Allogeneic Islet Transplantation Research Articles

Current state of pancreas transplantation in Japan based on the nationwide registry.

In Japan, 437 pancreas transplantations (PTx) were carried out between 2000 and 2019. Clinical data for all PTx cases are registered in the Japan Pancreas Transplant Registry of the Japan Society for Pancreas and Islet Transplantation. Here we analyzed the registry data to describe the current status of PTx in Japan. The 437 PTx included 410 from deceased donors (407 from brain‐dead and 3 from non‐heart‐beating donors) and 27 from living donors. We investigated the clinical characteristics of the 410 PTx from deceased donors. The rate of marginal donors using expanded donor criteria was higher in Japan than in other countries. At 1/5/10 years post‐PTx, the overall survival rates were 95.8%/94.2%/88.7%, and the graft survival rates were 85.9%/76.2%/67.4% for pancreas and 93.2%/90.8%/78.2% for kidney (non‐censored for death). These rates were comparable to those in other countries. When stratified by PTx category, survival was significantly better following simultaneous pancreas‐kidney transplantation (SPK) compared to pancreas‐after‐kidney transplantation (PAK) or PTx alone (PTA). Immunological rejection was more frequently the cause of graft loss in PAK/PTA cases than in SPK cases, potentially contributing to the poorer survival in PAK/PTA. These outcomes highlight two main concerns: substantial incidence of pancreas graft loss, and inferior outcomes after PAK/PTA. Overall, PTx outcome is favorable in Japan, despite the high rate of marginal donors. To improve outcomes, it is important to prevent and manage each cause of pancreas graft loss. Overcoming the poorer survival in PAK/PTA may require new immunosuppressive protocols or allogenic islet transplantation.

A comparison of the inflammatory response following autologous compared with allogenic islet cell transplantation.

BackgroundThe initial response to islet transplantation and the subsequent acute inflammation is responsible for significant attrition of islets following both autologous and allogenic procedures. This multicentre study compares this inflammatory response using cytokine profiles and complement activation.MethodsInflammatory cytokine and complement pathway activity were examined in two cohorts of patients undergoing total pancreatectomy followed either by autologous (n=11) or allogenic (n=6) islet transplantation. Two patients who underwent total pancreatectomy alone (n=2) served as controls.ResultsThe peak of cytokine production occurred immediately following induction of anaesthesia and during surgery. There was found to be a greater elevation of the following cytokines: TNF-alpha (P<0.01), MCP-1 (P=0.0013), MIP-1α (P=0.001), MIP-1β (P=0.00020), IP-10 (P=0.001), IL-8 (P=0.004), IL-1α (P=0.001), IL-1ra (0.0018), IL-10 (P=0.001), GM-CSF (P=0.001), G-CSF (P=0.0198), and Eotaxin (P=0.01) in the allogenic group compared to autografts and controls. Complement activation and consumption was observed in all three pathways, and there were no significant differences in between the groups although following allogenic transplantation ∆IL-10 and ∆VEGF levels were significantly elevated those patients who became insulin-independent compared with those who were insulin-dependent.ConclusionsThe cytokine profiles following islet transplantation suggests a significantly greater acute inflammatory response following allogenic islet transplantation compared with auto-transplantation although a significant, non-specific inflammatory response occurs following both forms of islet transplantation.

Bioenergetics of Islet Preparations in a Pilot Clinical Trial of Peri-Transplant Hydroxychloroquine for Autologous Islet Transplantation

The inflammatory response is an obstacle to success in both allogeneic and autologous islet transplantation. In autologous islet transplantation (AIT), however, the recipient is also the donor, permitting pretreatment of donor/recipient for a controlled duration prior to transplantation. We sought to exploit this feature of (AIT) by pretreating donor/recipients with chronic pancreatitis undergoing total pancreatectomy and autologous islet transplantation (TPAIT) to test the hypothesis that peri-transplant treatment with the FDA-approved anti-inflammatory hydroxychloroquine (HCQ) improves graft function. In this randomized placebo-controlled pilot clinical study, patients (n = 6) were treated with oral HCQ for 30 days prior to and 90 days after TPAIT. In vivo islet function was assessed via Mixed Meal Tolerance Testing before HCQ treatment, 6- and 12-months after surgery. In vitro islet bioenergetics were assessed at the time of transplantation via extracellular flux analysis of islet preparation samples from the clinical trial cohort and six additional patients (n = 12). Our study shows that HCQ did not alter clinical endpoints, but HCQ-treated patients showed greater spare respiratory capacity (SRC) compared to samples from control patients (P=0.028). Glycolytic metabolism of islet preparations directly correlated with stimulated C-peptide secretion both before and after TPAIT (P=0.01, R2=0.489 and P=0.03, R2=0.674, respectively), and predicted in vivo islet function better than mitochondrial metabolism of islet preps or islet equivalents infused. Overnight culture of islet preparations altered bioenergetic function, significantly decreasing SRC and maximal respiration (P<0.001). In conclusion, while HCQ did not alter clinical outcomes, it was associated with significantly increased SRC in islet preparations. Bioenergetic analyses of islet preparations suggests that culture should be avoided and that glycolysis may be a more sensitive indicator of in vivo islet function than current metrics, including islet oxygen consumption and islet equivalents infused.

Designing Biomaterials for the Modulation of Allogeneic and Autoimmune Responses to Cellular Implants in Type 1 Diabetes

The effective suppression of the adaptive immune responses is essential for the success of allogeneic cell therapies. For islet transplantation for Type 1 Diabetes, pre-existing autoimmunity provides an additional hurdle, as the memory autoimmune T cells mediate both an autoantigen-specific attack on the donor beta cells and an alloantigen-specific attack on the donor graft cells. Immunosuppressive agents used for islet transplantation, while generally successful in suppressing alloimmune responses, dramatically hinder the widespread adoption of this therapeutic approach, while also failing to control the memory T cell populations, leaving the graft vulnerable to destruction. In this review, we highlight the capacity of biomaterials to provide local and nuanced instruction to suppress or alter immune pathways activated in response to an allogeneic islet transplant. Biomaterial immunoisolation is a common approach employed to block direct antigen recognition and downstream cell-mediated graft destruction; however, immunoisolation alone still permits shed donor antigens to escape into the host environment, resulting in indirect antigen recognition, immune cell activation, and the creation of a toxic graft site. Designing materials to decrease antigen shedding, improve cell viability, and increase material compatibility are all approaches that can decrease antigen shedding and danger signals in the implant microenvironment. Implant materials can be further enhanced through the local delivery of anti-inflammatory, suppressive, chemotactic, or tolerogenic agents, aimed at controlling both the innate and adaptive immune responses to the implant, with a benefit of reduced systemic effects. Lessons learned from the understanding how to manipulate allogeneic and autogenic immune responses to pancreatic islets can be applied to numerous other cell therapies to improve graft efficacy and duration.

Pancreas transplantation for type 1 diabetes in Japan: past, present and future prospects.

In Japan, the first pancreas transplantation was performed in 1984 from a brain-dead donor; subsequently, however, the concept of brain death became a social issue. Thereafter, the "Organ Transplant Act", which enables brain-dead transplantation, was enacted in 1997, and then revised in 2010 so that donation after brain death became possible only with the consent of the family. Under the recipient selection and registration system developed after the enactment of the "Organ Transplant Act", more than 400 pancreas transplants have been carried out at facilities certified for brain-dead pancreas transplantation in Japan. Of the 410 total cadaveric pancreas transplants performed by the end of 2019, the patient survival and pancreatic and kidney graft survival rates were considered to be comparable to those in the United States and Europe despite the high frequency of marginal donors. Minimally invasive allogenic islet transplantation came to be covered by national health insurance in 2020 following good outcomes of a recent trial. Furthermore, to overcome the serious donor shortage in Japan, development of xenogeneic islet transplantation and regenerative medicine using stem cells is in progress, with xenotransplantation using porcine islets appearing particularly promising.

Hyaluronan synthesis inhibition impairs antigen presentation and delays transplantation rejection

A coat of pericellular hyaluronan surrounds mature dendritic cells (DC) and contributes to cell-cell interactions. We asked whether 4-methylumbelliferone (4MU), an oral inhibitor of HA synthesis, could inhibit antigen presentation. We find that 4MU treatment reduces pericellular hyaluronan, destabilizes interactions between DC and T-cells, and prevents T-cell proliferation in vitro and in vivo. These effects were observed only when 4MU was added prior to initial antigen presentation but not later, consistent with 4MU-mediated inhibition of de novo antigenic responses. Building on these findings, we find that 4MU delays rejection of allogeneic pancreatic islet transplant and allogeneic cardiac transplants in mice and suppresses allogeneic T-cell activation in human mixed lymphocyte reactions. We conclude that 4MU, an approved drug, may have benefit as an adjunctive agent to delay transplantation rejection.

A novel prevascularized tissue-engineered chamber as a site for allogeneic and xenogeneic islet transplantation to establish a bioartificial pancreas.

Although sites for clinical or experimental islet transplantation are well established, pancreatic islet survival and function in these locations remain unsatisfactory. A possible factor that might account for this outcome is local hypoxia caused by the limited blood supply. Here, we modified a prevascularized tissue-engineered chamber (TEC) that facilitated the viability and function of the seeded islets in vivo by providing a microvascular network prior to transplantation. TECs were created, filled with Growth Factor-Matrigel™ (Matrigel™) and then implanted into the groins of mice with streptozotocin-induced diabetes. The degree of microvascularization in each TECs was analyzed by histology, real-time PCR, and Western blotting. Three hundred syngeneic islets were seeded into each chamber on days 0, 14, and 28 post-chamber implantation, and 300, 200, or 100 syngeneic islets were seeded into additional chambers on day 28 post-implantation, respectively. Furthermore, allogeneic or xenogeneic islet transplantation is a potential solution for organ shortage. The feasibility of TECs as transplantation sites for islet allografts or xenografts and treatment with anti-CD45RB and/or anti-CD40L (MR-1) was therefore explored. A highly developed microvascularized network was established in each TEC on day 28 post-implantation. Normalization of blood glucose levels in diabetic mice was negatively correlated with the duration of prevascularization and the number of seeded syngeneic islets. Combined treatment with anti-CD45RB and MR-1 resulted in long-term survival of the grafts following allotransplantation (5/5, 100%) and xenotransplantation (16/20, 80%). Flow cytometry demonstrated that the frequency of CD4+Foxp3-Treg and CD4+IL-4+-Th2 cells increased significantly after tolerogenic xenograft transplantation, while the number of CD4+IFN-γ-Th1 cells decreased. These findings demonstrate that highly developed microvascularized constructs can facilitate the survival of transplanted islets in a TECs, implying its potential application as artificial pancreas in the future.

Alpha-1 antitrypsin suppresses macrophage activation and promotes islet graft survival after intrahepatic islet transplantation.

Alpha-1 antitrypsin (AAT) has protective functions in animal islet transplantation models. While the therapeutic effect of AAT therapy is currently being tested in clinical trials, we investigated the mechanism of AAT protection in a clinically relevant marginal intrahepatic human islet transplantation model. In recipients receiving islets and AAT, 68.9% (20/29) reached normoglycemia, compared to 35.7% (10/28) in those receiving islets only, at 60days posttransplant (PT). AAT-treated mice had lower serum levels of inflammatory cytokines immediately PT. Reduced M1 macrophages were observed in livers of AAT-treated recipients compared to controls as evidenced by flow cytometry and RNA-seq transcriptional profiling analysis. In vitro AAT suppressed IFN-γ-induced M1 macrophage activation/polarization via suppression of STAT1 phosphorylation and iNOS production. AAT inhibits macrophage activation induced by cytokines or dying islets, and consequently leads to islet cell survival. In a macrophage depletion mouse model, the presence of M1 macrophages in the liver contributed to graft death. AAT, through suppressing macrophage activation, protected transplanted islets from death and dysfunction in the human islet and NOD-SCID mouse model. The protective effect of AAT was confirmed in a major mismatch allogeneic islet transplantation model. Taken together, AAT suppresses liver macrophage activation that contributes to graft survival after transplantation.

Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re-emerging phenotype is associated with graft function.

Islet transplantation is an effective therapy for life-threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet-specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty-eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet-specific T cell responses was not significantly different over time (pre-Tx: 59%; 1-6m posttransplant: 38%; 7-12m: 44%; 13-24m: 47%; and >24m: 45%). However, phenotype shifted significantly, with IFN-γ-dominated response in the pretransplant group replaced by IL-10-dominated response in the 1-6m posttransplant group, reverting to predominantly IFN-γ-oriented response in the >24m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN-γ and IL-10 phenotypes, respectively. IL-10-oriented posttransplant response was associated with relatively low graft function. Recipients within the IL-10+ cluster had a significant decline in C-peptide levels in the period preceding the IL-10 response, but stable graft function following the response. In contrast, an IFN-γ response was associated with subsequently decreased C-peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet-specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function.

The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation.

Background.Potential adverse effects, such as functional impairment of islets, render conventional immunosuppressive drugs unsuitable for use in islet transplantation. In addition, as a single therapy, they cannot prolong islet allograft survival. Here, we investigated the utility of the mitogen-activated protein kinase inhibitor trametinib and asked whether it ameliorates acute rejection of transplanted islets without the need for conventional immunosuppressants.Methods.Islets from fully major histocompatibility complex-mismatched BALB/c mice were transplanted into streptozotocin-induced diabetic C57BL/6 mice via the portal vein. These mice received trametinib or vehicle (orally) for 28 days. Isolated islets from BALB/c mice were incubated in vitro with different concentrations of trametinib to determine viability and function.Results.Trametinib (0.1 and 0.3 mg/kg) prolonged graft survival significantly (P = 0.0007 and P = 0.005, respectively) when compared with vehicle. Histologic analyses revealed that cellular infiltration of the graft by lymphocytes was inhibited significantly on day 7 (P < 0.05). In addition, trametinib suppressed functional differentiation of naive CD4+ T cells in recipients. Expression of mRNA encoding inflammatory cytokines interleukin (IL)-2, tumor necrosis factor α, and interferon γ in recipients treated with trametinib was also inhibited (P < 0.001, P < 0.05, and P < 0.01, respectively). Trametinib also increased production of IL-4 and IL-10 (P < 0.05 and P = 0.20, respectively). In vitro, islets incubated with different concentrations of trametinib exhibited no harmful effects with respect to viability and function.Conclusions.Trametinib delayed islet graft rejection by inhibiting functional differentiation of naive CD4+ T cells and regulating inflammatory cytokines. Trametinib might be a promising candidate for maintenance immunosuppressive therapy after allogeneic islet transplantation.

Pancreatic islet transplantation: toward definitive treatment for diabetes mellitus.

Since the late 20th century, advances in pancreatic islet transplantation have targeted improved glycemic control and fewer hypoglycemic events in patients with type 1 diabetes, and some important milestones have been reached. Following the Edmonton group's success in achieving insulin independence in all transplanted patients with type 1 diabetes, clinical islet transplantation is now performed worldwide. β cell replacement therapy for type 1 diabetes was established based on the favorable outcomes of a phase 3, prospective, open-label, single-arm, clinical study conducted at 8 centers in North America, in which 42 of 48 patients who underwent islet transplantation from 2008 to 2011 achieved HbA1c < 7.0% (53 mmol/mol) at day 365, which was maintained at 2 years in 34 patients. In Japan, a phase 2 multicenter clinical trial of islet transplantation for type 1 diabetes patients is currently ongoing and will end soon, but the interim results have already led to positive changes, with allogeneic islet transplantation being covered by the national health insurance system since April 2020. Current efforts are being made to solve the problem of donor shortage by studying alternative donor sources, such as porcine islets and pancreatic progenitor cells derived from pluripotent stem cells. The results of clinical trials in this area are eagerly awaited. It is hoped that they will contribute to establishing alternative sources for insulin-producing β cells in the near future.

Acute murine cytomegalovirus disrupts established transplantation tolerance and causes recipient allo-sensitization.

We have previously shown that acute cytomegalovirus (CMV) infection disrupts the induction of transplantation tolerance. However, what impact acute CMV infection would have on the maintenance of established tolerance and on subsequent recipient allo-sensitization is a clinically important unanswered question. Here we used an allogeneic murine islet transplantation tolerance model to examine the impact of acute CMV infection on: (a) disruption of established transplantation tolerance during tolerance maintenance; and (b) the possibility of recipient allo-sensitization by CMV-mediated disruption of stable tolerance. We demonstrated that acute CMV infection abrogated transplantation tolerance during the maintenance stage in 50%-60% recipients. We further demonstrated that acute CMV infection-mediated tolerance disruption led to recipient allo-sensitization by reverting the tolerant state of allo-specific T cells and promoting their differentiation to allo-specific memory cells. Consequently, a second same-donor islet allograft was rejected in an accelerated fashion by these recipients. Our study therefore supports close monitoring for allo-sensitization in previously tolerant transplant recipients in whom tolerance maintenance is disrupted by an episode of acute CMV infection.

Pancreatic Islet Cell Transplantation: Graft Stability and Metabolic Outcomes.

Pancreatic islet transplantation is a rapidly evolving field. It has been increasingly regarded as a promising approach for the correction of dysglycemia associated with type 1 diabetes mellitus (allogenic islet transplantation), or the prevention of surgical diabetes in chronic pancreatitis subjects undergoing total pancreatectomy (autologous islet transplantation). In this review, we discuss the latest literature pertaining to metabolic outcomes of autologous and allogenic islet transplantation, shedding close light on our own latest experience in the autologous islet transplantation setting.

Improved human islets’ viability and functionality with mesenchymal stem cells and arg-gly-asp tripeptides supplementation of alginate micro-encapsulated islets in vitro

IntroductionThe extension of islet transplantation to a wider number of type 1 diabetes patients is compromised by severe adverse events related to the immunosuppressant therapy required for allogenic islet transplantation. In this context, microencapsulation offers the prospects of immunosuppressive-free therapy by physically isolating islets from the immune system. However, current biomaterials need to be optimized to: improve biocompatibility, guaranty the maintenance of graft viability and functionality, and prevent fibrosis overgrowth around the capsule in vivo. Accumulating evidence suggest that mesenchymal stem cells (MSCs) and anchor points consisting of tripeptides arg-gly-asp (RGD) have cytoprotective effects on pancreatic islets. Here, we investigated the effect of supplementing reference M-rich alginate microcapsules with MSCs and RGD-G rich alginate on bioprocessing as well as on human pancreatic islets viability and functionality. MethodsWe characterized the microcapsules components, and then for the new microcapsule composite product: we analyzed the empty capsules biocompatibility and then investigated the benefits of MSCs and RGD-G rich alginate on viability and functionality on the encapsulated human pancreatic islets in vitro. We performed viability tests by confocal microscopy and glucose stimulated insulin secretion (GSIS) test in vitro to assess the functionality of naked and encapsulated islets. ResultsEncapsulation in reference M-rich alginate capsules induced a reduction in viability and functionality compared to naked islets. This side-effect of encapsulation was in part counteracted by the presence of MSCs but the restoration was complete with the combination of both MSCs and the RGD-G rich alginate. ConclusionsThe present findings show that bioprocessing a favorable composite environment inside the M-rich alginate capsule with both MSCs and RGD-G rich alginate improves human islets survival and functionality in vitro.

1681-P: Alpha-1 Antitrypsin Suppresses Macrophage Activation Post Islet Transplantation

Macrophage activation contributes to islet graft loss after transplantation by secretion of proinflammatory cytokines. We showed in previous studies that treatment with alpha-1 antitrypsin (AAT) improved human islet survival after transplantation into the livers of streptozotocin-induced diabetic NOD-SCID mice. To further understand the cellular targets of AAT, we isolated macrophages from control or AAT-treated recipients at day 1 post transplantation (PT) and compared their mRNA profile using RNAseq analysis. 344 genes were changed in AAT-treated recipients compared to controls. Clusters of the inflammatory response, chemokine activity and cytokine and cytokine receptor Gene Otology categories and pathways were significantly affected by AAT-treatment. In vitro, AAT suppressed IFN-γ-induced Raw267.4 cell activation via suppression of STAT1 phosphorylation and iNOS production. This was translated in vitro when human islets were co-transplanted with IFN-γ-treated Raw cells, in the presence or absence of AAT, into diabetic NOD-SCID mice in which macrophages were depleted by liposome. At day 21, all macrophage-depleted diabetic recipients receiving islets alone achieved normoglycemia (n=6). In contrast, only 55.6% (n=9, p=0.001) receiving islets and IFN-γ-treated Raw cells achieved normoglycemia, compared to 90% receiving AAT-treated IFN-γ Raw cells (n=10, p=0.003), suggesting AAT improved islet graft survival via suppressing macrophage activation. The effect of AAT was further confirmed in a major mismatch allogeneic islet transplantation model (Balb/c, H-2b to C57BL/6 H-2d mice) in which macrophage activation contributed to primary nonfunction (PNF) of the transplanted islets. In this model, PNF occurred in 16.7% of AAT-treated recipients (n=6) but in 40% of controls (n=5) when 400 islets were transplanted. In summary, this study further identified that AAT contributed to islet graft survival after transplantation by suppressing macrophage activation. Disclosure W. Gou: None. C. Strange: None. H. Wang: None. Funding National Institutes of Health (DK105183, DK120394, DK118529)

Longitudinal proteomics analysis in the immediate microenvironment of islet allografts during progression of rejection

The applicability and benefits of pancreatic islet transplantation are limited due to various issues including the need to avoid immune-mediated rejection. Here, we used our experimental platform of allogeneic islet transplant in the anterior chamber of the eye (ACE-platform) to longitudinally monitor the progress of rejection in mice and obtain aqueous humor samples representative of the microenvironment of the graft for accurately-timed proteomic analyses. LC-MS/MS-based proteomics performed on such mass-limited samples (~5 μL) identified a total of 1296 proteins. Various analyses revealed distinct protein patterns associated with the mounting of the inflammatory and immune responses and their evolution with the progression of the rejection. Pathway analyses indicated predominant changes in cytotoxic functions, cell movement, and innate and adaptive immune responses. Network prediction analyses revealed transition from humoral to cellular immune response and exacerbation of pro-inflammatory signaling. One of the proteins identified by this localized proteomics as a candidate biomarker of islet rejection, Cystatin 3, was further validated by ELISA in the aqueous humor. This study provides (1) experimental evidence demonstrating the feasibility of longitudinal localized proteomics using small aqueous humor samples and (2) proof-of-concept for the discovery of biomarkers of impending immune attack from the immediate local microenvironment of ACE-transplanted islets. SignificanceThe combination of the ACE-platform and longitudinal localized proteomics offers a powerful approach to biomarker discovery during the various stages of immune reactions mounted against transplanted tissues including pancreatic islets. It also supports proteomics-assisted drug discovery and development efforts aimed at preventing rejection through efficacy assessment of new agents by noninvasive and longitudinal graft monitoring.

Donor-Specific Regulatory T Cell-Mediated Immune Tolerance in an Intrahepatic Murine Allogeneic Islet Transplantation Model with Short-Term Anti-CD154 mAb Single Treatment

Anti-CD154 blockade-based regimens remain unequaled in prolonging graft survival in various organ transplantation models. Several studies have focused on transplantation tolerance with the anti-CD154 blockade, but none of these studies has investigated the mechanisms associated with its use as the sole treatment in animal models, delaying our understanding of anti-CD154 blockade-mediated immune tolerance. The purpose of this study was to investigate the mechanism underlying the anti-CD154 monoclonal antibody (mAb) blockade in inducing immune tolerance using an intrahepatic murine allogeneic islet transplantation model. Allogeneic BALB/c AnHsd (BALB/c) islets were infused into the liver of diabetic C57BL/6 (B6) mice via the cecal vein. Anti-CD154 mAb (MR1) was administered on −1, 0, 1, 3, 5, and 7 d posttransplantation at 0.5 mg per mouse. We showed that short-term MR1 monotherapy could prolong the allogeneic islet grafts to more than 250 d in the murine intrahepatic islet transplantation model. The second islet grafts transplanted under the kidney capsule of the recipients were protected from rejection. We also found that rejection of same-donor skin grafts transplanted to the tolerant mice was modestly delayed. Using a DEREG mouse model, FoxP3+ regulatory T (Treg) cells were shown to play important roles in transplantation tolerance. In mixed lymphocyte reactions, Treg cells from the tolerant mice showed more potency in suppressing BALB/c splenocyte-stimulated Teff cell proliferation than those from naïve mice. In this study, we demonstrated for the first time that a short-term anti-CD154 mAb single treatment could induce FoxP3+ Treg cell-mediated immune tolerance in the intrahepatic murine allogeneic islet transplantation model.

The Role of Vitamin D and Omega-3 PUFAs in Islet Transplantation.

Recurrence of autoimmunity and allograft rejection represent major challenges that impact the success of islet transplantation. Despite the remarkable improvements achieved in immunosuppression strategies after the publication of the Edmonton protocol, long-term data of intra-hepatic islet transplantation show a gradual decline in beta-cell function. Therefore, there is a growing interest in the investigation of novel, safe and effective anti-inflammatory and immunomodulatory strategies able to promote long-term islet graft survival and notable improvements in clinical outcomes of islet transplant recipients. Vitamin D has been shown to exert anti-inflammatory and immunomodulatory effects. Pre-clinical studies investigating the use of vitamin D and its analogs (alone or in combination with immunosuppressive agents and/or other anti-inflammatory agents, such as omega-3 polyunsaturated fatty acids) showed beneficial results in terms of islet graft survival and prevention of recurrence of autoimmunity/allograft rejection in animal models of syngeneic and allogeneic islet transplantation. Moreover, epidemiologic studies demonstrated that vitamin D deficiency is highly prevalent after solid organ transplantation (e.g., heart, liver or kidney transplantation). However, studies that critically assess the prevalence of vitamin D deficiency among islet transplant recipients have yet to be conducted. In addition, prospective studies aimed to address the safety and efficacy of vitamin D supplementation as an adjuvant immunomodulatory strategy in islet transplant recipients are lacking and are therefore awaited in the future.

Successful allogeneic islet transplantation after total pancreatectomy with islet autotransplantation to restore normoglycemia: a case report.

Successful allogeneic islet transplantation after total pancreatectomy with islet autotransplantation to restore normoglycemia: a case report.

Ten-Year Outcome of Islet Alone or Islet After Kidney Transplantation in Type 1 Diabetes: A Prospective Parallel-Arm Cohort Study.

The long-term outcome of allogenic islet transplantation is unknown. The aim of this study was to evaluate the 10-year outcome of islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a functioning kidney graft. We enrolled in this prospective parallel-arm cohort study 28 subjects with type 1 diabetes who received islet transplantation either alone (ITA) or after a kidney graft (IAK). Islet transplantation consisted of two or three intraportal infusions of allogenic islets administered within (median [interquartile range]) 68 days (43-92). Immunosuppression was induced with interleukin-2 receptor antibodies and maintained with sirolimus and tacrolimus. The primary outcome was insulin independence with A1C ≤6.5% (48 mmol/mol). Secondary outcomes were patient and graft survival, severe hypoglycemic events (SHEs), metabolic control, and renal function. The primary outcome was met by (Kaplan-Meier estimates [95% CI]) 39% (22-57) and 28% (13-45) of patients 5 and 10 years after islet transplantation, respectively. Graft function persisted in 82% (62-92) and 78% (57-89) of case subjects after 5 and 10 years, respectively, and was associated with improved glucose control, reduced need for exogenous insulin, and a marked decrease of SHEs. ITA and IAK had similar outcomes. Primary graft function, evaluated 1 month after the last islet infusion, was significantly associated with the duration of graft function and insulin independence. Islet transplantation with the Edmonton protocol can provide 10-year markedly improved metabolic control without SHEs in three-quarters of patients with type 1 diabetes, kidney transplanted or not.