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Arefanian H, Ramji Q, Gupta N, Spigelman AF, Grynoch D, MacDonald PE, Mueller TF, Gazda LS, Rajotte RV, Rayat GR. Yield, cell composition, and function of islets isolated from different ages of neonatal pigs. Front Endocrinol (Lausanne) 2022; 13:1032906. [PMID: 36619563 PMCID: PMC9811407 DOI: 10.3389/fendo.2022.1032906] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/01/2022] [Indexed: 12/24/2022] Open
Abstract
The yield, cell composition, and function of islets isolated from various ages of neonatal pigs were characterized using in vitro and in vivo experimental models. Islets from 7- and 10-day-old pigs showed significantly better function both in vitro and in vivo compared to islets from 3- and 5-day-old pigs however, the islet yield from 10-day-old pigs were significantly less than those obtained from the other pigs. Since islets from 3-day-old pigs were used in our previous studies and islets from 7-day-old pigs reversed diabetes more efficiently than islets from other groups, we further evaluated the function of these islets post-transplantation. B6 rag-/- mouse recipients of various numbers of islets from 7-day-old pigs achieved normoglycemia faster and showed significantly improved response to glucose challenge compared to the recipients of the same numbers of islets from 3-day-old pigs. These results are in line with the findings that islets from 7-day-old pigs showed reduced voltage-dependent K+ (Kv) channel activity and their ability to recover from post-hypoxia/reoxygenation stress. Despite more resident immune cells and immunogenic characteristics detected in islets from 7-day-old pigs compared to islets from 3-day-old pigs, the combination of anti-LFA-1 and anti-CD154 monoclonal antibodies are equally effective at preventing the rejection of islets from both age groups of pigs. Collectively, these results suggest that islets from various ages of neonatal pigs vary in yield, cellular composition, and function. Such parameters may be considered when defining the optimal pancreas donor for islet xenotransplantation studies.
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Affiliation(s)
- Hossein Arefanian
- Alberta Diabetes Institute, Ray Rajotte Surgical-Medical Research Institute, Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- Department of Immunology & Microbiology, Dasman Diabetes Institute, Dasman, Kuwait
| | - Qahir Ramji
- Alberta Diabetes Institute, Ray Rajotte Surgical-Medical Research Institute, Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Nancy Gupta
- Alberta Diabetes Institute, Ray Rajotte Surgical-Medical Research Institute, Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Aliya F. Spigelman
- Alberta Diabetes Institute, Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Donald Grynoch
- Alberta Precision Labs, Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Patrick E. MacDonald
- Alberta Diabetes Institute, Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Thomas F. Mueller
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | | | - Ray V. Rajotte
- Alberta Diabetes Institute, Ray Rajotte Surgical-Medical Research Institute, Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- *Correspondence: Gina R. Rayat, ; Ray V. Rajotte,
| | - Gina R. Rayat
- Alberta Diabetes Institute, Ray Rajotte Surgical-Medical Research Institute, Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- *Correspondence: Gina R. Rayat, ; Ray V. Rajotte,
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Lau H, Khosrawipour T, Li S, Alexander M, Frelkiewicz P, Labbé MK, Stieglitz S, Lakey JRT, Kielan W, Khosrawipour V. Exploring Insulin Production Following Alveolar Islet Transplantation (AIT). Int J Mol Sci 2021; 22:ijms221910185. [PMID: 34638521 PMCID: PMC8508311 DOI: 10.3390/ijms221910185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 09/11/2021] [Accepted: 09/16/2021] [Indexed: 11/29/2022] Open
Abstract
Recent studies have demonstrated the feasibility of islet implantation into the alveoli. However, until today, there are no data on islet behavior and morphology at their transplant site. This study is the first to investigate islet distribution as well insulin production at the implant site. Using an ex vivo postmortem swine model, porcine pancreatic islets were isolated and aerosolized into the lung using an endoscopic spray-catheter. Lung tissue was explanted and bronchial airways were surgically isolated and connected to a perfusor. Correct implantation was confirmed via histology. The purpose of using this new lung perfusion model was to measure static as well as dynamic insulin excretions following glucose stimulation. Alveolar islet implantation was confirmed after aerosolization. Over 82% of islets were correctly implanted into the intra-alveolar space. The medium contact area to the alveolar surface was estimated at 60 +/− 3% of the total islet surface. The new constructed lung perfusion model was technically feasible. Following static glucose stimulation, insulin secretion was detected, and dynamic glucose stimulation revealed a biphasic insulin secretion capacity during perfusion. Our data indicate that islets secrete insulin following implantation into the alveoli and display an adapted response to dynamic changes in glucose. These preliminary results are encouraging and mark a first step toward endoscopically assisted islet implantation in the lung.
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Affiliation(s)
- Hien Lau
- Department of Surgery, University of California, Irvine (UCI), Orange, CA 92868, USA; (M.A.); (J.R.T.L.); (V.K.)
- Correspondence: (H.L.); (T.K.)
| | - Tanja Khosrawipour
- Department of Surgery (A), University-Hospital Düsseldorf, Heinrich-Heine University, Moorenstrasse 5, D-40225 Duesseldorf, Germany
- Correspondence: (H.L.); (T.K.)
| | - Shiri Li
- Department of Surgery, Weill Medical College of Cornell University, New York, NY 10065, USA;
| | - Michael Alexander
- Department of Surgery, University of California, Irvine (UCI), Orange, CA 92868, USA; (M.A.); (J.R.T.L.); (V.K.)
| | - Piotr Frelkiewicz
- Center for Experimental Diagnostics and Biomedical Innovations, Wroclaw University of Environmental and Life Sciences, 50-375 Wroclaw, Poland;
| | - Maya Karine Labbé
- School of Dentistry, Wroclaw Medical University, 50-367 Wroclaw, Poland;
| | - Sven Stieglitz
- Department Pulmonary Medicine, Petrus-Hospital Wuppertal, University of Witten-Herdecke, D-42283 Wuppertal, Germany;
| | - Jonathan Robert Todd Lakey
- Department of Surgery, University of California, Irvine (UCI), Orange, CA 92868, USA; (M.A.); (J.R.T.L.); (V.K.)
| | - Wojciech Kielan
- 2nd Department of General Surgery and Surgical Oncology, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Veria Khosrawipour
- Department of Surgery, University of California, Irvine (UCI), Orange, CA 92868, USA; (M.A.); (J.R.T.L.); (V.K.)
- 2nd Department of General Surgery and Surgical Oncology, Wroclaw Medical University, 50-556 Wroclaw, Poland;
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3
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Lau H, Khosrawipour T, Alexander M, Li S, Mikolajczyk A, Nicpon J, Schubert J, Bania J, Lakey JRT, Khosrawipour V. Islet Transplantation in the Lung via Endoscopic Aerosolization: Investigation of Feasibility, Islet Cluster Cell Vitality, and Structural Integrity. Cell Transplant 2021; 29:963689720949244. [PMID: 32967455 PMCID: PMC7784503 DOI: 10.1177/0963689720949244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Aerosolized drug delivery has recently attracted much attention as a possible new tool for the delivery of complex nanoparticles. This study aims to investigate whether catheter-based aerosolization of islets via endobronchial systems is a feasible option in islet transplantation. Besides investigating the feasibility of islet aerosolization, we also examined cluster cell vitality and structural integrity of the islets following aerosolization. Using an ex vivo postmortem swine model, porcine pancreatic islets were isolated and aerosolized with an endoscopic spray catheter. Following aerosolization, islet cell vitality and function were assessed via Calcein AM and propidium iodide as well as insulin production after glucose exposure. In the final step, the overall feasibility of the procedure and structural integrity of cells were analyzed and evaluated with respect to clinical applicability. No significant difference was detected in the viability of control islets (90.67 ± 2.19) vs aerosolized islets (90.68 ± 1.20). Similarly, there was no significant difference in control islets (1.62 ± 0.086) vs aerosolized islets (1.42 ± 0.11) regarding insulin release after stimulation. Indocyanine green marked islets were transplanted into the lung without major difficulty. Histological analysis confirmed retained structural integrity and predominant location in the alveolar cavity. Our ex vivo data suggest that catheter-based aerosolized islet cell delivery is a promising tool for the application of cell clusters. According to our data, islet cell clusters delivery is feasible from a mechanical and physical perspective. Moreover, cell vitality and structural integrity remain largely unaffected following aerosolization. These preliminary results are encouraging and represent a first step toward endoscopically assisted islet cell implantation in the lung.
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Affiliation(s)
- Hien Lau
- Department of Surgery, 8788University of California, Irvine (UCI), Orange, CA, USA
| | - Tanja Khosrawipour
- Department of Surgery, 8788University of California, Irvine (UCI), Orange, CA, USA.,Department of Surgery (A), University-Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany
| | - Michael Alexander
- Department of Surgery, 8788University of California, Irvine (UCI), Orange, CA, USA
| | - Shiri Li
- Department of Surgery, 8788University of California, Irvine (UCI), Orange, CA, USA
| | - Agata Mikolajczyk
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Sciences, 56641Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland
| | - Jakub Nicpon
- Department of Surgery, Faculty of Veterinary Sciences, Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland
| | - Justyna Schubert
- Department of Food Hygiene and Consumer Health Protection, 56641Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland
| | - Jacek Bania
- Department of Food Hygiene and Consumer Health Protection, 56641Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland
| | | | - Veria Khosrawipour
- Department of Surgery, 8788University of California, Irvine (UCI), Orange, CA, USA.,Department of Biochemistry and Molecular Biology, Faculty of Veterinary Sciences, 56641Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland
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Ayuso M, Buyssens L, Stroe M, Valenzuela A, Allegaert K, Smits A, Annaert P, Mulder A, Carpentier S, Van Ginneken C, Van Cruchten S. The Neonatal and Juvenile Pig in Pediatric Drug Discovery and Development. Pharmaceutics 2020; 13:44. [PMID: 33396805 PMCID: PMC7823749 DOI: 10.3390/pharmaceutics13010044] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/22/2020] [Accepted: 12/22/2020] [Indexed: 02/06/2023] Open
Abstract
Pharmacotherapy in pediatric patients is challenging in view of the maturation of organ systems and processes that affect pharmacokinetics and pharmacodynamics. Especially for the youngest age groups and for pediatric-only indications, neonatal and juvenile animal models can be useful to assess drug safety and to better understand the mechanisms of diseases or conditions. In this respect, the use of neonatal and juvenile pigs in the field of pediatric drug discovery and development is promising, although still limited at this point. This review summarizes the comparative postnatal development of pigs and humans and discusses the advantages of the juvenile pig in view of developmental pharmacology, pediatric diseases, drug discovery and drug safety testing. Furthermore, limitations and unexplored aspects of this large animal model are covered. At this point in time, the potential of the neonatal and juvenile pig as nonclinical safety models for pediatric drug development is underexplored.
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Affiliation(s)
- Miriam Ayuso
- Comparative Perinatal Development, Department of Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium; (L.B.); (M.S.); (A.V.); (C.V.G.)
| | - Laura Buyssens
- Comparative Perinatal Development, Department of Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium; (L.B.); (M.S.); (A.V.); (C.V.G.)
| | - Marina Stroe
- Comparative Perinatal Development, Department of Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium; (L.B.); (M.S.); (A.V.); (C.V.G.)
| | - Allan Valenzuela
- Comparative Perinatal Development, Department of Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium; (L.B.); (M.S.); (A.V.); (C.V.G.)
| | - Karel Allegaert
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium; (K.A.); (P.A.)
- Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium;
- Department of Hospital Pharmacy, Erasmus MC Rotterdam, 3000 CA Rotterdam, The Netherlands
| | - Anne Smits
- Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium;
- Neonatal Intensive Care Unit, University Hospitals UZ Leuven, 3000 Leuven, Belgium
| | - Pieter Annaert
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium; (K.A.); (P.A.)
| | - Antonius Mulder
- Department of Neonatology, University Hospital Antwerp, 2650 Edegem, Belgium;
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, 2610 Wilrijk, Belgium
| | | | - Chris Van Ginneken
- Comparative Perinatal Development, Department of Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium; (L.B.); (M.S.); (A.V.); (C.V.G.)
| | - Steven Van Cruchten
- Comparative Perinatal Development, Department of Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium; (L.B.); (M.S.); (A.V.); (C.V.G.)
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5
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NHP-immunome: A translational research-oriented database of non-human primate immune system proteins. Cell Immunol 2019; 347:103999. [PMID: 31733823 DOI: 10.1016/j.cellimm.2019.103999] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 10/21/2019] [Accepted: 10/29/2019] [Indexed: 11/22/2022]
Abstract
We are currently living the advent of a new age for medicine in which basic research is being quickly translated into marketable drugs, and the widespread access to genomics data is allowing the design and implementation of personalized solutions to medical conditions. Non-human primates (NHP) have gained an essential role in drug discovery and safety testing due to their close phylogenetic relationship to humans. In this study, a collection of well characterized genes of the human immune system was used to define the orthology-based immunome in four NHP species, with carefully curated annotations available based on multi-tissue RNA-seq datasets. A broad variation in the frequency of expressed protein isoforms was observed between species. Finally, this analysis also revealed the lack of expression of at least four different chemokines in new-world primates. In addition, transcripts corresponding to four genes including interleukin 12 subunit alpha were expressed in humans but no other primate species analyzed. Access to the non-human primate immunome is available in http://www.fidic.org.co:90/proyecto/.
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6
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Rodriguez S, Lau H, Corrales N, Heng J, Lee S, Stiner R, Alexander M, Lakey JRT. Characterization of chelator-mediated recovery of pancreatic islets from barium-stabilized alginate microcapsules. Xenotransplantation 2019; 27:e12554. [PMID: 31495985 DOI: 10.1111/xen.12554] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 07/29/2019] [Accepted: 08/07/2019] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Islet recovery from within alginate-based microcapsules is necessary for certain analytical assays like flow cytometry; however, this technology has not been widely characterized. In this study, we explore the ability of EDTA, EGTA, and sodium citrate to induce reverse alginate polymerization via chelation and assess the toxicity of each chelator on pancreatic islets. METHODS EDTA, EGTA, and sodium citrate were used to dissolve single-layered Ba2+ alginate encapsulated islets and the rate of capsule breakdown calculated from analysis of imaging data. The effect of chelator exposure on islet viability and recovery was assessed using flow cytometry, while glucose-stimulated insulin release (GSIR) assay was used to measure effects on islet function. RESULTS EGTA demonstrated the most rapid microcapsule dissolving rate followed by EDTA and sodium citrate. Islet recovery was significantly better when encapsulated islets were treated with EDTA than EGTA and Na+ citrate. A decrease in viability and increase in apoptotic cells were observed when encapsulated islets were treated with Na+ citrate compared to islets treated with EDTA and EGTA. Islets treated with EDTA and EGTA demonstrated comparable stimulation index values to non-treated control. Conversely, islets treated with Na+ citrate exhibited significantly decreased SI values compared to control. All chelator groups showed significantly lower insulin secretion than non-treated islets. CONCLUSION Islet recovery from alginate microcapsule is possible using common chelators like Na+ citrate, EDTA, and EGTA. Chelation of encapsulated islets using EDTA demonstrated the most efficient dissolving capabilities with the least toxicity toward islet recovery and health.
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Affiliation(s)
- Samuel Rodriguez
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - Hien Lau
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - Nicole Corrales
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - Jennifer Heng
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - Sarah Lee
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - Rachel Stiner
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - Michael Alexander
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - Jonathan R T Lakey
- Department of Surgery, University of California Irvine, Orange, CA, USA.,Department of Biomedical Engineering, University of California Irvine, Orange, CA, USA
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7
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Smith KE, Purvis WG, Davis MA, Min CG, Cooksey AM, Weber CS, Jandova J, Price ND, Molano DS, Stanton JB, Kelly AC, Steyn LV, Lynch RM, Limesand SW, Alexander M, Lakey JRT, Seeberger K, Korbutt GS, Mueller KR, Hering BJ, McCarthy FM, Papas KK. In vitro characterization of neonatal, juvenile, and adult porcine islet oxygen demand, β-cell function, and transcriptomes. Xenotransplantation 2018; 25:e12432. [PMID: 30052287 DOI: 10.1111/xen.12432] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 04/20/2018] [Accepted: 05/24/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND There is currently a shortage of human donor pancreata which limits the broad application of islet transplantation as a treatment for type 1 diabetes. Porcine islets have demonstrated potential as an alternative source, but a study evaluating islets from different donor ages under unified protocols has yet to be conducted. METHODS Neonatal porcine islets (NPI; 1-3 days), juvenile porcine islets (JPI; 18-21 days), and adult porcine islets (API; 2+ years) were compared in vitro, including assessments of oxygen consumption rate, membrane integrity determined by FDA/PI staining, β-cell proliferation, dynamic glucose-stimulated insulin secretion, and RNA sequencing. RESULTS Oxygen consumption rate normalized to DNA was not significantly different between ages. Membrane integrity was age dependent, and API had the highest percentage of intact cells. API also had the highest glucose-stimulated insulin secretion response during a dynamic insulin secretion assay and had 50-fold higher total insulin content compared to NPI and JPI. NPI and JPI had similar glucose responsiveness, β-cell percentage, and β-cell proliferation rate. Transcriptome analysis was consistent with physiological assessments. API transcriptomes were enriched for cellular metabolic and insulin secretory pathways, while NPI exhibited higher expression of genes associated with proliferation. CONCLUSIONS The oxygen demand, membrane integrity, β-cell function and proliferation, and transcriptomes of islets from API, JPI, and NPI provide a comprehensive physiological comparison for future studies. These assessments will inform the optimal application of each age of porcine islet to expand the availability of islet transplantation.
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Affiliation(s)
- Kate E Smith
- Department of Physiological Sciences, University of Arizona, Tucson, AZ, USA.,Department of Surgery, University of Arizona, Tucson, AZ, USA
| | | | - Melissa A Davis
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, USA
| | - Catherine G Min
- Department of Physiological Sciences, University of Arizona, Tucson, AZ, USA.,Department of Surgery, University of Arizona, Tucson, AZ, USA
| | - Amanda M Cooksey
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, USA
| | - Craig S Weber
- Department of Physiology, University of Arizona, Tucson, AZ, USA
| | - Jana Jandova
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, USA
| | | | - Diana S Molano
- Department of Surgery, University of Arizona, Tucson, AZ, USA
| | | | - Amy C Kelly
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, USA
| | - Leah V Steyn
- Department of Surgery, University of Arizona, Tucson, AZ, USA
| | - Ronald M Lynch
- Department of Physiology, University of Arizona, Tucson, AZ, USA
| | - Sean W Limesand
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, USA
| | - Michael Alexander
- Department of Surgery, University of California-Irvine, Orange, CA, USA
| | | | - Karen Seeberger
- Department of Surgery, Alberta Diabetes Institute, University of Alberta, Edmonton, AL, Canada
| | - Gregory S Korbutt
- Department of Surgery, Alberta Diabetes Institute, University of Alberta, Edmonton, AL, Canada
| | - Kate R Mueller
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Bernhard J Hering
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Fiona M McCarthy
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, USA
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8
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Park H, Park JB, Kim JH, Lee KW, Lee HS, Kim GS, Shin DY, Oh SH, Jin SM, Kim SJ. Simultaneous Subtotal Pancreatectomy and Streptozotocin Injection for Diabetes Modeling in Cynomolgus Monkeys. Transplant Proc 2018; 49:1142-1149. [PMID: 28583545 DOI: 10.1016/j.transproceed.2017.03.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND In an experimental animal model of islet transplantation, stable induction of insulin-dependent diabetes mellitus (IDDM) and islet isolation from donor pancreas are essential. Total pancreatectomy for IDDM induction and islet procurement in nonhuman primates leads to unwanted loss of exocrine function and may lead to morbidities associated with IDDM. METHODS IDDM induction with streptozotocin (STZ) is associated with drug toxicity of STZ and necessitates the killing of another animal for islet procurement. In this study, we performed a subtotal pancreatectomy combined with reduced STZ injection to induce IDDM and procure islets in a nonhuman primate model. RESULTS Twelve cynomolgus monkeys received low-dose STZ injections (60 mg/kg) simultaneously with subtotal pancreatectomy. All monkeys recovered from the procedure without complications. IDDM was induced in the animals. 57,691 ± 16,050 islets were isolated from the resected pancreas and transplanted into other monkeys. CONCLUSIONS Simultaneous subtotal pancreatectomy and low-dose STZ injection represent an effective and safe method to create an animal model of insulin dependence diabetes, while at the same time providing sufficient amounts of fresh islet cells for allotransplantation without requiring killing of additional animals.
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Affiliation(s)
- H Park
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - J B Park
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
| | - J H Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
| | - K W Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - H S Lee
- Transplantation Research Center, Samsung Biomedical Research Institute, Seoul, Korea
| | - G-S Kim
- Transplantation Research Center, Samsung Biomedical Research Institute, Seoul, Korea
| | - D-Y Shin
- Transplantation Research Center, Samsung Biomedical Research Institute, Seoul, Korea
| | - S-H Oh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - S-M Jin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - S J Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Transplantation Research Center, Samsung Biomedical Research Institute, Seoul, Korea
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9
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Kinasiewicz J, Antosiak-Iwanska M, Godlewska E, Sitarek E, Sabat M, Fiedor P, Granicka L. Effect of Over 10-Year Cryopreserved Encapsulated Pancreatic Islets Of Langerhans. EXP CLIN TRANSPLANT 2017; 16:461-465. [PMID: 28847262 DOI: 10.6002/ect.2016.0343] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Immunoisolation of pancreatic islets of Langerhans performed by the encapsulation process may be a method to avoid immunosuppressive therapy after transplant. The main problem related to islet transplant is shortage of human pancreata. Resolution of this obstacle may be cryopreservation of encapsulated islets, which enables collection of sufficient numbers of isolated islets required for transplant and long-term storage. Here, we assessed the ability of encapsulated islets to function after long-term banking at low temperature. MATERIALS AND METHODS Islets of Langerhans isolated from rat, pig, and human pancreata were encapsulated within alginate-poly-L-lysine-alginate microcapsules. Cryopreservation was carried out using a controlled method of freezing (Kriomedpol freezer; Kriomedpol, Warsaw, Poland), and samples were stored in liquid nitrogen. After 10 years, the samples were thawed with the rapid method (with 0.75 M of sucrose) and then cultured. RESULTS We observed that microcapsules containing islets maintained their shape and integrity after thawing. During culture, free islets were defragmented into single cells, whereas encapsulated islets were still round in shape and compact. After 1, 4, and 7 days of culture of encapsulated islets, the use of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tests showed increased mitochondrial activity. After they were thawed, the insulin secretion capacity was comparable with that obtained with fresh islets. CONCLUSIONS Cryopreservation and storage of free and microencapsulated islets were possible for about 10 years, although only encapsulated islets retained viability and secretory properties.
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Affiliation(s)
- Joanna Kinasiewicz
- From the Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Warsaw, Poland
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10
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Zhu H, Yu L, He Y, Lyu Y, Wang B. Microencapsulated Pig Islet Xenotransplantation as an Alternative Treatment of Diabetes. TISSUE ENGINEERING PART B-REVIEWS 2015; 21:474-89. [PMID: 26028249 DOI: 10.1089/ten.teb.2014.0499] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Haitao Zhu
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
- Heart Center, Northwest Women's and Children's Hospital, Xi'an, China
| | - Liang Yu
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Yayi He
- Department of Endocrinology, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Yi Lyu
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
- Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an, China
| | - Bo Wang
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
- Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an, China
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Zhu HT, Yu L, Lyu Y, Wang B. Optimal pig donor selection in islet xenotransplantation: current status and future perspectives. J Zhejiang Univ Sci B 2015; 15:681-91. [PMID: 25091986 DOI: 10.1631/jzus.b1400120] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
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.
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Affiliation(s)
- Hai-tao Zhu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an 710061, China
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12
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Samy KP, Martin BM, Turgeon NA, Kirk AD. Islet cell xenotransplantation: a serious look toward the clinic. Xenotransplantation 2014; 21:221-9. [PMID: 24806830 DOI: 10.1111/xen.12095] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 02/14/2014] [Indexed: 01/09/2023]
Abstract
Type I diabetes remains a significant clinical problem in need of a reliable, generally applicable solution. Both whole organ pancreas and islet allotransplantation have been shown to grant patients insulin independence, but organ availability has restricted these procedures to an exceptionally small subset of the diabetic population. Porcine islet xenotransplantation has been pursued as a potential means of overcoming the limits of allotransplantation, and several preclinical studies have achieved near-physiologic function and year-long survival in clinically relevant pig-to-primate model systems. These proof-of-concept studies have suggested that xenogeneic islets may be poised for use in clinical trials. In this review, we examine recent progress in islet xenotransplantation, with a critical eye toward the gaps between the current state of the art and the state required for appropriate clinical investigation.
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Affiliation(s)
- Kannan P Samy
- Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
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13
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Colton CK. Oxygen supply to encapsulated therapeutic cells. Adv Drug Deliv Rev 2014; 67-68:93-110. [PMID: 24582600 DOI: 10.1016/j.addr.2014.02.007] [Citation(s) in RCA: 111] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Revised: 01/06/2014] [Accepted: 02/19/2014] [Indexed: 02/07/2023]
Abstract
Therapeutic cells encapsulated in immunobarrier devices have promise for treatment of a variety of human diseases without immunosuppression. The absence of sufficient oxygen supply to maintain viability and function of encapsulated tissue has been the most critical impediment to progress. Within the framework of oxygen supply limitations, we review the major issues related to development of these devices, primarily in the context of encapsulated islets of Langerhans for treating diabetes, including device designs and materials, supply of tissue, protection from immune rejection, and maintenance of cell viability and function. We describe various defensive measures investigated to enhance survival of transplanted tissue, and we review the diverse approaches to enhancement of oxygen transport to encapsulated tissue, including manipulation of diffusion distances and oxygen permeability of materials, induction of neovascularization with angiogenic factors and vascularizing membranes, and methods for increasing the oxygen concentration adjacent to encapsulated tissue so as to exceed that in the microvasculature. Recent developments, particularly in this latter area, suggest that the field is ready for clinical trials of encapsulated therapeutic cells to treat diabetes.
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Zhu HT, Wang WL, Yu L, Wang B. Pig-islet xenotransplantation: recent progress and current perspectives. Front Surg 2014; 1:7. [PMID: 25593932 PMCID: PMC4287008 DOI: 10.3389/fsurg.2014.00007] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Accepted: 03/07/2014] [Indexed: 01/23/2023] Open
Abstract
Islet xenotransplantation is one prospective treatment to bridge the gap between available human cells and needs of patients with diabetes. Pig represents an ideal candidate for obtaining such available cells. However, potential clinical application of pig islet still faces obstacles including inadequate yield of high-quality functional islets and xenorejection of the transplants. Adequate amounts of available islets can be obtained by selection of a suitable pathogen-free source herd and the development of isolation and purification method. Several studies demonstrated the feasibility of successful preclinical pig-islet xenotransplantation and provided insights and possible mechanisms of xenogeneic immune recognition and rejection. Particularly promising is the achievement of long-term insulin independence in diabetic models by means of distinct islet products and novel immunotherapeutic strategies. Nonetheless, further efforts are needed to obtain much more safety and efficacy data to translate these findings into clinic.
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Affiliation(s)
- Hai-Tao Zhu
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College, Xi’an Jiaotong University, Xi’an, China
| | - Wan-Li Wang
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College, Xi’an Jiaotong University, Xi’an, China
| | - Liang Yu
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College, Xi’an Jiaotong University, Xi’an, China
| | - Bo Wang
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College, Xi’an Jiaotong University, Xi’an, China
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15
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Lee JI, Shin JS, Jung WY, Lee G, Kim MS, Kim YS, Choi JW, Park CG, Kim SJ. Porcine islet adaptation to metabolic need of monkeys in pig-to-monkey intraportal islet xenotransplantation. Transplant Proc 2014; 45:1866-8. [PMID: 23769059 DOI: 10.1016/j.transproceed.2013.01.090] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 01/24/2013] [Indexed: 11/15/2022]
Abstract
BACKGROUND Physiologic regulation of glucose metabolism is different between donor and recipient of xenogeneic pancreatic islet transplantation. We sought to assess whether the capacity of donor islets to adapt to recipient metabolic requirements should be considered in determining the success of pancreatic islet xenotransplantation. METHODS Rhesus macaque hosts rendered diabetic by streptozotocin were transplanted with porcine islets into the liver. Porcine c-peptide and insulin levels as well as intravenous glucose tolerance test (IVGTT) were measured at intervals. RESULTS At 2 months after islet transplantation, glucose responses on IVGTT showed a normoglycemic pattern. There was a 2.48 fold increase in C-peptide level during the initial 15 minutes of IVGTT in normal monkeys: from 3.122 ng/mL at baseline to 7.728 ng/mL at 15 minutes. Monkeys transplanted with porcine islets showed 2.38- and 2.45-folds the initial increases in C-peptide on IVGTT at 2 and 4 months after transplantation, respectively. Histopathologic evaluation identified the host endothelial cells having well lined the vessels of the porcine islets in the monkey liver. CONCLUSIONS The glucose response on IVGTT of porcine islets engrafted in the monkey liver resembled the normal monkey pattern rather than that of pigs. The presence of monkey endothelial cells suggested that porcine islets were well adapted to the local environment of the recipient.
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Affiliation(s)
- J-I Lee
- Xenotransplantation Research Center, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea
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Seita M, Noguchi H, Kubota Y, Kawamoto H, Nakaji S, Kobayashi N, Fujiwara T. Development of Canine Models of Type 1 Diabetes With Partial Pancreatectomy and the Administration of Streptozotocin. CELL MEDICINE 2013; 6:25-31. [PMID: 26858877 DOI: 10.3727/215517913x674289] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
We created canine models of type 1 diabetes that were suitable for the assessment of cell therapies, such as islet transplantation and bioartificial pancreas, with low-dose streptozotocin (STZ) injection and partial pancreatectomy. In our model, a 50% pancreatectomy was performed with general anesthesia, followed by systemic injection of 35 mg/kg STZ into a vein of the foreleg. Four weeks after the administration of STZ, the fasting blood glucose level of our model dogs was found to be over 200 mg/dl twice on different days, and we could not detect any canine insulin by the intravenous glucose tolerance test (IVGTT). We therefore diagnosed the dogs to have induced diabetes. Some studies have reported high-dose STZ to be very toxic for both the kidney and liver, and therefore a lower dose is desirable to induce diabetic models without any associated kidney or liver damage. We think that the combination of a partial pancreatectomy can thus make it possible to reduce the dose of STZ, and it is therefore useful for the creation of type 1 diabetes models. We believe that our model is a safe and reliable model for type 1 diabetes in canines to assess the efficacy of pancreas-targeted cell therapies.
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Affiliation(s)
- Masayuki Seita
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan
| | - Hirofumi Noguchi
- † Department of Surgery, Clinical Research Center, Chiba-East National Hospital, National Hospital Organization , Chiba , Japan
| | - Yasuhiro Kubota
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan
| | - Hironobu Kawamoto
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan
| | - Shuhei Nakaji
- ‡ Department of Biomedical Engineering, School of Engineering, Okayama University of Science , Okayama , Japan
| | - Naoya Kobayashi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan
| | - Toshiyoshi Fujiwara
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan
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Shin S, Yoo YJ. Separation of empty microcapsules after microencapsulation of porcine neonatal islets. Biotechnol Lett 2013; 35:2185-91. [DOI: 10.1007/s10529-013-1300-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Accepted: 07/19/2013] [Indexed: 10/26/2022]
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Graham ML, Schuurman HJ. The usefulness and limitations of the diabetic macaque model in evaluating long-term porcine islet xenograft survival. Xenotransplantation 2012. [PMID: 23190260 DOI: 10.1111/xen.12012] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Various groups have reported prolonged diabetes reversal and graft function after porcine islet transplantation into diabetic macaques using different experimental designs (macaque source, islet source, type of immunosuppression): subsequently, the International Xenotransplantation Association has published recommendations for entering a clinical trial. Our experiments showed limitations that affected consistent achievement of long-term survival. We aimed to identify these limitations and underlying causes to emphasize the translational value of this highly relevant type 1 diabetic macaque model. METHODS We reviewed data from our institution and literature data on long-term porcine islet xenograft survival in the diabetic macaque model, especially focusing on aspects of incomplete diabetes reversal relative to macaque normal values. This phenomenon was compared with diabetes reversal in an allo-islet transplant model in macaques and with chronic insulin treatment of diabetic macaques, all with 180-day follow-up. This comparison enabled to identify potential model limitations and underlying causative factors. RESULTS Especially in the xenograft model, the achievement of long-term graft survival revealed limitations including chronic, mild hyperglycemia and absence of body weight (BW) gain or even progressive BW loss. Metabolic incompatibilities in glycemic control (i.e., insulin kinetics) between the pig and macaque species underlie chronic, mild hyperglycemia. This phenomenon might not bear relevance for the pig-to-human species combination because the glycemic control in pigs and humans is similar and differs from that in nonhuman primates (NHP). Weight loss could be related to changes in the gastrointestinal tract related with local high exposure to orally administered immunosuppressants; these must be given at higher dose levels because of low bioavailability in macaques to achieve systemic exposure at therapeutic levels. This is aggravated by insufficient graft insulin production in proportion to the needs of macaques: this model limitation has no translational value to the pig-to-human setting. Nutritional deficits can result in incorrect interpretation of blood glucose levels and C-peptide levels regarding graft function. Likewise, nutritional status alters physiologic responses, influencing susceptibility to infectious and noninfectious complications. CONCLUSION THE model-induced confounding described interferes with accurate interpretation of safety and efficacy studies, which affects the translational value of pig-to-NHP islet cell transplant studies to the pig-to-human transplant condition.
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Affiliation(s)
- Melanie L Graham
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, USA.
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19
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Luan NM, Iwata H. Xenotransplantation of islets enclosed in agarose microcapsule carrying soluble complement receptor 1. Biomaterials 2012; 33:8075-81. [DOI: 10.1016/j.biomaterials.2012.07.048] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2012] [Accepted: 07/24/2012] [Indexed: 10/28/2022]
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Jin X, Zeng L, Zhang S, He S, Ren Y, Chen Y, Wei L, Wang L, Li H, Cheng J, Lu Y. Human insulin versus porcine insulin in rhesus monkeys with diabetes mellitus. J Med Primatol 2012; 42:1-9. [PMID: 23106308 DOI: 10.1111/jmp.12025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2012] [Indexed: 02/05/2023]
Abstract
BACKGROUND Monkeys with insulin-dependent diabetes are important preclinical animal models for islet transplantation. Exogenous insulin should be administered to achieve good glycemic control and minimize the long-term vascular complications associated with diabetes until the graft function recovered completely. However, the effect of multiple daily injections of porcine or human insulin and the long-term effects of porcine insulin have not been studied in diabetic rhesus monkeys. METHODS Diabetic rhesus monkeys, using a 6-month self-control insulin comparison experiment, were used to detect the incidence of adverse events and long-term diabetes complication events after long-term administration of porcine insulin. RESULTS In this study, we found that a 20% higher dose of porcine insulin results in similar glycemic control as the human insulin regimen, and adverse events were seldom reported when porcine insulin was administered. Moreover, long-term injection with porcine insulin could delay the rate and severity of diabetes-related complications. CONCLUSIONS Porcine insulin as a competent candidate for regular insulin therapy to maintain blood glucose levels in insulin-dependent diabetic monkeys during preclinical studies of islet transplantation.
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Affiliation(s)
- Xi Jin
- Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
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Percutaneous transhepatic portal catheterization guided by ultrasound technology for islet transplantation in rhesus monkey. Hepatobiliary Pancreat Dis Int 2012; 11:154-9. [PMID: 22484583 DOI: 10.1016/s1499-3872(12)60141-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Pig islet xenotransplantation has the potential to overcome the shortage of donated human islets for islet cell transplantation in type 1 diabetes. Testing in non-human primate models is necessary before clinical application in humans. Intraportal islet transplantation in monkeys is usually performed by surgical infusion during laparotomy or laparoscopy. In this paper, we describe a new method of percutaneous transhepatic portal catheterization (PTPC) as an alternative to current methods of islet transplantation in rhesus monkeys. METHODS We performed ultrasound-guided PTPC in five adult rhesus monkeys weighing 7-8 kg, with portal vein catheterization confirmed by digital subtraction angiography. We monitored for complications in the thoracic and abdominal cavity. To evaluate the safety of ultrasound-guided PTPC, we recorded the changes in portal pressure throughout the microbead transplantation procedure. RESULTS Ultrasound-guided PTPC and infusion of 16 000 microbeads/kg body weight into the portal vein was successful in all five monkeys. Differences in the hepatobiliary anatomy of rhesus monkeys compared to humans led to a higher initial complication rate. The first monkey died of abdominal hemorrhage 10 hours post-transplantation. The second suffered from a mild pneumothorax but recovered fully after taking only conservative measures. After gaining experience with the first two monkeys, we decreased both the hepatic puncture time and the number of puncture attempts required, with the remaining three monkeys experiencing no complications. Portal pressures initially increased proportional to the number of transplanted microbeads but returned to pre-infusion levels at 30 minutes post-transplantation. The changes in portal pressures occurring during the procedure were not significantly different. CONCLUSIONS Ultrasound-guided PTPC is an effective, convenient, and minimally invasive method suitable for use in non-human primate models of islet cell transplantation provided that care is taken with hepatic puncture. Its advantages must be weighed against the risks of procedure-related complications.
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Kuise T, Noguchi H. Recent progress in pancreatic islet transplantation. World J Transplant 2011; 1:13-8. [PMID: 24175188 PMCID: PMC3782227 DOI: 10.5500/wjt.v1.i1.13] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Revised: 10/26/2011] [Accepted: 12/19/2011] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus remains a major burden. More than 200 million people are affected worldwide, which represents 6% of the world’s population. Type 1 diabetes mellitus is an autoimmune disease, which induces the permanent destruction of the β-cells of the pancreatic islets of Langerhans. Although intensive insulin therapy has proven effective to delay and sometimes prevent the progression of complications such as nephropathy, neuropathy or retinopathy, it is difficult to achieve and maintain long term in most subjects. The successes achieved over the last few decades by the transplantation of whole pancreas and isolated islets suggest that diabetes can be cured by the replenishment of deficient β cells. However, islet transplantation efforts have various limitations, including the limited supply of donor pancreata, the paucity of experienced islet isolation teams, side effects of immunosuppressants and poor long term results. The purpose of this article is to review the recent progress in clinical islet transplantation for the treatment of diabetes and to describe the recent progress on pancreatic stem/progenitor cell research, which has opened up several possibilities for the development of new treatments for diabetes.
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Affiliation(s)
- Takashi Kuise
- Takashi Kuise, Hirofumi Noguchi, Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
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Induction of protective genes leads to islet survival and function. J Transplant 2011; 2011:141898. [PMID: 22220267 PMCID: PMC3246756 DOI: 10.1155/2011/141898] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2011] [Accepted: 09/01/2011] [Indexed: 12/16/2022] Open
Abstract
Islet transplantation is the most valid approach to the treatment of type 1 diabetes. However, the function of transplanted islets is often compromised since a large number of β cells undergo apoptosis induced by stress and the immune rejection response elicited by the recipient after transplantation. Conventional treatment for islet transplantation is to administer immunosuppressive drugs to the recipient to suppress the immune rejection response mounted against transplanted islets. Induction of protective genes in the recipient (e.g., heme oxygenase-1 (HO-1), A20/tumor necrosis factor alpha inducible protein3 (tnfaip3), biliverdin reductase (BVR), Bcl2, and others) or administration of one or more of the products of HO-1 to the donor, the islets themselves, and/or the recipient offers an alternative or synergistic approach to improve islet graft survival and function. In this perspective, we summarize studies describing the protective effects of these genes on islet survival and function in rodent allogeneic and xenogeneic transplantation models and the prevention of onset of diabetes, with emphasis on HO-1, A20, and BVR. Such approaches are also appealing to islet autotransplantation in patients with chronic pancreatitis after total pancreatectomy, a procedure that currently only leads to 1/3 of transplanted patients being diabetes-free.
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Basta G, Calafiore R. Immunoisolation of pancreatic islet grafts with no recipient's immunosuppression: actual and future perspectives. Curr Diab Rep 2011; 11:384-91. [PMID: 21826429 DOI: 10.1007/s11892-011-0219-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In spite of steady and remarkable progress, islet transplantation in patients with type 1 diabetes mellitus (T1DM) continues to face two major bottlenecks: inadequate availability of human pancreatic donors and necessity to totally immunosuppress the graft recipients lifelong. Microencapsulation of the islet grafts within highly biocompatible and selective permeable biomembranes could obviate use of the immunosuppressants, while potentially offering the opportunity to use a wide array of insulin-producing cells, in active development, including xenogeneic pig islets. Although macrodevices and microcapsules, which essentially differ by size/configuration, and both serve for immunoisolation devices, have been used for many years with initial human applications, new products on development in both areas might open new perspectives for more focused use in patients with T1DM. Physical-chemical properties and material engineering of these devices are critically reviewed to assess where we actually stand and where the future expansion of these technologies may go.
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Affiliation(s)
- Giuseppe Basta
- Department of Internal Medicine, Section of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, via Enrico dal Pozzo, snc, Perugia, Italy.
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Abstract
PURPOSE OF REVIEW Porcine islet xenotransplantation into humans faces two major hurdles - safety issues related to xenosis and xenorejection of the transplants. The former has been overcome mainly by selection of a suitable disease-free source herd. RECENT FINDINGS Four strategies have been employed to date to overcome the rejection, all of which have shown some efficacy in animal models. SUMMARY Immune suppression, Sertoli cell co-transplantation and microencapsulation have been tried in type 1 diabetic humans with some clinical benefit derived reported from the latter two. Unaware hypoglycemia in particular seems amenable to the microencapsulation approach.
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Thompson P, Cardona K, Russell M, Badell IR, Shaffer V, Korbutt G, Rayat GR, Cano J, Song M, Jiang W, Strobert E, Rajotte R, Pearson T, Kirk AD, Larsen CP. CD40-specific costimulation blockade enhances neonatal porcine islet survival in nonhuman primates. Am J Transplant 2011; 11:947-57. [PMID: 21521467 PMCID: PMC4845096 DOI: 10.1111/j.1600-6143.2011.03509.x] [Citation(s) in RCA: 133] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The widespread clinical implementation of alloislet transplantation as therapy for type 1 diabetes has been hindered by the lack of suitable islet donors. Pig-to-human islet xenotransplantation is one strategy with potential to alleviate this shortage. Long-term survival of porcine islets has been achieved using CD154-specific antibodies to interrupt the CD40/CD154 costimulation pathway; however, CD154-specific antibodies seem unlikely candidates for clinical translation. An alternative strategy for CD40/CD154 pathway interruption is use of CD40-specific antibodies. Herein, we evaluate the ability of a chimeric CD40-specific monoclonal antibody (Chi220) to protect islet xenografts. Neonatal porcine islets (~50,000 IEQ/kg) were transplanted intraportally into pancreatectomized diabetic macaques. Immunosuppression consisted of induction therapy with Chi220 and the IL-2 receptor-specific antibody basiliximab, and maintenance therapy with sirolimus and the B7-specific fusion protein belatacept. Chi220 effectively promoted xenoislet engraftment and survival, with five of six treated recipients achieving insulin-independent normoglycemia (median rejection-free survival 59 days; mean 90.8 days, maximum 203 days). No thromboembolic phenomena were observed. CD40 represents a promising alternative to CD154 as a therapeutic target, and the efficacy of CD40-specific antibodies in islet xenotransplantation warrants further investigation.
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Affiliation(s)
- P Thompson
- Emory Transplant Center, Emory University, Atlanta, GA, USA
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Gillard P, Mathieu C. Immune and cell therapy in type 1 diabetes: too little too late? Expert Opin Biol Ther 2011; 11:609-21. [PMID: 21406028 DOI: 10.1517/14712598.2011.560568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Type 1 diabetes is caused by autoimmune destruction of insulin-producing β-cells. Intensive insulin therapy protects most patients against chronic complications of diabetes, but exposes patients to acute complications like hypoglycaemia and impacts on quality of life. Therapies that aim at protecting or restoring endogenous insulin secretion might help in decreasing the risk of severe hypoglycemia and long-term complications. AREAS COVERED This article reviews the literature of clinical immunotherapy and β-cell transplantation in treatment of type 1 diabetes with specific focus on the effect on preserving and restoring β-cell mass. EXPERT OPINION Several studies in recent-onset type 1 diabetic patients have provided proof of principle that immunotherapy can preserve residual functional β-cell mass. The observation that this strategy is most effective early in the disease process opens possibilities of arresting and even preventing type 1 diabetes. In patients with too few or no surviving β-cells, current protocols of β-cell transplantation can restore functional β-cell mass up to 25% of levels in healthy controls. Unfortunately, both strategies to date are followed by progressive decline of endogenous insulin secretion later on. Strategies to restore functional β-cell mass to a higher level and to restore immune tolerance are thus needed.
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Affiliation(s)
- Pieter Gillard
- University Hospital Leuven, Department of Experimental Medicine and Endocrinology, KULeuven, Herestraat 49, B-3000 Leuven, Belgium
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Hoesli CA, Raghuram K, Kiang RL, Mocinecová D, Hu X, Johnson JD, Lacík I, Kieffer TJ, Piret JM. Pancreatic cell immobilization in alginate beads produced by emulsion and internal gelation. Biotechnol Bioeng 2010; 108:424-34. [DOI: 10.1002/bit.22959] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Atchison NA, Fan W, Papas KK, Hering BJ, Tsapatsis M, Kokkoli E. Binding of the fibronectin-mimetic peptide, PR_b, to alpha5beta1 on pig islet cells increases fibronectin production and facilitates internalization of PR_b functionalized liposomes. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2010; 26:14081-8. [PMID: 20704278 PMCID: PMC2932789 DOI: 10.1021/la101264h] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
Islet transplantation is a promising treatment for type 1 diabetes. Recent studies have demonstrated that human islet allografts can restore insulin independence to patients with this disease. As islet isolation and immunotherapeutic techniques improve, the demand for this cell-based therapy will dictate the need for other sources of islets. Pig islets could provide an unlimited supply for xenotransplantation and have shown promise as an alternative to human islet allografts. However, stresses imposed during islet isolation and transplantation decrease islet viability, leading to loss of graft function. In this study, we investigated the ability of a fibronectin-mimetic peptide, PR_b, which specifically binds to the alpha(5)beta(1) integrin, to re-establish lost extracellular matrix (ECM) around isolated pig islets and increase internalization of liposomes. Confocal microscopy and Western blotting were used to show the presence of the integrin alpha(5)beta(1) on the pig islets on day 0 (day of isolation) as well as on different days of islet culture. Islets cultured in medium supplemented with free PR_b for 48 h were found to have increased levels of ECM fibronectin secretion compared to islets in normal culture conditions. Using confocal microscopy and flow cytometry, we found that PR_b peptide-amphiphile functionalized liposomes delivered to the pig islets internalized into the cells in a PR_b concentration dependent manner and nonfunctionalized liposomes showed minimal internalization. These studies proved that the fibronectin-mimetic peptide, PR_b, is an appropriate peptide bullet for applications involving alpha(5)beta(1) expressing pig islet cells. Fibronectin production stimulated through alpha(5)beta(1) PR_b binding may decrease apoptosis and therefore increase islet viability in culture. In addition, PR_b peptide-amphiphile functionalized liposomes may be used for targeted delivery of different agents to pig islet cells.
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Affiliation(s)
- Nicole A. Atchison
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455
| | - Wei Fan
- Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN 55455
| | - Klearchos K. Papas
- Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN 55455
| | - Bernhard J. Hering
- Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN 55455
| | - Michael Tsapatsis
- Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN 55455
| | - Efrosini Kokkoli
- Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN 55455
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Halley K, Dyson EL, Kaur G, Mital P, Uong PM, Dass B, Crowell SN, Dufour JM. Delivery of a therapeutic protein by immune-privileged Sertoli cells. Cell Transplant 2010; 19:1645-57. [PMID: 20719072 PMCID: PMC3087628 DOI: 10.3727/096368910x516628] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Immune-privileged Sertoli cells survive long term after allogeneic or xenogeneic transplantation without the use of immunosuppressive drugs, suggesting they could be used as a vehicle to deliver therapeutic proteins. As a model to test this, we engineered Sertoli cells to transiently produce basal levels of insulin and then examined their ability to lower blood glucose levels after transplantation into diabetic SCID mice. Mouse and porcine Sertoli cells transduced with a recombinant adenoviral vector containing furin-modified human proinsulin cDNA expressed insulin mRNA and secreted insulin protein. Transplantation of 5-20 million insulin-expressing porcine Sertoli cells into diabetic SCID mice significantly decreased blood glucose levels in a dose-dependent manner, with 20 million Sertoli cells decreasing blood glucose levels to 9.8 ± 2.7 mM. Similar results were obtained when 20 million insulin-positive, BALB/c mouse Sertoli cells were transplanted; blood glucose levels dropped to 6.3 ± 2.4 mM and remained significantly lower for 5 days. To our knowledge, this is the first study to demonstrate Sertoli cells can be engineered to produce and secrete a clinically relevant factor that has a therapeutic effect, thus supporting the concept of using immune-privileged Sertoli cells as a potential vehicle for gene therapy.
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Affiliation(s)
- Katelyn Halley
- Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
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Basic techniques for pancreatic research. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2010. [PMID: 20700840 DOI: 10.1007/978-90-481-9060-7_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Can cells and biomaterials in therapeutic medicine be shielded from innate immune recognition? Trends Immunol 2010; 31:32-8. [PMID: 19836998 DOI: 10.1016/j.it.2009.09.005] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2009] [Revised: 09/11/2009] [Accepted: 09/11/2009] [Indexed: 10/20/2022]
Abstract
Biomaterials (e.g. polymers, metals, or ceramics), cell and cell cluster (e.g. pancreatic islets) transplantation are beginning to offer novel treatment modalities for some otherwise intractable diseases. The innate immune system is involved in incompatibility reactions that occur when biomaterials or cells are introduced into the blood circulation. In particular, the complement, coagulation and contact systems are involved in the recognition of biomaterials and cells, eliciting activation of platelets and leukocytes. Such treatments are associated with anaphylactoid and thrombotic reactions, inflammation, and rejection of biomaterials and cells, leading to treatment failures and adverse reactions. We discuss here the new technologies that are being developed to shield the biomaterial and cell surfaces from recognition by the innate immune system.
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Islet amyloid deposition limits the viability of human islet grafts but not porcine islet grafts. Proc Natl Acad Sci U S A 2010; 107:4305-10. [PMID: 20160085 DOI: 10.1073/pnas.0909024107] [Citation(s) in RCA: 145] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
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.
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Abstract
PURPOSE OF REVIEW Allogeneic islet transplantation faces difficulties because organ shortage is recurrent; several pancreas donors are often needed to treat one diabetic recipient; and the intrahepatic site of islet implantation may not be the most appropriate one. Another source of insulin-producing cells, therefore, would be of major interest, and pigs represent a possible and serious source for obtaining such cells. RECENT FINDINGS Pig islet grafts may appear difficult because of the species barrier, but recent studies demonstrate that pig islets may function in diabetic primates for at least 6 months. SUMMARY Pig islet xenotransplantation, however, must still overcome the selection of a suitable pig donor to translate preclinical findings into clinical applications. This review summarizes the actual acquired knowledge of pig islet transplantation in primates to select the 'ideal' pig donor.
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Noguchi H. Pancreatic islet transplantation. World J Gastrointest Surg 2009; 1:16-20. [PMID: 21160790 PMCID: PMC2999120 DOI: 10.4240/wjgs.v1.i1.16] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2009] [Revised: 11/10/2009] [Accepted: 11/17/2009] [Indexed: 02/06/2023] Open
Abstract
Type 1 diabetes mellitus is an autoimmune disease, which results in the permanent destruction of β-cells of the pancreatic islets of Langerhans. While exogenous insulin therapy has dramatically improved the quality of life, chronic diabetic complications develop in a substantial proportion of subjects and these complications generally progress and worsen over time. Although intensive insulin therapy has proven effective to delay and sometimes prevent the progression of complications such as nephropathy, neuropathy or retinopathy, it is difficult to achieve and maintain long term in most subjects. Reasons for this difficulty include compliance issues and the increased risk of severe hypoglycemic episodes, which are generally associated with intensification of exogenous insulin therapy. Clinical studies have shown that transplantation of pancreas or purified pancreatic islets can support glucose homeostasis in type 1 diabetic patients. Islet transplantation carries the special advantages of being less invasive and resulting in fewer complications compared with the traditional pancreas or pancreas-kidney transplantation. However, islet transplantation efforts have limitations including the short supply of donor pancreata, the paucity of experienced islet isolation teams, side effects of immunosuppressants and poor long-term results. The purpose of this article is to review recent progress in clinical islet transplantation for the treatment of diabetes.
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Affiliation(s)
- Hirofumi Noguchi
- Hirofumi Noguchi, Regenerative Research Islet Cell Transplant Program, Baylor All Saints Medical Center, Baylor Research Institute, Fort Worth, TX 76104, United States
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Cooper DKC, Casu A. Chapter 4: Pre-clinical efficacy and complication data required to justify a clinical trial. Xenotransplantation 2009; 16:229-238. [DOI: 10.1111/j.1399-3089.2009.00543.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Alginate-PLL cell encapsulation system Co-entrapping PLGA-microspheres for the continuous release of anti-inflammatory drugs. Biomed Microdevices 2009; 11:1103-13. [DOI: 10.1007/s10544-009-9327-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Hering BJ, Walawalkar N. Pig-to-nonhuman primate islet xenotransplantation. Transpl Immunol 2009; 21:81-6. [PMID: 19427901 DOI: 10.1016/j.trim.2009.05.001] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2009] [Revised: 05/01/2009] [Accepted: 05/05/2009] [Indexed: 02/07/2023]
Abstract
Type 1 diabetes continues to present a therapeutic challenge. The restoration of normoglycemia and insulin independence in immunosuppressed type 1 diabetic recipients of human islet allografts has highlighted the potential of cell-based diabetes therapy. The unlimited and on-demand availability of pig islets from healthy, young, living, designated pathogen-free, and potentially genetically modified donors presents unique opportunities for improving the availability and outcomes of islet replacement therapies in diabetes. One of the fundamental prerequisites for initiating clinical research is a favorable benefit-over-harm determination in the stringent preclinical transplant model in nonhuman primates. To date, xenotransplants of pig islet cell therapy products have been reported by 15 institutions in 181 NHPs, including xenotransplants in 72 non-diabetic and 109 diabetic recipients. These studies have demonstrated the feasibility of successful preclinical islet xenotransplantation and have provided insights into the critical events operative in the immune recognition and destruction of islet xenografts in nonhuman primates. Particularly promising is the recent achievement of prolonged insulin independence in this model by means of several distinct islet xenotransplantation products, implantation sites, and immunotherapeutic strategies. Further progress appears likely and the development of suitable source pigs will position the scientific community to translate these findings safely to the clinic.
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Affiliation(s)
- Bernhard J Hering
- Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN 55455, USA.
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Jaeckel E, Lehner F. [Pancreas and islet transplantation]. Internist (Berl) 2009; 50:536-49. [PMID: 19390835 DOI: 10.1007/s00108-008-2272-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Pancreas transplantation is a successful and effective procedure resulting in tight glucose control. Due to the postoperative morbidity and the need for immunosuppression pancreas transplantation should be considered in patients with type I diabetes at the time of kidney transplantation. Besides this pancreas transplantation alone can be taken into consideration for patients with very poor metabolic control and quality of life despite optimal medical treatment. Recently, islet transplantation became a less invasive alternative to pancreas transplantation. Due to the lack of long-term follow-up and due to the need of multiple donor grafts for one recipient, islet transplantation should be performed under experimental settings in experienced centers. New developments in protecting transplanted islets and in the induction of donor-specific tolerance could increase the indication to perform the procedure. Therefore alternative sources of beta-cells have to be identified.
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Affiliation(s)
- E Jaeckel
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover.
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Schneider MKJ, Seebach JD. Xenotransplantation literature update: September-October 2008. Xenotransplantation 2009; 15:417-21. [PMID: 19152670 DOI: 10.1111/j.1399-3089.2008.00500.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Mårten K J Schneider
- Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland.
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