Removal of primate xenoreactive natural antibodies by extracorporeal perfusion of pig kidneys and livers

Azimzadeh, Agnes M.; Meyer, C; Watier, Hervé; Beller, J.P.; Chenard-Neu, Marie-Pierre; Kiény, R; Boudjéma, Karim; Jaeck, Daniel; Cinqualbre, J; Wolf, P

doi:10.1016/s0966-3274(98)80030-0

Cited by 32 publications

(24 citation statements)

References 33 publications

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“…Blocking antibody interaction with the graft, through removal of the recipient's antibodies by immunoabsorption or plasmapheresis [4,5] or by overloading the recipient's antigen binding capacity with decoy carbohydrates [6], usually prevents the initial graft-specific insult. A second general approach, used either as an alternative to or as an adjunct to antibody-directed approaches, involves abrogating the main pathogenic consequence of binding of anti-pig antibody to the endothelial surface: classical pathway complement activation.…”

Section: Pathogenesis Of Hyperacute Rejectionmentioning

confidence: 99%

“…Further, antibodies of other isotype classes (particularly complement-fixing IgM, but also IgA and IgE) are not depleted, and could certainly contribute to tissue injury by various well-described mechanisms. Perfusion of pig organs (kidney, liver, lung, spleen) specifically removes anti-pig natural antibodies in various models [5,[10][11][12][13]. 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].…”

Section: Strategies To Deplete Anti-pig Antibodiesmentioning

confidence: 99%

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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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Section: Pathogenesis Of Hyperacute Rejectionmentioning

confidence: 99%

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 vascular resistance, calculated as percent of the vascular resistance value at 1 min (Fig. lB), of the kidneys perfused with human blood supplemented with G a l a l 3 G a l and Galal-2Gal were 1 (Table 1) in the lactose and control groups showed a distinct decrease and was less than 1 ml/min x 100 8-l kidney tissue at 30min. The Galal-3Gal and Galal-2Gal groups showed a stable level of urine production of 3.0 and 3.7 mlimin x 100 g-' at 30 rnin (Table 1).…”

Section: Renal Blood Flow Vascular Resistance and Urine Productionmentioning

confidence: 98%

Blocking of human anti-pig xenoantibodies by soluble GALα1-3GAL and Galα1-2GAL disaccharides; studies in a pig kidney in vitro perfusion model

Magnusson¹,

Strokan²,

Mölne³

et al. 2000

Transplant Int

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Depletion of anti‐pig xenoantibodies reduces cell cytotoxicity of human serum to pig endothelial cells and lymphocytes. The aim of this study was to test, in a pig kidney xenoperfusion model, the ability of soluble αGal terminated disaccharides to prevent the hyperacute rejection process in an organ. Porcine kidneys were perfused with whole human blood lacking saccharide and blood supplemented with Galα1‐3GAL, Galα1‐2Gal and lactose. Parameters evaluated were, urine production, renal blood flow, vascular resistance, renal clearance, blood cell counts, xenoantibody titers, complement activation and histopathology. The blood flow was higher in the Galα1‐3Gal (155 ± 31 ml/min × 100 g‐1 kidney tissue) group compared to Galα1‐2Gal (138 ± 16), lactose (92 ± 78) and controls (69 ± 16). When calculated as percent of the blood flow value at 1 min, the blood flow at 30 min was 157% for the Galα‐3Gal and for 187% the Galα1‐2Gal. The corresponding values for the lactose and control groups were 102% and 74%, respectively. Urine production in the lactose/control groups was lower (0.7 ml/min × 100 g‐1 kidney tissue) compared to Galα1‐3Gal (3.0) and Galα1‐2Gal (3.7). Urine sodium excretion was reduced in the lactose/control groups, compared to the Galααl ‐ groups during the perfusions. An increase in urine potassium excretion was found in the Galαα1‐groups while a reduction occurred in the lactose/control experiments. An initial 40–50% reduction in platelet count was observed in all groups while the leukocyte count showed a continuous decrease. Immunohistochemistry revealed less deposition of IgM, IgG, C3 and C1 q in the Galαα1‐saccharide groups compared to the lactose/control groups. Soluble Galαa1‐disaccharides improved both functional and histological parameters. However, significant pathological changes were still present indicating that this approach to inhibit HAR must be used in combination with additional therapeutic approaches such as solid phase xenoantibody immunoadsorption and blocking of complement activation.

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“…Unfortunately, anti-gal returns to normal levels within a few days 18 . Attempts have been made to prevent the anti-gal response through the use of a a-gal toxin 19 to eliminate the plasma cells capable of producing this antibody.…”

Section: Prevention Of the Anti-gal Response In Recipientsmentioning

confidence: 99%

Xenotransplantation: where are we today?

Dooldeniya

Warrens

2003

JRSM

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Removal of primate xenoreactive natural antibodies by extracorporeal perfusion of pig kidneys and livers

Cited by 32 publications

References 33 publications

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

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

Blocking of human anti-pig xenoantibodies by soluble GALα1-3GAL and Galα1-2GAL disaccharides; studies in a pig kidney in vitro perfusion model

Xenotransplantation: where are we today?

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