G-CSF and Exenatide Might Be Associated with Increased Long-Term Survival of Allogeneic Pancreatic Islet Grafts.
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ABSTRACT: Allogeneic human islet transplantation is an effective therapy for the treatment of patients with Type 1 Diabetes (T1D). The low number of islet transplants performed worldwide and the different transplantation protocols used limit the identification of the most effective therapeutic options to improve the efficacy of this approach.We present a retrospective analysis on the data collected from 44 patients with T1D who underwent islet transplantation at our institute between 2000 and 2007. Several variables were included: recipient demographics and immunological characteristics, donor and transplant characteristics, induction protocols, and additional medical treatment received. Immunosuppression was induced with anti-CD25 (Daclizumab), alone or in association with anti-tumor necrosis factor alpha (TNF-?) treatments (Etanercept or Infliximab), or with anti-CD52 (Alemtuzumab) in association with anti-TNF-? treatments (Etanercept or Infliximab). Subsets of patients were treated with Filgrastim for moderate/severe neutropenia and/or Exenatide for post prandial hyperglycemia.The analysis performed indicates a negative association between graft survival (c-peptide level ? 0.3 ng/ml) and islet infusion volume, with the caveat that, the progressive reduction of infusion volumes over the years has been paralleled by improved immunosuppressive protocols. A positive association is instead suggested between graft survival and administration of Exenatide and Filgrastim, alone or in combination.This retrospective analysis may be of assistance to further improve long-term outcomes of protocols for transplant of islets and other organs.
<h4>Background</h4>Allogeneic human islet transplantation is an effective therapy for the treatment of patients with Type 1 Diabetes (T1D). The low number of islet transplants performed worldwide and the different transplantation protocols used limit the identification of the most effective therapeutic options to improve the efficacy of this approach.<h4>Methods</h4>We present a retrospective analysis on the data collected from 44 patients with T1D who underwent islet transplantation at our inst ...[more]
Project description:To assess the role of sex mismatch on graft survival after pancreas transplantation. We evaluated 24,195 pancreas-transplant recipients reported in the Scientific Registry of Transplant Recipients over a 25-year period. Pancreatic graft survival (PGS) was analyzed according to donor-recipient sex pairing using Kaplan-Meier estimations. Hazard ratios were estimated using Cox proportional hazard models. A total of 14,187 male and 10,008 female recipients were included in final analyses. Mean follow-up was 8.3?±?5.7 years. In multivariate analyses, neither recipient sex nor donor sex was associated with pancreatic graft failure (PGF), but donor-recipient sex mismatch (regardless of recipient sex) was an independent predictor of PGS (HR, 1.09; 95% CI, 1.04-1.14; p?<?0.001). Compared with M???M sex-matched recipients in univariate analyses, M???F and F???M sex mismatches were associated with an increased risk of PGF. Adjustment for significant recipient and donor factors eliminated the association between F???M sex mismatch and PGF (HR, 1.02; 95% CI, 0.93-1.10; p?=?0.752), but not M???F (1.09; 1.02-1.17; 0.020). Stratified analyses suggested that the negative effect of donor-recipient sex mismatch could be neutralized in older patients. These findings suggest that donor-recipient sex pairing should be taken into consideration in organ-allocation strategies.
Project description:Information regarding the longevity of transplanted pancreatic islet grafts could provide valuable information for treatment options. In our previous studies, we showed that isolated autologous pancreatic islets could be labeled with iron oxide nanoparticles and monitored after transplantation using MRI. Here, we report on in vivo monitoring of a secondary damage that occurs at the later stages because of allogeneic immune rejection.In the proof-of-principle studies, iron oxide-labeled autologous pancreatic islets were transplanted under the renal capsules of nonhuman primates. To demonstrate acute graft loss, the animals were injected with streptozotocin. Graft monitoring was performed by in vivo MRI. Next, iron oxide-labeled allogeneic islets were transplanted into the liver and monitored by MRI after withdrawal of immunosuppression.In autologous model, we observed a pronounced drop in graft volume after streptozotocin challenge as assessed by MRI. In allogeneic model of islet transplantation, there was an initial islet loss after the procedure followed by relative stabilization of the graft volume. After immunosuppression was discontinued, there was a noticeable drop in graft volume that gradually continued during the course of the study. Importantly, the loss of graft volume observed on MR preceded the raise in blood glucose.This study demonstrated that in vivo MRI was able to reveal graft volume loss before any changes in blood glucose that can be measured by standard methods. We believe that these results could provide means for clinicians to follow islet fate noninvasively and longitudinally using clinically relevant scanners.
Project description:The transplantation of pancreatic islet cells could restore glycaemic control in patients with type-I diabetes. Microspheres for islet encapsulation have enabled long-term glycaemic control in diabetic rodent models; yet human patients transplanted with equivalent microsphere formulations have experienced only transient islet-graft function, owing to a vigorous foreign-body reaction (FBR), to pericapsular fibrotic overgrowth (PFO) and, in upright bipedal species, to the sedimentation of the microspheres within the peritoneal cavity. Here, we report the results of the testing, in non-human primate (NHP) models, of seven alginate formulations that were efficacious in rodents, including three that led to transient islet-graft function in clinical trials. Although one month post-implantation all formulations elicited significant FBR and PFO, three chemically modified, immune-modulating alginate formulations elicited reduced FBR. In conjunction with a minimally invasive transplantation technique into the bursa omentalis of NHPs, the most promising chemically modified alginate derivative (Z1-Y15) protected viable and glucose-responsive allogeneic islets for 4 months without the need for immunosuppression. Chemically modified alginate formulations may enable the long-term transplantation of islets for the correction of insulin deficiency.
Project description:A major challenge for human allogeneic islet transplantation is the development of effective methods to induce donor-specific tolerance to obviate the need for life-long immunosuppression that is toxic to the insulin-producing beta cells and detrimental to the host. We developed an efficient donor-specific tolerance therapy that utilizes infusions of ethylene carbodiimide (ECDI)-treated donor splenic antigen-presenting cells that results in indefinite survival of allogeneic islet grafts in the absence of immunosuppression. Furthermore, we show that induction of tolerance is critically dependent on synergistic effects between an intact programmed death 1 receptor-programmed death ligand 1 signaling pathway and CD4(+)CD25(+)Foxp3(+) regulatory T cells. This highly efficient antigen-specific therapy with a complete avoidance of immunosuppression has significant therapeutic potential in human islet cell transplantation.
Project description:BACKGROUND:Progressive graft dysfunction (GDF) and loss of insulin independence (II) have been invariably observed in islet transplant recipients under the "Edmonton protocol." To reestablish II, we performed supplemental islet infusions (SI) in recipients of allogeneic islet transplant alone, displaying GDF. To improve the engraftment and long-term graft function of SI, exenatide (EXN) and etanercept treatment at islet infusion, and long-term EXN treatment were tested in a non-randomized pilot clinical trial. METHODS:Patients with GDF received SI under Edmonton-like immunosuppression with daclizumab induction, either without interventions (SI-control; n=5) or with EXN and etanercept treatment (SI-EXN; n=4). Clinical and metabolic profiles were assessed during 18-month follow-up. RESULTS:Long-term II (18 months) was observed in 100% of SI-EXN and in 20% of SI-control (P=0.04). SI-EXN subjects demonstrated restoration of function better than that seen after initial islet infusions. Comparison of SI-EXN and SI-control groups demonstrated better responses in SI-EXN subjects at 3 months post-SI. During the 18 months of follow-up, function was sustained in the SI-EXN subjects better than in SI-controls. Acute effects of EXN during mixed meal tolerance test and intravenous glucose tolerance test results in improved first and second phase insulin release in response to intravenous glucose tolerance test and suppressed postprandial hyperglucagonemia after mixed meal tolerance test. CONCLUSION:These results suggest that the combination of EXN and etanercept improve engraftment and long-term islet survival and function in subjects undergoing SI. This data, however, must be interpreted with some caution because of small sample size, lack of randomization, and sequential comparison with historical controls.
Project description:BackgroundOsteonecrosis of the femoral head (ONFH) is a disabling disease, which often involves young patients. Recently, various hip-preserving surgeries were recommended to delay total hip arthroplasty (THA).Questions/purposesThis study aimed to compare clinical outcomes and survival rate in the long-term follow-up between core decompression combined with a non-vascularized autologous fibular graft (group A) and an allogeneic fibular graft (group B) for the treatment of ONFH.Patients and methodsWe retrospectively evaluated 117 patients (153 hips) with ONFH (Association Research Circulation Osseous [ARCO] stages IIa to IIIc) who underwent the abovementioned hip-preserving surgeries between January 2003 and June 2012. The mean (range) follow-up times (years) were 12.9 (7-16) and 9.3 (6-16) in groups A and B, respectively. Clinical outcomes were assessed using the Harris Hip Score (HHS), visual analog scale (VAS) score, and forgotten joint score (FJS). A survival analysis was performed using the Kaplan-Meier method. The end point was THA.ResultsGroups A and B showed postoperative improvements, respectively, in HHS from 65 ± 7.2 to 80.3 ± 14.5 and from 66 ± 5.9 to 82.4 ± 13.6 (p < 0.05), and in VAS score from 6.3 ± 1.1 to 2.3 ± 1.6 and from 6.1 ± 1 to 2.2 ± 2.2 (p < 0.05). However, no significant differences in the HHS, VAS score, and hip FJS at the last follow-up (p > 0.05) and 15-year survival rate (84.1% and 86%, respectively, p > 0.05) were found between groups A and B.ConclusionsAutologous and allogeneic fibular grafts can attain equally good clinical outcomes and high survival rates in long-term follow-up, and thus can greatly delay THA owing to good bone osseointegration and sufficient mechanical support. Notably, the ratio of failure will increase when patients were more than 37 years old.Level of evidenceLevel III, therapeutic study.
Project description:ObjectivesThis study sought to evaluate the long-term differences in survival between multiple arterial grafts (MAG) and single arterial grafts (SAG) in patients who underwent coronary artery bypass grafting (CABG) in the SYNTAX study.MethodsThe present analysis included the randomized and registry-treated CABG patients (n = 1509) from the SYNTAX Extended Survival study (SYNTAXES). Patients with only venous (n = 42) or synthetic grafts (n = 1) were excluded. The primary end point was all-cause death at the longest follow-up. Multivariable Cox regression was used to adjust for differences in baseline characteristics. Sensitivity analysis using propensity matching with inverse probability for treatment weights was performed.ResultsOf the 1466 included patients, 465 (31.7%) received MAG and 1001 (68.3%) SAG. Patients receiving MAG were younger and at lower risk. At the longest follow-up of 12.6 years, all-cause death occurred in 23.6% of MAG and 40.0% of SAG patients [adjusted hazard ratio (HR) 0.74, 95% confidence interval (CI) (0.55-0.98); P = 0.038], which was confirmed by sensitivity analysis. MAG in patients with the three-vessel disease was associated with significant lower unadjusted and adjusted all-cause death at 12.6 years [adjusted HR 0.65, 95% CI (0.44-0.97); P = 0.033]. In contrast, no significance was observed after risk adjustment in patients with the left main disease, with and without diabetes, or among SYNTAX score tertiles.ConclusionsIn the present post hoc analysis of all-comers patients from the SYNTAX trial, MAG resulted in markedly lower all-cause death at 12.6-year follow-up compared to a SAG strategy. Hence, this striking long-term survival benefit of MAG over SAG encourages more extensive use of multiple arterial grafting in selected patients with reasonable life expectancy.Trial registrationSYNTAXES ClinicalTrials.gov reference: NCT03417050; SYNTAX ClinicalTrials.gov reference: NCT00114972.
Project description:PurposeAllogeneic hematopoietic cell transplantation (HCT) is curative but is associated with life-threatening complications. Most deaths occur within the first 2 years after transplantation. In this report, we examine long-term survival in 2-year survivors in the largest cohort ever studied.Patients and methodsRecords of 10,632 patients worldwide reported to the Center for International Blood and Marrow Transplant Research who were alive and disease free 2 years after receiving a myeloablative allogeneic HCT before 2004 for acute myelogenous or lymphoblastic leukemia, myelodysplastic syndrome, lymphoma, or severe aplastic anemia were reviewed.ResultsMedian follow-up was 9 years, and 3,788 patients had been observed for 10 or more years. The probability of being alive 10 years after HCT was 85%. The chief risk factors for late death included older age and chronic graft-versus-host disease (GVHD). For patients who underwent transplantation for malignancy, relapse was the most common cause of death. The greatest risk factor for late relapse was advanced disease at transplantation. Principal risk factors for nonrelapse deaths were older age and GVHD. When compared with age, sex, and nationality-matched general population, late deaths remained higher than expected for each disease, with the possible exception of lymphoma, although the relative risk generally receded over time.ConclusionThe prospect for long-term survival is excellent for 2-year survivors of allogeneic HCT. However, life expectancy remains lower than expected. Performance of HCT earlier in the course of disease, control of GVHD, enhancement of immune reconstitution, less toxic regimens, and prevention and early treatment of late complications are needed.
Project description:Islet transplantation is a promising treatment for diabetes but long-term success is limited by progressive graft loss. Aggregates of the beta cell peptide islet amyloid polypeptide (IAPP) promote beta cell apoptosis and rapid amyloid formation occurs in transplanted islets. Porcine islets are an attractive alternative islet source as they demonstrate long-term graft survival. We compared the capacity of transplanted human and porcine islets to form amyloid as an explanation for differences in graft survival. Human islets were transplanted into streptozotocin-diabetic immune-deficient mice. Amyloid deposition was detectable at 4 weeks posttransplantation and was associated with islet graft failure. More extensive amyloid deposition was observed after 8 weeks. By contrast, no amyloid was detected in transplanted neonatal or adult porcine islets that had maintained normoglycemia for up to 195 days. To determine whether differences in IAPP sequence between humans and pigs could explain differences in amyloid formation and transplant viability, we sequenced porcine IAPP. Porcine IAPP differs from the human sequence at 10 positions and includes substitutions predicted to reduce its amyloidogenicity. Synthetic porcine IAPP was considerably less amyloidogenic than human IAPP as determined by transmission electron microscopy, circular dichroism, and thioflavin T binding. Viability assays indicated that porcine IAPP is significantly less toxic to INS-1 beta cells than human IAPP. Our findings demonstrate that species differences in IAPP sequence can explain the lack of amyloid formation and improved survival of transplanted porcine islets. These data highlight the potential of porcine islet transplantation as a therapeutic approach for human diabetes.
Project description:The application of artificial intelligence (AI) and machine learning (ML) in biomedical research promises to unlock new information from the vast amounts of data being generated through the delivery of healthcare and the expanding high-throughput research applications. Such information can aid medical diagnoses and reveal various unique patterns of biochemical and immune features that can serve as early disease biomarkers. In this report, we demonstrate the feasibility of using an AI/ML approach in a relatively small dataset to discriminate among three categories of samples obtained from mice that either rejected or tolerated their pancreatic islet allografts following transplant in the anterior chamber of the eye, and from naïve controls. We created a locked software based on a support vector machine (SVM) technique for pattern recognition in electropherograms (EPGs) generated by micellar electrokinetic chromatography and laser induced fluorescence detection (MEKC-LIFD). Predictions were made based only on the aligned EPGs obtained in microliter-size aqueous humor samples representative of the immediate local microenvironment of the islet allografts. The analysis identified discriminative peaks in the EPGs of the three sample categories. Our classifier software was tested with targeted and untargeted peaks. Working with the patterns of untargeted peaks (i.e., based on the whole pattern of EPGs), it was able to achieve a 21 out of 22 positive classification score with a corresponding 95.45% prediction accuracy among the three sample categories, and 100% accuracy between the rejecting and tolerant recipients. These findings demonstrate the feasibility of AI/ML approaches to classify small numbers of samples and they warrant further studies to identify the analytes/biochemicals corresponding to discriminative features as potential biomarkers of islet allograft immune rejection and tolerance.
