Use of Von Willebrand Diseased Kidney as Donor in a Pig-to-Primate Model of Xenotransplantation1

Meyer, C; Wolf, P; Romain, Nathalie; Ravanat, Catherine; Roussi, J; Beller, J.P.; Imbs, Pierre; Chenard, Marie–Pierre; Fabre, M; Kiény, R; Bonneau, Michel; Drouet, Ludovic; Cazenave, Jean‐Pierre; Soulillou, Jean‐Paul; Azimzadeh, Agnes M.

doi:10.1097/00007890-199901150-00006

Cited by 31 publications

(24 citation statements)

References 20 publications

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“…Finally, expression of the HLA-E transgene appears to limit endothelial damage by preventing NK-cell activation and resulting cytotoxicity (52–53). As deletion of vWF results in a pig with high risk of bleeding (54), current efforts seek to replace key segments of pvWF with the analogous human vWF epitope (38). We monitor platelet and neutrophil sequestration and activation, and thrombin, thromboxane, and histamine generation, as well as lung survival or pulmonary vascular resistance; we find that each of the genetic modifications discussed here is associated with some improvement in one or more of these parameters (47).…”

Section: Text Of Reviewmentioning

confidence: 99%

Lung xenotransplantation

Laird

Burdorf

Pierson

2016

Current Opinion in Organ Transplantation

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Purpose-To review recent progress in the field of lung xenotransplantation, including mechanisms of xenograft injury, and the influence of mechanism-directed genetic modifications and other interventions that may soon enable therapeutic use of pig lungs in humans.Recent findings-An extensive series of lung xenotransplantation experiments demonstrates that multiple genetic modifications targeting known xenogeneic lung injury mechanisms are associated with incremental improvements in lung survival or function. Addition of human complement (hCD46, hCD55), coagulation (hEPCR, hTBM, hTFPI, hCD39), or antiinflammatory pathway regulatory genes (HO-1, HLA-E), and GalT and Neu5Gc gene knockout has each demonstrated protective effects on lung survival or function. In addition, drug treatments targeting key inflammatory and clotting pathways have been shown to attenuate residual mechanisms of lung injury. 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 soon be feasible.Summary-Genetic modification of pigs coupled with drugs targeting complement activation, coagulation, and inflammation have significantly increased duration of pig lung function in ex vivo human blood perfusion models, and life supporting lung xenograft survival in vivo .

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Section: Text Of Reviewmentioning

confidence: 99%

Lung xenotransplantation

Laird

Burdorf

Pierson

2016

Current Opinion in Organ Transplantation

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“…Transient loss of blood volume can be attenuated by various technical strategies, and depletion of neutrophils and platelets can be minimized by blood separation before adsorption, followed by perfusion of the organ with recipient plasma instead of whole blood [14]. However, complete depletion of antibodies in vivo is difficult, and furthermore often results in activation of the complement and coagulation cascades [15], a logical consequence of the approach since the perfused organ is "rejected" unless special precautions are taken (hypothermia, complement inhibition through calcium chelation, for example).…”

Section: Strategies To Deplete Anti-pig Antibodiesmentioning

confidence: 99%

Beyond Antibody-Mediated Rejection: Hyperacute Lung Rejection as a Paradigm for Dysregulated Inflammation

Nguyen¹,

Zwets²,

Schroeder³

et al. 2005

CDTCHD

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The use of animal organs for transplantation in humans is seen as a potential solution to the short supply of human donor organs available for clinical transplantation. However, to develop this therapeutic option as clinical reality will require surmounting formidable obstacles. The primary immunologic barrier to pig-to-human xenotransplantation is hyperacute rejection (HAR), a phenomenon previously characterized as resulting from antibody binding and complement activation. This article will first review recent progress in the development of specific strategies to overcome hyperacute lung rejection (HALR), through production of genetically engineered pig organs, modification of the host innate immunity and control of antibody and complement. Additional therapeutic targets identified in HALR are reviewed, with particular emphasis on recent studies describing a critical role for the coagulation cascade in HAR.

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“…However, most of these procedures failed to control the first step of thrombosis, which is platelet adhesion to endothelial cells. In vivo and at high shear rates, the initial binding of platelets to the damaged endothelium is thought mainly due to the interaction of GPIb with vWF [3]. Therefore, the binding of GPIb with vWF represents a therapeutic target for preventing platelet adhesion to endothelium and subsequently controlling the microthrombi formation and prolonging the xenografts survival.…”

Section: Discussionmentioning

confidence: 99%

TMVA, a novel GPIb‐binding protein, significantly prevents platelet microthrombi formation and prolongs discordant cardiac xenograft survival

Chen

Wei

Wang

et al. 2004

Xenotransplantation

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In xenotransplantation, donor endothelium is the first target of immunological attack. Activation of the endothelial cell by preformed natural antibodies leads to platelet binding via the interaction of the glycoprotein (GP) Ib and von Willebrand factor (vWF). TMVA is a novel GPIb-binding protein purified from the venom of Trimeresurus mucrosquamatus. In this study, the inhibitory effect of TMVA on platelet aggregation in rats and the effect on discordant guinea pig-to-rat cardiac xenograft survival were investigated. Three doses (8, 20 or 40 microg/kg) of TMVA were infused intravenously to 30 rats respectively. Platelet aggregation rate was assayed 0.5, 12, and 24 h after TMVA administration. Wister rats underwent guinea pig cardiac cervical heterotopic transplantation using single dosing of TMVA (20 microg/kg, i.v., 0.5 h before reperfusion). Additionally, levels of TXB(2) and 6-keto-PGF(1alpha) within rejected graft tissues were determined by radioimmunoassay. Treatment with TMVA at a dose of 20 or 40 microg/kg resulted in complete inhibition of platelet aggregation 0.5 h after TMVA administration. Rats receiving guinea pig cardiac xenografts after TMVA therapy had significantly prolonged xenograft survival. Histologic and immunopathologic analysis of cardiac xenografts in TMVA treatment group showed no intragraft platelet microthrombi formation and fibrin deposition. Additionally, the ratio of 6-keto-PGF(1alpha) to TXB(2) in TMVA treatment group was significantly higher than those in control group. We conclude that the use of this novel GPIb-binding protein was very effective in preventing platelet microthrombi formation and fibrin deposition in a guinea pig-to-rat model and resulted in prolongation of xenograft survival. The increased ratio of PGI(2)/TXA(2) in TMVA treatment group may protect xenografts from the endothelial cell activation and contribute to the prolongation of xenograft survival.

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Use of Von Willebrand Diseased Kidney as Donor in a Pig-to-Primate Model of Xenotransplantation1

Cited by 31 publications

References 20 publications

Lung xenotransplantation

Lung xenotransplantation

Beyond Antibody-Mediated Rejection: Hyperacute Lung Rejection as a Paradigm for Dysregulated Inflammation

TMVA, a novel GPIb‐binding protein, significantly prevents platelet microthrombi formation and prolongs discordant cardiac xenograft survival

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