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https://www.readbyqxmd.com/read/28058735/safe-use-of-anti-cd154-monoclonal-antibody-in-pig-islet-xenotransplantation-in-monkeys
#1
Rita Bottino, Michael F Knoll, Joshua Graeme-Wilson, Edwin C Klein, David Ayares, Massimo Trucco, David K C Cooper
Anti-CD154mAb is a powerful co-stimulation blockade agent that is efficacious in preventing rejection, even in xenogeneic settings. It has been used in the majority of successful long-term pig-to-non-human primate islet transplantation models. However, its clinical use was halted as a result of thromboembolic complications that were also observed in preclinical and clinical organ transplantation models. An anti-CD154mAb was administered to 14 streptozotocin-induced diabetic cynomolgus monkey recipients of porcine islets, some of which received the agent for many months...
January 6, 2017: Xenotransplantation
https://www.readbyqxmd.com/read/27938490/transgenic-expression-of-glucagon-like-peptide-1-glp-1-and-activated-muscarinic-receptor-m3r-significantly-improves-pig-islet-secretory-function
#2
Nizar Mourad, Andrea Perota, Daela Xhema, Cesare Galli, Pierre Gianello
Porcine islets have notoriously low insulin secretion levels in response to glucose stimulation. While this is somehowexpected in the case of immature islets isolated from fetal and neonatal pigs, disappointingly low secretory responses are frequently reported in studies using <em>in vitro</em>-maturated fetal and neonatal islets and even fully-differentiated adult islets. Herein, we show that beta-cell specific expression of a modified glucagon-like peptide 1 (GLP-1) and of a constitutively activated type 3 muscarinic receptor (M3R) efficiently amplifies glucose-stimulated insulin secretion (GSIS)...
November 22, 2016: Cell Transplantation
https://www.readbyqxmd.com/read/27938471/human-recombinant-antithrombin-atrynsup-sup-administration-improves-survival-and-prevents-intravascular-coagulation-after-intraportal-islet-transplantation-in-a-piglet-model
#3
Valery Gmyr, Caroline Bonner, Ericka Moerman, Antoine Tournoys, Nathalie Delalleau, Audrey Quenon, Julien Thevenet, Mikael Chetboun, Julie KerrConte, Franois Pattou, Thomas Hubert, Merce Jourdain
Human islet transplantation is a viable treatment option for type 1 diabetes mellitus (T1D). However, pancreatic isletinflammation after transplantation induced by innate immune responses is likely to hinder graft function. This is mediated by incompatibility between islets and the blood interface, known as instant blood-mediated inflammatory reaction (IBMIR). Herein, we hypothesized that portal venous administration of islet cells with human recombinant antithrombin (ATryn(®)), a serine protease inhibitor (serpin), which plays a central role in the physiological regulation of coagulation and exerts indirect anti-inflammatory activities may offset coagulation abnormalities such as Disseminated Intravascular Coagulation (DIC) and IBMIR...
27, 2016: Cell Transplantation
https://www.readbyqxmd.com/read/27931512/xenotransplanted-pig-sertoli-cells-inhibit-both-the-alternative-and-classical-pathways-of-complement-mediated-cell-lysis-while-pig-islets-are-killed
#4
Kandis Wright, Rachel Dziuk, Payal Mital, Gurvinder Kaur, Jannette M Dufour
Xenotransplantation has vast clinical potential but is limited by the potent immune responses generated against xenogeneic tissue. Immune-privileged Sertoli cells (SCs) survive xenotransplantation long term (90 days) without immunosuppression, making SCs an ideal model to identify xenograft survival mechanisms. Xenograft rejection includes the binding of natural and induced antibodies and the activation of the complement cascade. Using an in vitro cytotoxicity assay, wherein cells were cultured with human serum and complement, we demonstrated that neonatal pig SCs (NPSCs) are resistant to complement-mediated cell lysis and express complement inhibitory factors, membrane cofactor protein (MCP; CD46), and decay-accelerating factor (DAF; CD55) at significantly higher levels than neonatal pig islets (NPIs), which served as non-immune-privileged controls...
November 2016: Cell Transplantation
https://www.readbyqxmd.com/read/27909715/a-new-scaffold-containing-small-intestinal-submucosa-and-mesenchymal-stem-cells-improves-pancreatic-islet-function-and-survival-in%C3%A2-vitro-and-in%C3%A2-vivo
#5
Dan Wang, Xiaoming Ding, Wujun Xue, Jin Zheng, Xiaohui Tian, Yang Li, Xiaohong Wang, Huanjin Song, Hua Liu, Xiaohui Luo
It is unknown whether a scaffold containing both small intestinal submucosa (SIS) and mesenchymal stem cells (MSCs) for transplantation may improve pancreatic islet function and survival. In this study, we examined the effects of a SIS-MSC scaffold on islet function and survival in vitro and in vivo. MSCs and pancreatic islets were isolated from Sprague-Dawley rats, and SIS was isolated from Bamei pigs. The islets were apportioned among 3 experimental groups as follows: SIS-islets, SIS-MSC-islets and control-islets...
January 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/27893617/differential-role-of-b-cells-and-il-17-versus-ifn-%C3%AE-during-early-and-late-rejection-of-pig-islet-xenografts-in-mice
#6
Hee Kap Kang, Shusen Wang, Anil Dangi, Xiaomin Zhang, Amar Singh, Lei Zhang, James M Rosati, Wilma Suarez-Pinzon, Xuelian Deng, Xiaoyan Chen, Edward B Thorp, Bernhard J Hering, Stephen D Miller, Xunrong Luo
BACKGROUND: Xenogeneic islet transplantation is an emerging therapeutic option for diabetic patients. However, immunological tolerance to xenogeneic islets remains a challenge. METHODS: The current study used a pig-to-mouse discordant xenogeneic islet transplant model to examine anti-donor xenogeneic immune responses during early and late rejection, and to determine experimental therapeutic interventions that promote durable pig islet xenograft survival. RESULTS: We found that during early acute rejection of pig islet xenografts, the rejecting hosts exhibited a heavy graft infiltration with B220 B cells and a robust anti-pig antibody production...
November 23, 2016: Transplantation
https://www.readbyqxmd.com/read/27872471/recent-progress-in-xenotransplantation-with-emphasis-on-virological-safety
#7
Joachim Denner
Xenotransplantation is a new technology that may help to overcome the shortage of human tissues and organs available for the treatment of tissue and organ failure. Remarkable progress has recently been made in this field. First, understanding of the mechanisms of immunological rejection, mainly of the hyperacute rejection, allowed generating numerous genetically modified pigs to overcome rejection. Second, based on these genetically modified animals and new immunosuppression regimens, long-term survival of non-human primate recipients of heart, kidney, and islet cell cells has been reported...
November 22, 2016: Annals of Transplantation: Quarterly of the Polish Transplantation Society
https://www.readbyqxmd.com/read/27677465/no-perv-transmission-during-a-clinical-trial-of-pig-islet-cell-transplantation
#8
Vladimir A Morozov, Shaun Wynyard, Shinichi Matsumoto, Adrian Abalovich, Joachim Denner, Robert Elliott
Xenotransplantation of pig islet cells is a promising alternative for the treatment of diabetes with insulin and may help to prevent numerous late complications such as blindness and amputation. First encouraging results using porcine islets have been reported in preclinical animal models as well in the first clinical trial in New Zealand. The goal of this manuscript is to examine the biological safety of a second trial performed in Argentina, specifically in regards to the transmission of porcine endogenous retroviruses (PERVs) using improved detection methods As in the first trial encapsulated islet cells from the well-characterised Auckland Island pigs were used...
January 2, 2017: Virus Research
https://www.readbyqxmd.com/read/27586421/pancreatic-islets-methods-for-isolation-and-purification-of-juvenile-and-adult-pig-islets
#9
Heide Brandhorst, Paul R V Johnson, Daniel Brandhorst
The current situation of organ transplantation is mainly determined by the disbalance between the number of available organs and the number of patients on the waiting list. This obvious dilemma might be solved by the transplantation of porcine organs into human patients. The metabolic similarities which exist between both species made pancreatic islets of Langerhans to that donor tissue which will be most likely transplanted in human recipients. Nevertheless, the successful isolation of significant yields of viable porcine islets is extremely difficult and requires extensive experiences in the field...
2016: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27586419/the-different-faces-of-the-pancreatic-islet
#10
Midhat H Abdulreda, Rayner Rodriguez-Diaz, Over Cabrera, Alejandro Caicedo, Per-Olof Berggren
Type 1 diabetes (T1D) patients who receive pancreatic islet transplant experience significant improvement in their quality-of-life. This comes primarily through improved control of blood sugar levels, restored awareness of hypoglycemia, and prevention of serious and potentially life-threatening diabetes-associated complications, such as kidney failure, heart and vascular disease, stroke, nerve damage, and blindness. Therefore, beta cell replacement through transplantation of isolated islets is an important option in the treatment of T1D...
2016: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27569971/human-endothelial-protein-c-receptor-overexpression-protects-intraportal-islet-grafts-in-mice
#11
H Gock, K F E Lee, L Murray-Segal, T B Mysore, A J F d'Apice, E J Salvaris, P J Cowan
Islet transplantation can potentially cure type 1 diabetes mellitus, but it is limited by a shortage of human donors as well as by islet graft destruction by inflammatory and thrombotic mechanisms. A possible solution to these problems is to use genetically modified pig islets. Endothelial protein C receptor (EPCR) enhances protein C activation and regulates coagulation, inflammation, and apoptosis. We hypothesized that human EPCR (hEPCR) expression on donor islets would improve graft survival and function...
July 2016: Transplantation Proceedings
https://www.readbyqxmd.com/read/27517501/genetic-strategies-to-bring-islet-xenotransplantation-to-the-clinic
#12
Wayne J Hawthorne, Andrew M Lew, Helen E Thomas
PURPOSE OF REVIEW: Despite the benefits of islet and pancreas allotransplantation, their widespread use in type 1 diabetes is limited because of the paucity of suitable donors. Porcine xenotransplantation offers an alternative, and advances in genetic modification of pigs have opened up new potential for its clinical use. This review outlines the barriers to successful islet xenotransplantation, and genetic modifications that have been tested to overcome these. RECENT FINDINGS: Islets from pigs lacking α1,3-galactosyltransferase, to prevent hyperacute rejection, are now used as a background strain for further genetic modifications...
October 2016: Current Opinion in Organ Transplantation
https://www.readbyqxmd.com/read/27511303/molecular-immunology-profiles-of-monkeys-following-xenografting-with-the-islets-and-heart-of-%C3%AE-1-3-galactosyltransferase-knockout-pigs
#13
Sun A Ock, Jungkyu Lee, Keon Bong Oh, Seongsoo Hwang, Ik Jin Yun, Curie Ahn, Hyun Keun Chee, Hwajung Kim, Jae Berm Park, Sung Joo Kim, Youngim Kim, Gi-Sun Im, EungWoo Park
Effective immunosuppression strategies and genetically modified animals have been used to prevent hyperacute and acute xenograft rejection; however, the underlying mechanisms remain unknown. In this study, we evaluated the expression of a comprehensive set of immune system-related genes (89 genes, including five housekeeping genes) in the blood of cynomolgus monkeys (~5 yr old) used as graft recipients, before and after the xenografting of the islets and heart from single and double α-1,3-galactosyltransferase (GalT) knockout (KO) pigs (<6 weeks old)...
September 2016: Xenotransplantation
https://www.readbyqxmd.com/read/27464486/porcine-antigen-specific-ifn-%C3%AE-elispot-as-a-potentially-valuable-tool-for-monitoring-cellular-immune-responses-in-pig-to-non-human-primate-islet-xenotransplantation
#14
Hyun-Je Kim, Il-Hee Yoon, Byoung-Hoon Min, Yong-Hee Kim, Jun-Seop Shin, Jong-Min Kim, Jung-Sik Kim, Hye-Young Nam, Won-Woo Lee, Chung-Gyu Park
BACKGROUND: Recent progress in xenotransplantation of porcine islets to non-human primates (NHPs) gives hope for human clinical trials in the near future. Thus, implementation of an appropriate monitoring method to detect the development of detrimental porcine antigen-specific cellular immune responses is necessary. The enzyme-linked immunospot (ELISpot) assay has been widely used to monitor antigen-specific alloreactive T-cell responses in humans; however, the utility of porcine islet-specific ELISpot assay has not yet been thoroughly evaluated for pig-to-NHPs intraportal islet xenotransplantation...
July 2016: Xenotransplantation
https://www.readbyqxmd.com/read/27440468/islet-cell-transplantation-from-g%C3%A3-ttingen-minipigs-to-cynomolgus-monkeys-analysis-of-virus-safety
#15
Vladimir A Morozov, Stefan Ludwig, Barbara Ludwig, Avi Rotem, Uriel Barkai, Stefan R Bornstein, Joachim Denner
BACKGROUND: Xenotransplantation using pig cells, tissues or organs may be associated with the transmission of porcine zoonotic micro-organisms. Hepatitis E virus (HEV), porcine cytomegalovirus (PCMV) and porcine endogenous retroviruses (PERVs) are potentially zoonotic micro-organisms which do not show clinical symptoms in pigs and which are due to the low expression level difficult to detect. Göttingen Minipigs (GöMP) are often used for biomedical investigations and they are well characterized concerning the presence of numerous bacteria, fungi, viruses and parasites and therefore may be used for islet cell transplantation...
July 2016: Xenotransplantation
https://www.readbyqxmd.com/read/27433127/molecular-and-serological-epidemiology-of-japanese-encephalitis-virus-jev-in-a-remote-island-of-western-japan-an-implication-of-jev-migration-over-the-east-china-sea
#16
Akira Yoshikawa, Takeshi Nabeshima, Shingo Inoue, Masanobu Agoh, Kouichi Morita
BACKGROUND: Japanese encephalitis (JE) is a mosquito-borne infectious disease caused by Japanese encephalitis virus (JEV). About 1-10 cases with severe central nervous system symptoms have been constantly reported every year in Japan. To clarify the mechanism of maintenance of JEV, the present study surveyed pigs for serological evidence of JEV infection and isolated JEV strains from pigs and mosquitoes in Isahaya City (Isahaya) and Goto City (Goto) in the islets of Goto in Nagasaki Prefecture from 2008 to 2014...
2016: Tropical Medicine and Health
https://www.readbyqxmd.com/read/27423314/activation-of-islet-5-ht4-receptor-regulates-glycemic-control-through-promoting-insulin-secretion
#17
Hui Chen, Feng Hong, Ye Chen, Ji Li, Yuan-Sheng Yao, Yue Zhang, Li-Fei Zheng, Jin-Xia Zhu
Mosapride, a gastrointestinal prokinetic drug, is an agonist of 5-hydroxytryptamine (5-HT) receptor 4 that also reduces blood glucose. Whether 5-HT4 receptor is distributed in pancreatic islets and whether mosapride can directly stimulate insulin secretion is unclear. In the present study, the protein expression and cellular location of 5-HT4 receptor in pancreas was detected through western blotting and immunofluorescence. The acute effects of 5-HT4 receptor agonists, mosapride and prucalopride, on insulin secretion were investigated in vivo and in vitro in normal and alloxan-induced diabetes rats...
October 15, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27387829/failure-of-transplantation-tolerance-induction-by-autologous-regulatory-t-cells-in-the-pig-to-non-human-primate-islet-xenotransplantation-model
#18
Jun-Seop Shin, Byoung-Hoon Min, Jong-Min Kim, Jung-Sik Kim, Il Hee Yoon, Hyun Je Kim, Yong-Hee Kim, Jae Yool Jang, Hee Jung Kang, Dong-Gyun Lim, Jongwon Ha, Sang-Joon Kim, Chung-Gyu Park
BACKGROUND: Islet allotransplantation is a promising way to treat some type 1 diabetic (T1D) patients with frequent hypoglycemic unawareness, and islet xenotransplantation is emerging to overcome the problem of donor organ shortage. Our recent study showing reproducible long-term survival of porcine islets in non-human primates (NHPs) allows us to examine whether autologous regulatory T-cell (Treg) infusion at peri-transplantation period would induce transplantation tolerance in xenotransplantation setting...
July 2016: Xenotransplantation
https://www.readbyqxmd.com/read/27320609/supplemental-analysis-for-n-linked-sugars-in-adult-pig-islets
#19
H Eguchi, T Kawamura, N Kashiyama, R Matsuura, R Sakai, K Nakahata, P-C Lo, M Asada, A Maeda, M Goto, M Toyoda, H Okuyama, S Miyagawa
The pig pancreas is considered to be one of the most suitable sources of islets for clinical xenotransplantation. However, after producing α1-3galactosyltransferase knockout pigs, most of the organs of these pigs showed less antigenicity to the human body. Wild-type adult pig islets (APIs) that originally produced negligible levels of α-Gal, different from neonatal porcine islet-like cell clusters, showed a clear antigenicity to human serum. Concerning the so-called non-Gal epitopes, many studies related to glycoproteins and glycolipids are ongoing in efforts to identify them...
May 2016: Transplantation Proceedings
https://www.readbyqxmd.com/read/27305664/xenotransplanted-pig-sertoli-cells-inhibit-both-the-alternative-and-classical-pathways-of-complement-mediated-cell-lysis-while-pig-islets-are-killed
#20
Kandis Wright, Rachel Dziuk, Payal Mital, Gurvinder Kaur, Jannette M Dufour
Xenotransplantation has vast clinical potential but is limited by the potent immune responses generated against xenogeneic tissue. Immune-privileged Sertoli cells (SC) survive xenotransplantation long-term (>90 days) without immunosuppression, making SC an ideal model to identify xenograft survival mechanisms. Xenograft rejection includes the binding of natural and induced antibodies, and activation of complement cascade. Using an in vitro cytotoxicity assay, where cells were cultured with human serum and complement, we demonstrated neonatal pig SC (NPSC) are resistant to complement mediated cell lysis and express complement inhibitory factors, membrane cofactor protein (MCP; CD46) and decay accelerating factor (DAF; CD55) at significantly higher levels than neonatal pig islets (NPI), non-immune privileged controls...
June 14, 2016: Cell Transplantation
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