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Islet transplant

Tahir Farooq, Kanwal Rehman, Arruje Hameed, Muhammad Sajid Hamid Akash
Type 1 diabetes mellitus (T1DM) is classified as an autoimmune disease which progressively results in the depletion of insulin-secreting β-cells. Consequently, the insulin secretion stops leading to hyperglycemic situations within the body. Under severe conditions, it also causes multi-organ diabetes-associated dysfunctionalities notably hypercoagulability, neuropathy, nephropathy, retinopathy, and sometimes organ failures. The prevalence of this disease has been noticed about 3% that has highlighted the serious concerns for healthcare professionals around the globe...
June 13, 2018: Advances in Experimental Medicine and Biology
Oscar K Serrano, Kent J Peterson, Tetyana Mettler, Joshua J Wilhelm, Melena D Bellin, Gregory J Beilman, Guru Trikudanathan, Timothy L Pruett, Ty B Dunn
Total pancreatectomy (TP) is a treatment option for patients experiencing chronic pancreatitis (CP) refractory to medical management. Patients who are candidates for TP benefit from islet autotransplantation (IAT), which preserves available β-cell mass and thereby reduces the risk of brittle diabetes. Malignancy is an absolute contraindication for IAT to prevent the transplantation of occult malignant cells. We present the case of a patient with CP who was approved to undergo TP with IAT (TPIAT) but was intraoperatively discovered to have a pancreatic neuroendocrine tumor...
July 2018: Pancreas
Clarissa Hernandez Stephens, Kara S Orr, Anthony J Acton, Sarah A Tersey, Raghavendra G Mirmira, Robert V Considine, Sherry L Voytik-Harbin
Widespread use of pancreatic islet transplantation for treatment of type 1 diabetes (T1D) is currently limited by requirements for long-term immunosuppression, limited donor supply, and poor long-term engraftment and function. Upon isolation from their native microenvironment, islets undergo rapid apoptosis, which is further exacerbated by poor oxygen and nutrient supply following infusion into the portal vein. Identifying alternative strategies to restore critical microenvironmental cues, while maximizing islet health and function, are needed to advance this cellular therapy...
June 12, 2018: American Journal of Physiology. Endocrinology and Metabolism
Clovis Chabert, Camille Laporte, Arnold Fertin, Emily Tubbs, Cécile Cottet-Rousselle, Florence Rivera, Magali Orhant-Prioux, Anaick Moisan, Eric Fontaine, Pierre-Yves Benhamou, Sandrine Lablanche
Co-encapsulation of pancreatic islets with mesenchymal stem cells in a three-dimensional biomaterial's structure is a promising technique to improve transplantation efficacy and to decrease immunosuppressant therapy. Currently, evaluation of graft quality after co-encapsulation is only based on insulin secretion. Viability measurement in a 3D conformation structure involving two different cell types is complex, mainly performed manually, highly time consuming and examiner dependent. Standardization of encapsulated graft viability analysis before transplantation is a key point for the translation of the method from the bench side to clinical practice...
2018: Frontiers in Endocrinology
Shiva Pathak, Shobha Regmi, Tiep Tien Nguyen, Biki Gupta, Milan Gautam, Chul Soon Yong, Jong Oh Kim, Youlim Son, Jae-Ryong Kim, Min Hui Park, Young Kyung Bae, So Young Park, Daewon Jeong, Simmyung Yook, Jee-Heon Jeong
Attenuation of senescence progression may be attractive way to preserve the functionality of pancreatic islets (PI) after transplantation. In this study, we developed a model for in vitro induction of premature senescence in rat PI and showed the effectiveness of quercetin (QU) to prevent the senescence. To provide targeted-delivery of QU to the PI after transplantation, we prepared the hybrid clusters (HC) of islet single cells (ISC) and QU-loaded polymeric microspheres (QU; ∼7.55 ng HC-1 ). Long-term culture of the HC revealed reduced levels of reactive oxygen species and decreased expression of senescence-associated beta galactosidase, Rb, p53, p16, and p21 compared to that of the control islets...
June 5, 2018: Acta Biomaterialia
Mercè Obach, Azadeh Hosseini-Tabatabaei, Joel Montane, Katarina Wind, Galina Souchkatcheva, Derek Dai, John J Priatel, Paul C Orban, C Bruce Verchere
Overexpression of the X-linked inhibitor of apoptosis (XIAP) prevents islet allograft rejection. We constructed an adeno-associated virus expressing XIAP driven by the rat insulin promoter (dsAAV8-RIP-XIAP) for long-term beta-cell gene expression in vivo. Pancreatic delivery of dsAAV8-RIP-XIAP prevented autoimmune diabetes in 70% of NOD mice, associated with decreased insulitis. Islets from Balb/c mice transduced with dsAAV8-RIP-XIAP were protected following transplantation into streptozotocin (STZ)-diabetic Bl/6 recipients, associated with decreased graft infiltration...
June 5, 2018: Molecular and Cellular Endocrinology
Nisha Vastani, Franziska Guenther, Clive Gentry, Amazon L Austin, Aileen J King, Stuart Bevan, David A Andersson
The mechanisms responsible for painful and insensate diabetic neuropathy are not completely understood. Here, we have investigated sensory neuropathy in the Ins2 +/Akita mouse, a hereditary model of diabetes. Akita mice become diabetic soon after weaning, and we show that this is accompanied by an impaired mechanical and thermal nociception and a significant loss of intraepidermal nerve fibers. Electrophysiological investigations of skin-nerve preparations identified a reduced rate of action potential discharge in Ins2 +/Akita mechanonociceptors compared to wildtype littermates, whereas the function of low threshold A-fibers was essentially intact...
June 6, 2018: Diabetes
Peter Daniel Rios, Michael Skoumal, Jeffrey Liu, R Youngblood, Ekaterina Kniazeva, Andrés J Garcia, Lonnie D Shea
Islet transplantation is a promising therapeutic option for Type 1 diabetes mellitus, yet the current delivery into the hepatic portal vasculature is limited by poor engraftment. Biomaterials have been employed as a means to promote engraftment and function at extrahepatic sites, with strategies being categorized as encapsulation or microporous scaffolds that can either isolate or integrate islets with the host tissue, respectively. While these approaches are typically studied separately using distinct material platforms, herein, we developed non-degradable polyethylene glycol (PEG)-based hydrogels for islet encapsulation or as microporous scaffolds for islet seeding in order to compare the initial engraftment and function of islets in syngeneic diabetic mice...
June 5, 2018: Biotechnology and Bioengineering
Tomoko Tanaka, Daibo Kojima, Toshiyuki Mera, Masahito Matsumoto, Yohichi Yasunami, Toshihiko Yanase
The shortage of donor islets is a significant obstacle for widespread clinical application of pancreatic islet transplantation. To investigate whether adipose tissue-derived mesenchymal stem cells (ADSCs) induce expansion of transplanted islets, we performed co-transplantation experiments in a mouse model. Streptozotosin (STZ)-induced diabetic mice transplanted with 50 syngeneic islets remained hyperglycemic. However, hyperglycemia was ameliorated gradually when 50 islets were co-transplanted with ADSCs but not separately grafted into the contralateral kidney...
May 2018: Heliyon
Federico Bertuzzi, Luciano De Carlis, Mario Marazzi, Antonio Gaetano Rampoldi, Matteo Bonomo, Barbara Antonioli, Marta Cecilia Tosca, Marta Galuzzi, Andrea Lauterio, Danila Fava, Patrizia Dorighet, Andrea De Gasperi, Giacomo Colussi
Islet transplantation has been reported to restore normoglycemia and the overall metabolic control in type 1 diabetes mellitus (DM). In the most experienced centers, islet transplantation clinical outcome is similar to that of the whole pancreas transplantation. Long-term islet transplantation function remains a very interesting matter worth discussing. A progressive islet function decrease was reported, probably due to islet exhaustion. In 5 islet-transplanted patients with at least 3-yr follow-up and still insulin independent, their glycemic control was characterized by a blinded retrospective continuous glucose monitoring system (CGMS)...
January 1, 2018: Cell Transplantation
Andrej Babic, Laurent Vinet, Vineetha Chellakudam, Karolina Janikowska, Eric Allemann, Norbert Lange
Novel drug delivery systems targeting native, transplanted or cancerous beta-cells are of utmost importance. Herein, we present new exendin-4 derivatives with modified unnatural amino acids at strategic positions within the polypeptide sequence. The modified peptides allowed modular orthogonal chemical modifications to attach imaging agents and amphiphilic squalene-PEG groups. The resulting conjugates, SQ-PEG-ExC1-Cy5 and SQ-PEG-ExC40-Cy5 fluorescence probes display low nM affinity to GLP-1R in fluorescence-based binding assays with EC50 at 1...
June 5, 2018: Bioconjugate Chemistry
Jeffrey M H Liu, Xiaomin Zhang, Shelby Joe, Xunrong Luo, Lonnie D Shea
Introduction: The development of novel immunomodulatory strategies that might decrease the need for systemic immune suppression would greatly enable the utility of cell-based therapies. Cell transplantation on biomaterial scaffolds offers a unique opportunity to engineer a site to locally polarize immunogenic antigen generation. Herein, we investigated the localized delivery of IL-33, which is a novel cytokine that has been shown to have beneficial immunomodulatory effects in certain transplant models as mediating anti-inflammatory properties in the adipose tissue, to determine its feasibility for use as an immunomodulatory agent...
March 2018: Journal of immunology and regenerative medicine
Elizabeth M Thompson, Jennifer L Sollinger, Emmanuel C Opara, Christopher A Adin
Currently, islet isolation is performed using harsh collagenases that cause nonspecific injury to both islets and exocrine tissue, negatively affecting the outcome of cell transplantation. We evaluated a novel islet isolation protocol utilizing high concentrations of glucose to cause selective osmotic shock (SOS). Islets have a membrane glucose transporter that allows adaptation to changes in glucose concentrations while exocrine tissue can be selectively destroyed by these osmolar shifts. Canine pancreata were obtained within 15 min after euthanasia from animals ( n = 6) euthanized for reasons unrelated to this study...
March 2018: Cell Transplantation
Carlos E B Couri, Kelen C R Malmegrim, Maria C Oliveira
Since the discovery of autoimmunity as the main pathophysiologic process involved in type 1 diabetes, many attempts have tried to delay or stop beta cell destruction. Most research protocols in humans have investigated the effects of therapeutic agents targeting specific steps of the autoimmune response. In spite of safety and some degree of beta cell preservation, the clinical impact of such approaches was similar to placebo. Recently, research groups have analyzed the effects of a more intense and wider immunologic approach in newly diagnosed type 1 diabetic individuals with the "immunologic reset," i...
2018: Frontiers in Immunology
Robert A Benson, Fabien Garcon, Asha Recino, John R Ferdinand, Menna R Clatworthy, Herman Waldmann, James M Brewer, Klaus Okkenhaug, Anne Cooke, Paul Garside, Maja Wållberg
We present a novel and readily accessible method facilitating cellular time-resolved imaging of transplanted pancreatic islets. Grafting of islets to the mouse ear pinna allows non-invasive, in vivo longitudinal imaging of events in the islets and enables improved acquisition of experimental data and use of fewer experimental animals than is possible using invasive techniques, as the same mouse can be assessed for the presence of islet infiltrating cells before and after immune intervention. We have applied this method to investigating therapeutic protection of beta cells through the well-established use of anti-CD3 injection, and have acquired unprecedented data on the nature and rapidity of the effect on the islet infiltrating T cells...
2018: Frontiers in Immunology
Devon M Headen, Kyle B Woodward, María M Coronel, Pradeep Shrestha, Jessica D Weaver, Hong Zhao, Min Tan, Michael D Hunckler, William S Bowen, Christopher T Johnson, Lonnie Shea, Esma S Yolcu, Andrés J García, Haval Shirwan
Islet transplantation is a promising therapy for type 1 diabetes. However, chronic immunosuppression to control rejection of allogeneic islets induces morbidities and impairs islet function. T effector cells are responsible for islet allograft rejection and express Fas death receptors following activation, becoming sensitive to Fas-mediated apoptosis. Here, we report that localized immunomodulation using microgels presenting an apoptotic form of the Fas ligand with streptavidin (SA-FasL) results in prolonged survival of allogeneic islet grafts in diabetic mice...
June 4, 2018: Nature Materials
Liza Grapensparr, Gustaf Christoffersson, Per-Ola Carlsson
Pancreatic islets isolated for transplantation are disconnected from their vascular supply and need to establish a new functional network posttransplantation. Due to poor revascularization, prevailing hypoxia with correlating increased apoptosis rates in experimental studies can be observed for months posttransplantation. Endothelial progenitor cells (EPCs) are bone marrow-derived cells that promote neovascularization. The present study tested the hypothesis that EPCs, isolated from human umbilical cord blood, could be coated to human islet surfaces and be used to promote islet vascular engraftment...
January 1, 2018: Cell Transplantation
B Naziruddin, M A Kanak, C A Chang, M Takita, M C Lawrence, A R Dennison, N Onaca, M F Levy
The efficacy of islet transplantation is compromised by a significant loss of islet mass posttransplant due to an innate inflammatory reaction. Here we report the use of a combination of etanercept and anakinra to block inflammatory islet damage in 100 patients undergoing total pancreatectomy with islet autotransplantation. The patients were divided into three groups: no treatment (CTL), etanercept alone (ETA), or a combination of etanercept and anakinra (ANA+ETA). Peritransplant serum samples were analyzed for protein markers of islet damage and for inflammatory cytokines...
June 4, 2018: American Journal of Transplantation
Julie B Sneddon, Qizhi Tang, Peter Stock, Jeffrey A Bluestone, Shuvo Roy, Tejal Desai, Matthias Hebrok
Restoration of insulin independence and normoglycemia has been the overarching goal in diabetes research and therapy. While whole-organ and islet transplantation have become gold-standard procedures in achieving glucose control in diabetic patients, the profound lack of suitable donor tissues severely hampers the broad application of these therapies. Here, we describe current efforts aimed at generating a sustainable source of functional human stem cell-derived insulin-producing islet cells for cell transplantation and present state-of-the-art efforts to protect such cells via immune modulation and encapsulation strategies...
June 1, 2018: Cell Stem Cell
Shareen Forbes, Anna Lam, Angela Koh, Sharleen Imes, Parastoo Dinyari, Andrew J Malcolm, Am James Shapiro, Peter A Senior
Following islet transplantation, mixed meal tolerance tests (MMTs) are routinely utilised to assess graft function, but how the 90-minute MMTT glucose value relates to a 120 minute glucose concentration of ≥11.1mmol/L used to diagnose diabetes following a standardised 75g-OGTT, is not known. We examined this relationship further. Thirteen subjects with Type 1 diabetes and stable transplant grafts, not on exogenous insulin with HbA1c<7% (53mmol/mol), were studied on 17 occasions with paired OGTTs and MMTTs...
May 31, 2018: Clinical Transplantation
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