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Porcine islet xenotransplantation has been highlighted as an alternative to allo islet transplantation. Despite the remarkable progress that has been made in porcine‐islet pre‐clinical studies in nonhuman primates, immunological tolerance to porcine islets has not been achieved to date. Therefore, allo islet transplantation could be required after the failure of porcine islet xenotransplantation. Here, we report the long‐term control of diabetes by allogeneic pancreatic islet transplantation in diabetic rhesus monkeys that rejected previously transplanted porcine islets. Four diabetic male rhesus monkeys received the porcine islets and then allo islets (5700—19 000 IEQ/kg) were re‐transplanted for a short or long period after the first xeno islet rejection. The recipient monkeys were treated with an immunosuppressive regimen consisting of ATG, humira, and anakinra for induction, and sirolimus and tofacitinib for maintenance therapy. The graft survival days of allo islets in these monkeys were >440, 395, >273, and 127, respectively, similar to that in allo islet transplanted cynomolgus monkeys that received the same immunosuppressive regimen without xeno sensitization. Taken together, it is likely that prior islet xenotransplantation does not affect the survival of subsequent allo islets under clinically applicable immunosuppressants. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: We assessed an immunosuppressant regimen composed of clinically available agents at porcine islet transplantation in consecutive diabetic NHPs. Results: Porcine islet graft survival in consecutive diabetic NHPs (n = 7; >222, >200, 181, 89, 62, 55, and 34 days) without severe adverse events. Conclusion: We believe that our study could contribute greatly to the initiation of islet xenotransplantation clinical trials. [ABSTRACT FROM AUTHOR]

Background: Xenogeneic islet transplantation using porcine pancreata has been a promising option for substituting human islet transplantation. Moreover, recent advances in pre‐clinical results have put islet xenotransplantation closer to the possibility of clinical application. While preparing for the era of clinical xenotransplantation, developing non‐invasive immune monitoring method which could predict the graft fate could benefit the patient. However, there are few reports showing predictive immune parameters associated with the fate of the graft in islet xenotransplantation. Methods: The absolute number and ratio of T‐cell subsets have been measured via flow cytometry from the peripheral blood of 16 rhesus monkeys before and after porcine islet xenotransplantation. The correlation between the graft survival and the absolute number or ratio of T cells was retrospectively analyzed. Results: The ratio of CD4+ versus CD8+ T cells was significantly reduced due to CD8+ effector memory cells' increase. Correlation analyses revealed that CD4+/CD8+, CD4+/CD8+ naïve, CD4+ naïve/CD8+ naïve, and CD4+ central memory/CD8+ naïve cell ratios negatively correlated with the duration of graft survival. Conversely, further analyses discovered strong, positive correlation of CD4+/CD8+ cell ratios within the early graft‐rejected monkeys (≤60 days). Conclusions: This retrospective study demonstrated that CD4+/CD8+ ratios correlated with graft survival, especially in recipients which rejected the graft in early post‐transplantation periods. CD4+/CD8+ ratios could be used as a surrogate marker to predict the graft fate in pig‐to‐NHP islet xenotransplantation. [ABSTRACT FROM AUTHOR]

The article discusses about the status of xenotransplantation in South Korea. Topics of discussion includes initiation of Xenotransplantation Research Center (XRC) at the Seoul National University (SNU) Hospital, production of genetically engineered galactosyltransferase knockout (GTKO) pig and pancreatic islet and cornea xenotransplantation.

Describes the characterization of Streptozotocin-induced diabetic rats and pharmacodynamics of insulin formulation. Cause of the functional changes of the rat pancreatic islets; Reduction of blood glucose of each formulation; Measurement of pharmacokinetic and pharmacodynamic properties of insulin.

Background: Anti‐CD154 monoclonal antibody (mAb) treatment has been known to have potential to induce immune tolerance in organ transplantation. Several studies have suggested the involvement of CD4+ regulatory T cells (Tregs) in xeno‐immune tolerance. However, the characteristics of Tregs and the mechanisms of their regulatory functions in islet xenotransplantation have not been clearly defined. Method: Adult porcine islet cells were isolated and purified, and were transplanted under the kidney capsule of diabetic C57BL/6J mice with the administration of 0.5 mg/mouse of anti‐CD154 mAb on 0, 1, 3, 5, and 7 days post‐transplantation (DPT). The graft survival was monitored by blood glucose level. The islet graft and recipients' cells were analyzed by immunohistochemistry (IHC), flow cytometry, enzyme‐linked immunosorbent spot (ELISPOT) assay, and mixed‐lymphocyte reaction. Results: Short‐term anti‐CD154 mAb monotherapy enabled the porcine islet graft to survive indefinitely in diabetic mice (n = 18). Immunohistochemical staining showed significantly higher ratio of CD4+Foxp3+ Tregs in the peri‐graft site, but not in the spleen and kidney‐draining lymph node of the recipient mice. Depletion of Tregs evoked graft rejection, and adoptive transfer of Tregs from anti‐CD154 mAb‐treated recipients provided protection to the graft from rejection. These Tregs showed more potent suppressive capacity than those from the untreated control and were found to be porcine antigen‐specific. Conclusions: In this study, we showed that anti‐CD154 mAb monotherapy resulted in indefinite porcine islet graft survival in mice. The porcine‐specific CD4+Foxp3+Tregs in the peri‐graft site played the critical role in the protection of islet graft from rejection, which suggests a prospective immunosuppressive strategy for islet xenotransplantation. [ABSTRACT FROM AUTHOR]

Pig‐to‐nonhuman primate (NHP) islet transplantation has been widely conducted as a preclinical xenotransplantation model prior to human clinical trial. Portal vein thrombosis is one of the complications associated with islet infusion through the portal vein into the liver. Here, we briefly report severe case of ascites formation accompanied by portal vein thrombi after pig‐to‐NHP islet xenotransplantation in a rhesus monkey. Meticulous prophylactic treatment such as continuous heparin infusion should be implemented to prevent portal vein thrombi in pig‐to‐NHP islet transplantation models. [ABSTRACT FROM AUTHOR]

Background: Subcutaneous tissue is an attractive extra‐hepatic heterotopic site for islet transplantation; however, poor oxygen tension and blood supply during early engraftment of implanted islets have limited the use of this site in clinical applications. Methods: This study investigated the vascularization potential of hypoxia‐preconditioned mesenchymal stem cells (3% O2; hypo‐MSCs) in PLGA‐based bio‐artificial beds for subsequent subcutaneous islet transplantation. Sheet‐typed polymeric PLGA scaffolds coated with hypo‐MSCs or normo‐MSCs (MSCs cultured under normoxia conditions, 21% O2) were implanted subcutaneously in mice. Results: Compared to normo‐MSCs, hypo‐MSCs significantly enhanced vasculogenesis, both on the interior and exterior surfaces of the implanted PLGA devices, which peaked 4 weeks after implantation. Further, infusion of porcine islets inside the prevascularized PLGA bed restored normal glycemic control in 6 of 6 STZ‐induced diabetic mice. The mass of the marginal islet was approximately 2000 IEQs, which is comparable to that required for the renal subcapsular space, a highly vascularized site. Conclusions: Therefore, PLGA‐based bio‐artificial devices prevascularized with hypo‐MSCs could be a useful modality for successful subcutaneous islet transplantation, which is of high clinical relevance. [ABSTRACT FROM AUTHOR]

• Low-dose bortezomib reduces the MHC class II expression on dendritic cells. • Low-dose bortezomib and rapamycin combination prolongs islet graft survival. • Low-dose bortezomib and rapamycin combination reduces Ag-specific IFN-γ + T cells. • Low-dose bortezomib and rapamycin combination increases FoxP3+ regulatory T cells. As the first FDA-approved proteasome inhibitor drug, bortezomib has been used for the treatment of multiple myeloma and lymphoma. However, its effects alone or in combination with other immunosuppressants on allogeneic islet transplantation have not been reported so far. In this study, we showed that the short-term combination treatment of low-dose bortezomib and rapamycin significantly prolonged the survival of islet allografts. Short-term treatment of low-dose (0.05 mg/kg or 0.1 mg/kg) bortezomib reduced the MHC class II expression in dendritic cells (DCs) of alloantigen-sensitized mice, and prolonged the islet allograft survival for up to 50 days in diabetic mice. Notably, when bortezomib was combined with rapamycin, it induced islet-specific immunological tolerance which allowed the acceptance of a second graft without additional immunosuppression. This regimen dramatically reduced the alloantigen-specific IFN-γ-producing T cells in the spleen, and increased regulatory T cells both at the graft site and in the spleen. Therefore, we propose that short-term treatment of low-dose bortezomib and rapamycin could be a new tolerance-promoting immunosuppressive regimen for allogeneic islet transplantation. [ABSTRACT FROM AUTHOR]