes mellitus (T1DM). However, some major obstacles are needed to be overcome, including shortage of islet supply and excessive immunosuppressive therapy. Xenotransplantation of bioartificial pancreas (BAP) made of microencapsulated pig islets will effectively solve these problems. Before widespread application of this therapy, several important issues should be addressed to further improve pig islet viability and functionality, such as pig islet source, optimization of microcapsule preparation, cryopreservation of implant, selection of biocompatible material, and implant site, as well as prevention of xenoreaction and biosafety concern. It is hoped that improvements in these critical aspects will lead to wider human application of microencapsulation of pig islets.

Potential for clinical pancreatic islet xenotransplantation

Diabetes mellitus is increasing worldwide. Type 1 diabetes can be treated successfully by islet allotransplantation, the results of which are steadily improving. However, the number of islets that can be obtained from deceased human donors will never be sufficient to cure more than a very small percentage of patients who might benefit from transplantation. Although there are some differences in glucose metabolism between pigs and humans, the use of pigs could provide an unlimited supply of islets, and the insulin produced would undoubtedly control glucose levels. Transplantation of islets into the portal vein results in islets residing in the liver; however, an early inflammatory response and rejection remain problematic, even when the recipient is receiving immunosuppressive therapy. In the long term, immunosuppressive drugs may exhibit toxicities to patients and specifically harm the islet cells. In contrast, encapsulation techniques provide islets with a physical barrier that prevents antibodies binding to the islet graft while still allowing insulin to be released into the recipient’s circulation; in theory, patients receiving encapsulated grafts might not require exogenous immunosuppressive therapy. Nonhuman primates with encapsulated pig islet transplants have remained insulin-independent for several weeks, but long-term efficacy remains uncertain. Furthermore, techniques are now available to knock out genes from the pig and/or insert human genes, thus rendering the antigenic structure of pigs closer to that of humans, and providing protection from the human immune response. Islet transplantation from genetically engineered pigs has been followed by insulin independence in a small number of nonhuman primates for greater than 1 year. Neonatal islets have some advantages over adult islets in that they are easier to isolate and culture, and have the ability to proliferate during the first few months after transplantation. In 2009, the International Xenotransplantation Association set up a group to encourage and advise on clinical trials of pig islet xenotransplantation; this group’s guidelines are discussed. Clinical trials of encapsulated pig islets are already under way.

Islet xenotransplantation: what is the optimal age of the islet-source pig?

The need for pig islet xenotransplantation in patients with type 1 diabetes is compelling; however, the ideal age at which islets should be isolated from the donor pig remains uncertain. Pig islet transplantation in primates, as a valuable pre-clinical model, has been explored using adult, neonatal, fetal pig islets, and also pancreatic primordia from pig embryos as beta cell donors. Neonatal pig islets have some advantages over adult and fetal islets, but the optimal age within the first month of life at which neonatal islets should be isolated and transplanted is as yet unclear. In an attempt to answer this question, we carried out a literature search, but limited the search primarily to evidence in the clinically-relevant pig-to-non-human primate model. We identified surprisingly few studies in this model directed to this topic. Even in pig-to-rodent models, there were few definitive data. From the few data available to us, we conclude that pancreatectomy and islet isolation from neonatal pigs may have advantages over adult pigs and that isolation during the first week of life may have minor advantages over later weeks.

Optimal pig donor selection in islet xenotransplantation: current status and future perspectives.

Islet transplantation is an attractive treatment of type 1 diabetes mellitus. Xenotransplantation, using the pig as a donor, offers the possibility of an unlimited supply of islet grafts. Published studies demonstrated that pig islets could function in diabetic primates for a long time (>6 months). However, pig-islet xenotransplantation must overcome the selection of an optimal pig donor to obtain an adequate supply of islets with high-quality, to reduce xeno-antigenicity of islet and prolong xenograft survival, and to translate experimental findings into clinical application. This review discusses the suitable pig donor for islet xenotransplantation in terms of pig age, strain, structure/function of islet, and genetically modified pig.

Ultrasound Molecular Detection of Instant Blood-Mediated Inflammatory Reaction Induced By Pig Islet Xenotransplantation.

Ultrasound Molecular Detection of Instant Blood-Mediated Inflammatory Reaction Induced By Pig Islet Xenotransplantation.