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Sudhakar Muthyala, Susan Safley, Kereen Gordan, Graham Barber, Collin Weber, Athanassios Sambanis
BACKGROUND: Adult porcine islets (APIs) constitute a promising alternative to human islets in treating type 1 diabetes. The intrahepatic site has been used in preclinical primate studies of API xenografts; however, an estimated two-thirds of donor islets are destroyed after intraportal infusion due to a number of factors, including the instant blood-mediated inflammatory reaction (IBMIR), immunosuppressant toxicity, and poor reestablishment of extracellular matrix connections. Intraperitoneal (ip) transplantation of non-vascularized encapsulated islets offers several advantages over intrahepatic transplantation of free islets, including avoidance of IBMIR, immunoprotection, accommodation of a larger graft volume, and reduced risk of hemorrhage...
January 2017: Xenotransplantation
Vaihere Delaune, Thierry Berney, Stéphanie Lacotte, Christian Toso
The portal vein remains the preferred site for pancreatic islet transplantation due to its easy access and low morbidity. However, despite great progress in isolation and transplantation protocols over the past few years, it is still associated with the early loss of some 50-70% of transplanted islets. The complex liver micro-environment itself presumably plays an important role in this loss. The present review focuses on the specifics of the liver micro-environment, notably the localized hepatic ischemia/reperfusion injury following transplantation, the low oxygenation of the portal vein, the instant blood mediated inflammatory reaction (IBMIR), the endogenous liver immune system, and the gut-liver axis, and how they can each have an impact on the transplanted islets...
January 21, 2017: Transplant International: Official Journal of the European Society for Organ Transplantation
Jingjing Wang, Zhen Sun, Wenyu Gou, David B Adams, Wanxing Cui, Katherine A Morgan, Charlie Strange, Hongjun Wang
Islet cell transplantation has limited effectiveness because of an instant blood-mediated inflammatory reaction (IBMIR) that occurs immediately after cell infusion and leads to dramatic β-cell death. In intraportal islet transplantation models using mouse and human islets, we demonstrated that α-1 antitrypsin (AAT; Prolastin-C), a serine protease inhibitor used for the treatment of AAT deficiency, inhibits IBMIR and cytokine-induced inflammation in islets. In mice, more diabetic recipients reached normoglycemia after intraportal islet transplantation when they were treated with AAT compared with mice treated with saline...
April 2017: Diabetes
Valery Gmyr, Caroline Bonner, Ericka Moerman, Antoine Tournoys, Nathalie Delalleau, Audrey Quenon, Julien Thevenet, Mikael Chetboun, Julie Kerr-Conte, François Pattou, Thomas Hubert, Merce Jourdain
Human islet transplantation is a viable treatment option for type 1 diabetes mellitus (T1DM). However, pancreatic islet inflammation 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...
February 16, 2017: Cell Transplantation
Kevin Vivot, Malika A Benahmed, Elodie Seyfritz, William Bietiger, Karim Elbayed, Elisa Ruhland, Allan Langlois, Elisa Maillard, Michel Pinget, Nathalie Jeandidier, Jean-Pierre Gies, Izzie-Jacques Namer, Séverine Sigrist, Nathalie Reix
Intrahepatic transplantation of islets requires a lot of islets because more than 50% of the graft is lost during the 24 hours following transplantation. We analyzed, in a rat model, early post-transplantation inflammation using systemic inflammatory markers, or directly in islet-transplanted livers by immunohistochemistry. (1)H HRMAS NMR was employed to investigate metabolic responses associated with the transplantation. Inflammatory markers (Interleukin-6, α2-macroglobulin) are not suitable to follow islet reactions as they are not islet specific...
2016: International Journal of Biological Sciences
David Liuwantara, Yi Vee Chew, Emmanuel J Favaloro, Joanne M Hawkes, Heather L Burns, Philip J O'Connell, Wayne J Hawthorne
INTRODUCTION: The instant blood-mediated inflammatory reaction (IBMIR) causes major loss of islets after transplantation and consequently represents the initial barrier to survival of porcine neonatal islet cell clusters (NICC) after xenotransplantation. METHODS: This study used novel assays designed to characterize the various immunologic components responsible for xenogeneic IBMIR to identify initiators and investigate processes of IBMIR-associated coagulation, complement activation and neutrophil infiltration...
June 2016: Transplantation Direct
Elisabet Gustafson, Sana Asif, Huda Kozarcanin, Graciela Elgue, Staffan Meurling, Kristina N Ekdahl, Bo Nilsson
Rapid destruction of hepatocytes after hepatocyte transplantation has hampered the application of this procedure clinically. The instant blood mediated inflammatory reaction (IBMIR) is a plausible underlying cause for this cell loss. The present study was designed to evaluate the capacity of low molecular weight dextran sulfate (LMWDS) to control these initial reactions from the innate immune system. Fresh and cryopreserved hepatocytes were tested in an in vitro whole blood model using ABOcompatible blood. The ability to elicit IBMIR and the capacity of LMW-DS (100 µg/mL) to attenuate the degree of activation of the cascade systems was monitored...
July 22, 2016: Cell Transplantation
Charlotte A Lee, Anil Dhawan, Richard A Smith, Ragai R Mitry, Emer Fitzpatrick
Hepatocyte transplantation (HT) is emerging as a promising alternative to orthotopic liver transplantation (OLT) in patients with certain liver-based metabolic disease and acute liver failure. Hepatocytes are generally infused into the portal venous system, from which they migrate into the liver cell plates of the native organ. One of the major hurdles to the sustained success of this therapy is early cell loss, with up to 70% of hepatocytes lost immediately following infusion. This is largely thought to be due to the instant blood-mediated inflammatory reaction (IBMIR), resulting in the activation of complement and coagulation pathways...
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
Takayuki Tanaka, Minoru Fujita, Rita Bottino, Jon D Piganelli, Kevin McGrath, Jiang Li, Whayoung Lee, Hayato Iwase, Martin Wijkstrom, Suzanne Bertera, Cassandra Long, Douglas Landsittel, Ken Haruma, David K C Cooper, Hidetaka Hara
Transplantation of islets into the gastric submucosal space (GSMS) has several advantages (e.g., avoidance of the instant blood-mediated inflammatory response [IBMIR], ability to biopsy). The aim of this study was to determine whether endoscopic biopsy of islet allografts transplanted into the GSMS in diabetic pigs can provide histopathological and immunohistochemical information that correlates with the clinical course (e.g.,, blood glucose level, insulin requirement). Islet allografts (Group1: 10,000 kIEq /kg [n = 4]; Group2: 15,000 kIEq /kg [n = 2]) were transplanted into the GSMS of diabetic pigs under immunosuppression...
2016: Islets
Ioannis Kourtzelis, Klara Kotlabova, Jong-Hyung Lim, Ioannis Mitroulis, Anaisa Ferreira, Lan-Sun Chen, Bettina Gercken, Anja Steffen, Elisabeth Kemter, Anne Klotzsche-von Ameln, Claudia Waskow, Kavita Hosur, Antonios Chatzigeorgiou, Barbara Ludwig, Eckhard Wolf, George Hajishengallis, Triantafyllos Chavakis
Platelet-monocyte interactions are strongly implicated in thrombo-inflammatory injury by actively contributing to intravascular inflammation, leukocyte recruitment to inflamed sites, and the amplification of the procoagulant response. Instant blood-mediated inflammatory reaction (IBMIR) represents thrombo-inflammatory injury elicited upon pancreatic islet transplantation (islet-Tx), thereby dramatically affecting transplant survival and function. Developmental endothelial locus-1 (Del-1) is a functionally versatile endothelial cell-derived homeostatic factor with anti-inflammatory properties, but its potential role in IBMIR has not been previously addressed...
April 2016: Thrombosis and Haemostasis
Fang Xiao, Liang Ma, Min Zhao, Richard A Smith, Guocai Huang, Peter M Jones, Shanta Persaud, Attilio Pingitore, Anthony Dorling, Robert Lechler, Giovanna Lombardi
BACKGROUND AND PURPOSE: A major obstacle to islet cell transplantation is the early loss of transplanted islets resulting from the instant blood-mediated inflammation reaction (IBMIR). The activation of complement pathways plays a central role in IBMIR. The aim of this study was to test the inhibitory effect of "painting" human islets with APT070, a membrane-localizing C3 convertase inhibitor, on inflammation evoked by exposure to human serum in vitro and by transplantation in vivo in a humanized diabetic mouse model...
February 2016: British Journal of Pharmacology
Ioannis Kourtzelis, Peetra U Magnusson, Klara Kotlabova, John D Lambris, Triantafyllos Chavakis
Xeno-transplantation of pancreatic islets represents a promising therapeutic alternative for the treatment of type 1 diabetes mellitus. However, potent innate immune responses induced shortly after the transplantation of donor islets to the recipient, comprising the Instant Blood Mediated Immune Reaction (IBMIR), exert detrimental actions on islet graft function. The coagulation and complement cascades together with the leukocyte and platelet populations are the major players in IBMIR. This innate immune attack affects dramatically islet integrity and leads to significant loss of function of the xenograft...
2015: Advances in Experimental Medicine and Biology
Santosh Nagaraju, Suzanne Bertera, Takayuki Tanaka, Hidetaka Hara, Gina R Rayat, Martin Wijkstrom, David Ayares, Massimo Trucco, David K C Cooper, Rita Bottino
BACKGROUND: Pig islet grafts have been successful in treating diabetes in animal models. One remaining question is whether neonatal pig isletlike cell clusters (NICC) are resistant to the early loss of islets from the instant blood-mediated inflammatory reaction (IBMIR). METHODS: Neonatal isletlike cell clusters were harvested from three groups of piglets-(i) wild-type (genetically unmodified), (ii) α1,3-galactosyltransferase gene-knockout (GTKO)/CD46, and (iii) GTKO/CD46/CD39...
July 2015: Xenotransplantation
Feng Gao, Qi Liang, Junling Li, Qiong Dong, Xiaoqian Ma, Wei Wang
OBJECTIVE: To study the feasibility of ultrasonic molecular imaging of immediately blood-mediated inflammatory reaction (IBMIR) in vitro.
 METHODS: IBMIR models in vitro were divided into 3 groups: Group A, no microbubbles were added; Group B, non-targeted micro-bubbles were added; Group C, Lys-Gly-Asp-Ser (KGDS)-targeted microbubbles (MBK) were added. The ultrasonic enhancement of IBMIR in loops by ultrasonic contrast imaging was evaluated.
 RESULTS: The contrast-enhanced US imaging did not show thrombus formation in the group A, whereas the thrombus was found in the Group B and C with a change in filling defects or ring enhancement, respectively...
June 2015: Zhong Nan da Xue Xue Bao. Yi Xue Ban, Journal of Central South University. Medical Sciences
Maria Hårdstedt, Susanne Lindblom, Alex Karlsson-Parra, Bo Nilsson, Olle Korsgren
The instant blood-mediated inflammatory reaction (IBMIR) has been studied in whole blood models of human allo-islet transplantation for short periods (<6 h). Beyond this time frame the innate response to intraportally transplanted islets is less well described. A novel whole blood model was applied to study blood-islet-graft interactions up to 48 h. Heparinized polyvinyl chloride tubing was sealed into small bags containing venous blood together with allogeneic human islets and exocrine tissue, respectively...
2016: Cell Transplantation
A Schaschkow, C Mura, W Bietiger, C Peronet, A Langlois, F Bodin, C Dissaux, C Bruant-Rodier, M Pinget, N Jeandidier, M T Juszczak, S Sigrist, E Maillard
Disruption of the pancreatic islet environment combined with the decrease in oxygen supply that occurs during isolation leads to poor islet survival. The aim of this study was to validate the benefit of using a plasma-based scaffold supplemented with perfluorodecalin to improve islet transplantation outcome. Rat islets were cultured in three conditions: i) control group, ii) plasma based-matrix (P-matrix), and iii) P-matrix supplemented with emulsified perfluorodecalin. After 24 h culture, matrix/cell contacts (Integrinβ1, p-FAK/FAK, p-Akt/Akt), survival (caspase 3, TUNEL, FDA/PI), function, and HIF-1α translocation were assessed...
June 2015: Biomaterials
B M Martin, K P Samy, M C Lowe, P W Thompson, J Cano, A B Farris, M Song, C R Dove, F V Leopardi, E A Strobert, J B Jenkins, B H Collins, C P Larsen, A D Kirk
Islet xenotransplantation is a potential treatment for diabetes without the limitations of tissue availability. Although successful experimentally, early islet loss remains substantial and attributed to an instant blood-mediated inflammatory reaction (IBMIR). This syndrome of islet destruction has been incompletely defined and characterization in pig-to-primate models has been hampered by logistical and statistical limitations of large animal studies. To further investigate IBMIR, we developed a novel in vivo dual islet transplant model to precisely characterize IBMIR as proof-of-concept that this model can serve to properly control experiments comparing modified xenoislet preparations...
May 2015: American Journal of Transplantation
B Reichart, H Niemann, T Chavakis, J Denner, E Jaeckel, B Ludwig, G Marckmann, A Schnieke, R Schwinzer, J Seissler, R R Tönjes, N Klymiuk, E Wolf, S R Bornstein
Solid organ and cell transplantation, including pancreatic islets constitute the treatment of choice for chronic terminal diseases. However, the clinical use of allogeneic transplantation is limited by the growing shortage of human organs. This has prompted us to initiate a unique multi-center and multi-team effort to promote translational research in xenotransplantation to bring xenotransplantation to the clinical setting. Supported by the German Research Foundation, an interdisciplinary group of surgeons, internal medicine doctors, diabetologists, material sciences experts, immunologists, cell biologists, virologists, veterinarians, and geneticists have established a collaborative research center (CRC) focusing on the biology of xenogeneic cell, tissue, and organ transplantation...
January 2015: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
Raina D Ramnath, Elisa Maillard, Katherine Jones, Paul A Bateman, Stephen S J Hughes, Jane Gralla, Paul R Johnson, Derek W R Gray
Culture of human pancreatic islets is now routinely carried out prior to clinical islet allotransplantation, using conditions that have been developed empirically. One of the major causes of early islet destruction after transplantation is the process termed instant blood-mediated inflammatory reaction (IBMIR). The aim of this study was to develop in vitro methods to investigate IBMIR and apply them to the culture conditions used routinely in our human islet isolation laboratory. Freshly isolated or precultured (24 h, 48 h) human islets were incubated in either ABO-compatible allogeneic human blood or Hank's buffered salt solution (HBSS) for 1 h at 37°C...
2015: Cell Transplantation
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