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Pig islets

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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Hiroki Shima, Akiko Inagaki, Takehiro Imura, Youhei Yamagata, Kimiko Watanabe, Kazuhiko Igarashi, Masafumi Goto, Kazutaka Murayama
The clostridial collagenases, H and G, play key roles in pancreatic islet isolation. Collagenases digest the peptide bond between Yaa and the subsequent Gly in Gly-Xaa-Yaa repeats. To fully understand the pancreatic islet isolation process, identification of the collagenase substrates in the tissue is very important. Although collagen types I and III were reported as possible substrates for collagenase H, the substrate for collagenase G remains unknown. In this study, collagen type V was focused upon as the target for collagenases...
2016: Journal of Diabetes Research
Anneli Rydén, Görel Nyman, Lovisa Nalin, Susanne Andreasson, Olle Korsgren, Olof Eriksson, Marianne Jensen-Waern
INTRODUCTION: Radiolabeled Exendin-4, a synthetic glucagon-like peptide-1 (GLP-1) analog, is used as a tracer for diagnostic purposes of β-cells and in experimental animal research. Exendin-4 can be radiolabeled with (68)Ga, (111)In or (99m)Tc and used for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging to diagnose insulinomas, visualization of pancreatic β-cell mass and transplanted Islets of Langerhans. In humans, Exendin-4 is widely used as a therapeutic agent for treatment of type 2 diabetes (T2D)...
July 2016: Nuclear Medicine and Biology
Andrea Bähr, Tobias Käser, Elisabeth Kemter, Wilhelm Gerner, Mayuko Kurome, Wiebke Baars, Nadja Herbach, Kirsti Witter, Annegret Wünsch, Stephanie C Talker, Barbara Kessler, Hiroshi Nagashima, Armin Saalmüller, Reinhard Schwinzer, Eckhard Wolf, Nikolai Klymiuk
We have successfully established and characterized a genetically modified pig line with ubiquitous expression of LEA29Y, a human CTLA4-Ig derivate. LEA29Y binds human B7.1/CD80 and B7.2/CD86 with high affinity and is thus a potent inhibitor of T cell co-stimulation via this pathway. We have characterized the expression pattern and the biological function of the transgene as well as its impact on the porcine immune system and have evaluated the potential of these transgenic pigs to propagate via assisted breeding methods...
2016: PloS One
Bradley P Weegman, Michael J Taylor, Simona C Baicu, Kate Mueller, Timothy D O'Brien, John Wilson, Klearchos K Papas
Diabetes is a major health problem worldwide and there is substantial interest in developing xenogeneic islet transplantation as a potential treatment. The potential to relieve the demand on an inadequate supply of human pancreata is dependent upon the efficiency of techniques for isolating and culturing islets from the source pancreata. Porcine islets are favored for xenotransplantation, but mature pigs (>2 years) present logistic and economic challenges and young pigs (3-6 months) have not yet proven to be an adequate source...
April 22, 2016: Cell Transplantation
Whayoung Lee, Hidetaka Hara, Mohamed B Ezzelarab, Hayato Iwase, Rita Bottino, Cassandra Long, Jagdeece Ramsoondar, David Ayares, David K C Cooper
BACKGROUND: The impact that the absence of expression of NeuGc in pigs might have on pig organ or cell transplantation in humans has been studied in vitro, but only using red blood cells (pRBCs) and peripheral blood mononuclear cells (pPBMCs) as the target cells for immune assays. We have extended this work in various in vitro models and now report our initial results. METHODS: The models we have used involve GTKO/hCD46 and GTKO/hCD46/NeuGcKO pig aortas and corneas, and pRBCs, pPBMCs, aortic endothelial cells (pAECs), corneal endothelial cells (pCECs), and isolated pancreatic islets...
March 2016: Xenotransplantation
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