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Article ; Online: Xenogeneic Lung Transplantation Models.

Burdorf, Lars / Azimzadeh, Agnes M / Pierson, Richard N

Methods in molecular biology (Clifton, N.J.)

2020 Volume 2110, Page(s) 173–196

Abstract: Study of lung xenografts has proven useful to understand the remaining barriers to successful transplantation of other organ xenografts. In this chapter, the history and current status of lung xenotransplantation will be briefly reviewed, and two ... ...

Abstract	Study of lung xenografts has proven useful to understand the remaining barriers to successful transplantation of other organ xenografts. In this chapter, the history and current status of lung xenotransplantation will be briefly reviewed, and two different experimental models, the ex vivo porcine-to-human lung perfusion and the in vivo xenogeneic lung transplantation, will be presented. We will focus on the technical details of these lung xenograft models in sufficient detail, list the needed materials, and mention analysis techniques to allow others to adopt them with minimal learning curve.
MeSH term(s)	Animals ; Biomarkers ; Catheters ; Cytokines/metabolism ; Graft Survival ; Hemodynamics ; Heterografts ; Humans ; Lung Transplantation/adverse effects ; Lung Transplantation/methods ; Lung Transplantation/trends ; Models, Animal ; Papio ; Perfusion ; Radiography, Thoracic ; Respiratory Function Tests ; Swine ; Transplantation, Heterologous/adverse effects ; Transplantation, Heterologous/methods ; Transplantation, Heterologous/trends
Chemical Substances	Biomarkers ; Cytokines
Language	English
Publishing date	2020-01-30
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-0255-3_12
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Article ; Online: Multi-gene technical assessment of qPCR and NanoString n-Counter analysis platforms in cynomolgus monkey cardiac allograft recipients.

Bergbower, Emily A S / Pierson, Richard N / Azimzadeh, Agnes M

Cellular immunology

2019 Volume 347, Page(s) 104019

Abstract: Quantitative gene expression profiling of cardiac allografts characterizes the phenotype of the alloimmune response, yields information regarding differential effects that may be associated with various anti-rejection drug regimens, and generates ... ...

Abstract	Quantitative gene expression profiling of cardiac allografts characterizes the phenotype of the alloimmune response, yields information regarding differential effects that may be associated with various anti-rejection drug regimens, and generates testable hypotheses regarding the pathogenesis of the chronic rejection lesions typically observed in non-human primate heart transplant models. The goal of this study was to assess interplatform performance and variability between the relatively novel NanoString nCounter Analysis System, ΔΔCT (relative) RT-qPCR, and standard curve (absolute) RT-qPCR utilizing cynomolgus monkey cardiac allografts. Methods for RNA isolation and preamplification were also systematically evaluated and effective methods are proposed. In this study, we demonstrate strong correlation between the two RT-qPCR methods, but variable and, at times, weak correlation between RT-qPCR and NanoString. NanoString fold change results demonstrate less sensitivity to small changes in gene expression than RT-qPCR. These findings appear to be driven by technical aspects of each platform that influence the conditions under which each technique is ideal. Collectively, our data contribute to the general effort to optimally utilize gene expression profiling techniques, not only for transplanted tissues, but for many other applications where accurate rank-order of gene expression versus precise quantification of absolute gene transcript number may be relatively valuable.
MeSH term(s)	Allografts ; Animals ; Endocardium/cytology ; Gene Expression/physiology ; Gene Expression Profiling/methods ; Genes, Essential/genetics ; Graft Rejection/genetics ; Heart Transplantation/methods ; Heart Ventricles/cytology ; Immunosuppression ; Macaca fascicularis ; Nucleic Acid Amplification Techniques ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Transplant Recipients
Chemical Substances	RNA, Messenger
Language	English
Publishing date	2019-11-08
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80094-6
ISSN	1090-2163 ; 0008-8749
ISSN (online)	1090-2163
ISSN	0008-8749
DOI	10.1016/j.cellimm.2019.104019
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Article ; Online: Progress and challenges in lung xenotransplantation: an update.

Burdorf, Lars / Azimzadeh, Agnes M / Pierson, Richard N

Current opinion in organ transplantation

2018 Volume 23, Issue 6, Page(s) 621–627

Abstract: Purpose of review: Recent progress in genetic engineering has facilitated development of transgenic donor animals designed to overcome the known barriers to discordant xenotransplantation, and greatly accelerated progress in the field of ... ...

Abstract	Purpose of review: Recent progress in genetic engineering has facilitated development of transgenic donor animals designed to overcome the known barriers to discordant xenotransplantation, and greatly accelerated progress in the field of xenotransplantation. Here we review and summarize recent progress in lung xenotransplantation, and discuss possible additional genetic modifications and other interventions that may further advance the use of pulmonary xenografts towards clinical applications based on known mechanisms of xeno lung injury. Recent findings: Ex-vivo lung perfusion experiments have shown that the addition of human complement (hCD46, hCD55), coagulation (hEPCR, hVWF, hTBM, hTFPI, hCD39), or anti-inflammatory pathway regulatory genes (HO-1, HLA-E), and the knockout (KO) of major porcine carbohydrates (GalT, Neu5Gc, B4Gal) have each protective effects on lung survival and function. The use of these transgenes in multitransgenic donor organs, targeting several known xenogeneic rejection mechanisms, combined with drug treatments addressing remaining known rejection pathways, have led to prolonged recipient survival of up to 31 days with in some cases preserved live-supporting organ function of the transplanted graft for several days. Pulmonary vascular resistance elevation, which has been found to be associated with high thromboxane levels and has been the major failure reason of xenogeneic lung grafts in the past years, has been successfully attenuated by the addition of a thromboxane synthase inhibitor (1-Benzylimidazole). Currently, the predominant failure mechanism of xenogeneic lung grafts is an inflammatory process, leading to vascular barrier function injury with interstitial and trachea edema. Work with other pig organs in primate models show that regimens based on costimulatory pathway blocking antibodies prolong xenograft function for months to years, suggesting that once initial lung inflammation mechanisms are fully controlled, clinically useful application of pig lung xenografts may be feasible. Summary: The use of multitransgenic donor pigs coupled with drugs targeting complement activation, coagulation, and inflammation have significantly improved the survival of xenogeneic pig lungs both during ex vivo human blood perfusion and in life-supporting in vivo models, and for the first time allowed consistent life-supporting function of lung xenografts. Overcoming delayed loss of vascular barrier function injury appears to be within reach, and will be essential to make lung xenografts a clinically relevant treatment option.
MeSH term(s)	Animals ; Humans ; Lung Transplantation/methods ; Swine ; Transplantation, Heterologous/methods
Language	English
Publishing date	2018-10-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1390429-2
ISSN	1531-7013 ; 1087-2418
ISSN (online)	1531-7013
ISSN	1087-2418
DOI	10.1097/MOT.0000000000000582
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Article ; Online: Transplantation: Negative vaccination to modulate transplant immunity.

Azimzadeh, Agnes M / Bromberg, Jonathan S

Nature reviews. Nephrology

2013 Volume 9, Issue 10, Page(s) 557–559

MeSH term(s)	Animals ; Dendritic Cells/transplantation ; Graft Survival/immunology ; Immune Tolerance/immunology ; Immunologic Memory/immunology ; Kidney Diseases/prevention & control ; Kidney Transplantation/immunology ; Male ; T-Lymphocytes, Regulatory/immunology
Language	English
Publishing date	2013-08-27
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	2490366-8
ISSN	1759-507X ; 1759-5061
ISSN (online)	1759-507X
ISSN	1759-5061
DOI	10.1038/nrneph.2013.172
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Zs.A 6334: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MG 107: Show issues

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Article ; Online: Increased human complement pathway regulatory protein gene dose is associated with increased endothelial expression and prolonged survival during ex-vivo perfusion of GTKO pig lungs with human blood.

Chaban, Ryan / McGrath, Gannon / Habibabady, Zahra / Rosales, Ivy / Burdorf, Lars / Ayares, David L / Rybak, Elana / Zhang, Tianshu / Harris, Donald G / Dahi, Siamak / Ali, Franchesca / Parsell, Dawn M / Braileanu, Gheorghe / Cheng, Xiangfei / Sievert, Evelyn / Phelps, Carol / Azimzadeh, Agnes M / Pierson, Richard N

Xenotransplantation

2023 Volume 30, Issue 4, Page(s) e12812

Abstract: Introduction: Expression of human complement pathway regulatory proteins (hCPRP's) such as CD46 or CD55 has been associated with improved survival of pig organ xenografts in multiple different models. Here we evaluate the hypothesis that an increased ... ...

Abstract	Introduction: Expression of human complement pathway regulatory proteins (hCPRP's) such as CD46 or CD55 has been associated with improved survival of pig organ xenografts in multiple different models. Here we evaluate the hypothesis that an increased human CD46 gene dose, through homozygosity or additional expression of a second hCPRP, is associated with increased protein expression and with improved protection from injury when GTKO lung xenografts are perfused with human blood. Methods: Twenty three GTKO lungs heterozygous for human CD46 (GTKO.heteroCD46), 10 lungs homozygous for hCD46 (GTKO.homoCD46), and six GTKO.homoCD46 lungs also heterozygous for hCD55 (GTKO.homoCD46.hCD55) were perfused with human blood for up to 4 h in an ex vivo circuit. Results: Relative to GTKO.heteroCD46 (152 min, range 5-240; 6/23 surviving at 4 h), survival was significantly improved for GTKO.homoCD46 (>240 min, range 45-240, p = .034; 7/10 surviving at 4 h) or GTKO.homoCD46.hCD55 lungs (>240 min, p = .001; 6/6 surviving at 4 h). Homozygosity was associated with increased capillary expression of hCD46 (p < .0001). Increased hCD46 expression was associated with significantly prolonged lung survival (p = .048),) but surprisingly not with reduction in measured complement factor C3a. Hematocrit, monocyte count, and pulmonary vascular resistance were not significantly altered in association with increased hCD46 gene dose or protein expression. Conclusion: Genetic engineering approaches designed to augment hCPRP activity - increasing the expression of hCD46 through homozygosity or co-expressing hCD55 with hCD46 - were associated with prolonged GTKO lung xenograft survival. Increased expression of hCD46 was associated with reduced coagulation cascade activation, but did not further reduce complement activation relative to lungs with relatively low CD46 expression. We conclude that coagulation pathway dysregulation contributes to injury in GTKO pig lung xenografts perfused with human blood, and that the survival advantage for lungs with increased hCPRP expression is likely attributable to improved endothelial thromboregulation.
MeSH term(s)	Animals ; Swine ; Humans ; Animals, Genetically Modified ; Transplantation, Heterologous ; Heterografts ; Lung ; Perfusion
Language	English
Publishing date	2023-07-28
Publishing country	Denmark
Document type	Journal Article
ZDB-ID	1236298-0
ISSN	1399-3089 ; 0908-665X
ISSN (online)	1399-3089
ISSN	0908-665X
DOI	10.1111/xen.12812
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Article ; Online: The role of sialic acids in the immune recognition of xenografts.

French, Beth M / Sendil, Selin / Pierson, Richard N / Azimzadeh, Agnes M

Xenotransplantation

2017 Volume 24, Issue 6

Abstract: Presentation of sialic acid (Sia) varies among different tissues and organs within each species, and between species. This diversity has biologically important consequences regarding the recognition of cells by "xeno" antibodies (Neu5Gc vs Neu5Ac). Sia ... ...

Abstract	Presentation of sialic acid (Sia) varies among different tissues and organs within each species, and between species. This diversity has biologically important consequences regarding the recognition of cells by "xeno" antibodies (Neu5Gc vs Neu5Ac). Sia also plays a central role in inflammation by influencing binding of the asialoglycoprotein receptor 1 (ASGR-1), Siglec-1 (Sialoadhesin), and cellular interactions mediated by the selectin, integrin, and galectin receptor families. This review will focus on what is known about basic Sia structure and function in association with xenotransplantation, how changes in sialylation may occur in this context (through desialylation or changes in sialyltransferases), and how this fundamental pathway modulates adhesive and cell activation pathways that appear to be particularly crucial to homeostasis and inflammation for xenografts.
MeSH term(s)	Animals ; Antibodies/metabolism ; Antigens, CD/immunology ; Heterografts/immunology ; Humans ; Lectins/metabolism ; Neuraminic Acids/metabolism ; Sialic Acids/metabolism ; Transplantation, Heterologous/methods
Chemical Substances	Antibodies ; Antigens, CD ; Lectins ; Neuraminic Acids ; Sialic Acids
Language	English
Publishing date	2017-10-22
Publishing country	Denmark
Document type	Journal Article ; Review
ZDB-ID	1236298-0
ISSN	1399-3089 ; 0908-665X
ISSN (online)	1399-3089
ISSN	0908-665X
DOI	10.1111/xen.12345
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Article ; Online: Genetic modifications designed for xenotransplantation attenuate sialoadhesin-dependent binding of human erythrocytes to porcine macrophages.

Petitpas, Kaitlyn / Habibabady, Zahra / Ritchie, Veronica / Connolly, Margaret R / Burdorf, Lars / Qin, Wenning / Kan, Yinan / Layer, Jacob V / Crabtree, Juliet N / Youd, Michele E / Westlin, William F / Magnani, Diogo M / Pierson, Richard N / Azimzadeh, Agnes M

Xenotransplantation

2022 Volume 29, Issue 6, Page(s) e12780

Abstract: The phenomenon of diminishing hematocrit after in vivo liver and lung xenotransplantation and during ex vivo liver xenoperfusion has largely been attributed to action by resident liver porcine macrophages, which bind and destroy human erythrocytes. ... ...

Abstract	The phenomenon of diminishing hematocrit after in vivo liver and lung xenotransplantation and during ex vivo liver xenoperfusion has largely been attributed to action by resident liver porcine macrophages, which bind and destroy human erythrocytes. Porcine sialoadhesin (siglec-1) was implicated previously in this interaction. This study examines the effect of porcine genetic modifications, including knockout of the CMAH gene responsible for expression of Neu5Gc sialic acid, on the adhesion of human red blood cells (RBCs) to porcine macrophages. Wild-type (WT) porcine macrophages and macrophages from several strains of genetically engineered pigs, including CMAH gene knockout and several human transgenes (TKO+hTg), were incubated with human RBCs and "rosettes" (≥3 erythrocytes bound to one macrophage) were quantified by microscopy. Our results show that TKO+hTg genetic modifications significantly reduced rosette formation. The monoclonal antibody 1F1, which blocks porcine sialoadhesin, significantly reduced rosette formation by WT and TKO+hTg macrophages compared with an isotype control antibody. Further, desialation of human RBCs with neuraminidase before addition to WT or TKO+hTg macrophages resulted in near-complete abrogation of rosette formation, to a level not significantly different from porcine RBC rosette formation on porcine macrophages. These observations are consistent with rosette formation being mediated by binding of sialic acid on human RBCs to sialoadhesin on porcine macrophages. In conclusion, the data predict that TKO+hTg genetic modifications, coupled with targeting of porcine sialoadhesin by the 1F1 mAb, will attenuate erythrocyte sequestration and anemia during ex vivo xenoperfusion and following in vivo liver, lung, and potentially other organ xenotransplantation.
MeSH term(s)	Humans ; Swine ; Animals ; Sialic Acid Binding Ig-like Lectin 1/genetics ; Transplantation, Heterologous/methods ; N-Acetylneuraminic Acid/metabolism ; Macrophages ; Erythrocytes/metabolism
Chemical Substances	Sialic Acid Binding Ig-like Lectin 1 ; N-Acetylneuraminic Acid (GZP2782OP0)
Language	English
Publishing date	2022-09-20
Publishing country	Denmark
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1236298-0
ISSN	1399-3089 ; 0908-665X
ISSN (online)	1399-3089
ISSN	0908-665X
DOI	10.1111/xen.12780
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Article ; Online: Update on CD40 and CD154 blockade in transplant models.

Zhang, Tianshu / Pierson, Richard N / Azimzadeh, Agnes M

Immunotherapy

2015 Volume 7, Issue 8, Page(s) 899–911

Abstract: Generation of an effective immune response against foreign antigens requires two distinct molecular signals: a primary signal provided by the binding of antigen-specific T-cell receptor to peptide-MHC on antigen-presenting cells and a secondary signal ... ...

Abstract	Generation of an effective immune response against foreign antigens requires two distinct molecular signals: a primary signal provided by the binding of antigen-specific T-cell receptor to peptide-MHC on antigen-presenting cells and a secondary signal delivered via the engagement of costimulatory molecules. Among various costimulatory signaling pathways, the interactions between CD40 and its ligand CD154 have been extensively investigated given their essential roles in the modulation of adaptive immunity. Here, we review current understanding of the role CD40/CD154 costimulation pathway has in alloimmunity, and summarize recent mechanistic and preclinical advances in the evaluation of candidate therapeutic approaches to target this receptor-ligand pair in transplantation.
MeSH term(s)	Animals ; Antigen-Presenting Cells/immunology ; CD40 Antigens/immunology ; CD40 Ligand/immunology ; Humans ; Lymphocyte Activation/immunology ; Models, Immunological ; Signal Transduction/immunology ; Tissue Transplantation/methods ; Transplantation Immunology/immunology
Chemical Substances	CD40 Antigens ; CD40 Ligand (147205-72-9)
Language	English
Publishing date	2015
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ISSN	1750-7448
ISSN (online)	1750-7448
DOI	10.2217/IMT.15.54
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Article ; Online: Human erythrocyte fragmentation during ex-vivo pig organ perfusion.

Habibabady, Zahra A / Sendil, Selin / Ellett, Felix / Pollok, Franziska / Elias, Gabriela F / French, Beth M / Sun, Wenji / Braileanu, Gheorghe / Burdorf, Lars / Irimia, Daniel / Pierson, Richard N / Azimzadeh, Agnes M

Xenotransplantation

2022 Volume 29, Issue 2, Page(s) e12729

Abstract: Platelet sequestration is a common process during organ reperfusion after transplantation. However, instead of lower platelet counts, when using traditional hemocytometers and light microscopy, we observed physiologically implausible platelet counts in ... ...

Abstract	Platelet sequestration is a common process during organ reperfusion after transplantation. However, instead of lower platelet counts, when using traditional hemocytometers and light microscopy, we observed physiologically implausible platelet counts in the course of ex-vivo lung and liver xenograft organ perfusion studies. We employed conventional flow cytometry (FC) and imaging FC (AMINS ImageStream X) to investigate the findings and found platelet-sized fragments in the circulation that are mainly derived from red blood cell membranes. We speculate that this erythrocyte fragmentation contributes to anemia during in-vivo organ xenotransplant.
MeSH term(s)	Animals ; Erythrocytes ; Heterografts ; Humans ; Perfusion ; Swine ; Thrombocytopenia ; Transplantation, Heterologous/methods
Language	English
Publishing date	2022-02-02
Publishing country	Denmark
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1236298-0
ISSN	1399-3089 ; 0908-665X
ISSN (online)	1399-3089
ISSN	0908-665X
DOI	10.1111/xen.12729
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Article ; Online: hEPCR.hTBM.hCD47.hHO-1 with donor clodronate and DDAVP treatment improves perfusion and function of GalTKO.hCD46 porcine livers perfused with human blood.

Cimeno, Arielle / Kuravi, Kasinath / Sorrells, Lori / Dandro, Amy / Sendil, Selin / Burdorf, Lars / Parsell, Dawn M / Eyestone, Will / Phelps, Carol / Ayares, David / Azimzadeh, Agnes M / Pierson, Richard N / Barth, Rolf N / LaMattina, John C

Xenotransplantation

2022 Volume 29, Issue 2, Page(s) e12731

Abstract: Introduction: Platelet sequestration, inflammation, and inappropriate coagulation cascade activation are prominent in liver xenotransplant models and are associated with poor outcomes. Here, we evaluate a cassette of six additional genetic modifications ...

Abstract	Introduction: Platelet sequestration, inflammation, and inappropriate coagulation cascade activation are prominent in liver xenotransplant models and are associated with poor outcomes. Here, we evaluate a cassette of six additional genetic modifications to reduce anti-pig antibody binding (α-1,3-galactosyl transferase knockout [GalTKO]) and target coagulation dysregulation (human endothelial protein C receptor [hEPRC] and thrombomodulin [hTBM]), complement pathway regulation (human membrane cofactor protein, hCD46), inflammation heme oxygenase 1 [hHO-1]), and a self-recognition receptor (integrin-associated protein [hCD47]), as well as donor pharmacologic treatments designed to blunt these phenomena. Methods: Livers from GaltKO.hCD46 pigs ("2-gene," n = 3) and GalTKO.hCD46 pigs also transgenic for hEPRC, hTBM, hCD47, and hHO-1 ("6-gene," n = 4) were perfused ex vivo with whole human blood. Six-gene pigs were additionally pretreated with desmopressin (DDAVP) and clodronate liposomes to deplete vWF and kupffer cells, respectively. Results: The average perfusion times increased from 304 (±148) min in the 2-gene group to 856 (±61) min in the 6-gene group (p = .010). The average heparin administration was decreased from 8837 U/h in the 2-gene to 1354 U/h in the 6-gene group (p = .047). Platelet sequestration tended to be delayed in the 6-gene group (p = .070), while thromboxane B2 (TXB2, a platelet activation marker) levels were lower over the first hour (p = .044) (401 ± 124 vs. 2048 ± 712 at 60 min). Thrombin production as measured by F1+2 levels tended to be lower in the 6-gene group (p = .058). Conclusions: The combination of the hEPCR.hTBM.hCD47.hHO-1 cassette along with donor pig DDAVP and clodronate liposome pretreatment was associated with prolonged function of xenoperfused livers, reduced coagulation pathway perturbations, and decreased TXB2 elaboration, and reflects significant progress to modulate liver xenograft injury in a pig to human model.
MeSH term(s)	Animals ; Animals, Genetically Modified ; Clodronic Acid/pharmacology ; Deamino Arginine Vasopressin ; Graft Survival ; Heme Oxygenase-1/genetics ; Humans ; Inflammation ; Liver ; Perfusion ; Swine ; Thrombocytopenia ; Transplantation, Heterologous
Chemical Substances	Clodronic Acid (0813BZ6866) ; Heme Oxygenase-1 (EC 1.14.14.18) ; Deamino Arginine Vasopressin (ENR1LLB0FP)
Language	English
Publishing date	2022-02-15
Publishing country	Denmark
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1236298-0
ISSN	1399-3089 ; 0908-665X
ISSN (online)	1399-3089
ISSN	0908-665X
DOI	10.1111/xen.12731
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