Dextran sulfate acts as an endothelial cell protectant and inhibits human complement and natural killer cell-mediated cytotoxicity against porcine cells

Laumonier, Thomas; Walpen, Alexander J; Maurus, Christine; Mohaçsi, Paul; Matozan, Katja; Korchagina, Elena; Bovin, Nicolai V.; Vanhove, Bernard; Seebach, Jörg Dieter; Rieben, Robert

doi:10.1097/01.tp.0000078898.28399.0a

Cited by 58 publications

(63 citation statements)

References 24 publications

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“…Repeated DXS injections did not induce systemic complement depletion, nor did they affect serum levels of anti-hamster Ab. However, we recently demonstrated that DXS acts as an EC protectant and prevents human complement-and NK cell-mediated cytotoxicity towards porcine cells in vitro (14). Here, we show binding of DXS-Fluo to the graft EC one day after cardiac xenotransplantation, supporting our hypothesis that DXS acts locally and might functionally replace HSPG that are known to be shed from the EC surface upon activation (13).…”

Section: Discussionsupporting

confidence: 84%

“…It was shown in vitro, that porcine EC pretreated with human anti-pig IgM became resistant over the next day to complement-mediated damage (28), and in the hamster-to-rat model Soares and coworkers hypothesized that the gradual exposure of the graft to increasing amount of anti-donor Ab could induce a protective phenotype of EC (29). We reported earlier that DXS does not inhibit human IgM deposition on porcine EC (14). Here, we show that DXS adhered to the activated xenograft endothelium and protected it from complement-mediated damage, but did not suppress Ab deposition and up-regulation of protective genes such as HO-1.…”

Section: Discussionmentioning

confidence: 99%

“…Two recipients received one single i.v. injection of fluorescein-labeled DXS (DXS-Fluo, 25 mg/kg, diluted in sterile PBS) (14) one day after surgery. These animals were killed for analysis of the grafts 15-20 min after injection of DXS-Fluo.…”

Section: Cardiac Xenotransplantationmentioning

confidence: 99%

“…Moreover, HSPG regulate multiple functions such as leukocyte-endothelial interactions and extravasation (12) and are rapidly released under conditions of inflammation and tissue damage (13). We showed recently that low molecular weight dextran sulfate (DXS) acts as an EC protectant and prevents human complement-and NK cellmediated cytotoxicity towards porcine cells in vitro (14). DXS is a sulfated, linear or slightly branched polysaccharide (15) and is known to inhibit all three pathways of complement activation.…”

Section: Introductionmentioning

confidence: 99%

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Endothelial Cell Protection by Dextran Sulfate: A Novel Strategy to Prevent Acute Vascular Rejection in Xenotransplantation

Laumonier¹,

Mohaçsi²,

Matozan³

et al. 2004

American Journal of Transplantation

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We showed recently that low molecular weight dextran sulfate (DXS) acts as an endothelial cell (EC) protectant and prevents human complement-and NK cellmediated cytotoxicity towards porcine cells in vitro. We therefore hypothesized that DXS, combined with cyclosporine A (CyA), could prevent acute vascular rejection (AVR) in the hamster-to-rat cardiac xenotransplantation model. Untreated, CyA-only, and DXS-only treated rats rejected their grafts within 4-5 days. Of the hearts grafted into rats receiving DXS in combination with CyA, 28% survived more than 30 days. Deposition of anti-hamster antibodies and complement was detected in long-term surviving grafts. Combined with the expression of hemoxygenase 1 (HO-1) on graft EC, these results indicate that accommodation had occurred. Complement activity was normal in rat sera after DXS injection, and while systemic inhibition of the coagulation cascade was observed 1 h after DXS injection, it was absent after 24 h. Moreover, using a fluorescein-labeled DXS (DXS-Fluo) injected 1 day after surgery, we observed a specific binding of DXS-Fluo to the xenograft endothelium. In conclusion, we show here that DXS + + CyA induces long-term xenograft survival and we provide evidence that DXS might act as a local EC protectant also in vivo.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Cardiac Xenotransplantationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Endothelial Cell Protection by Dextran Sulfate: A Novel Strategy to Prevent Acute Vascular Rejection in Xenotransplantation

Laumonier¹,

Mohaçsi²,

Matozan³

et al. 2004

American Journal of Transplantation

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“…Indeed, our results show that glomerular C3 staining was reduced in the DXS group compared with control. Studies have shown that DXS inhibits all three pathways of complement activation and dose-dependently protected pig cells from deposition of human complement, and the EC-protective effect of DXS correlated with binding of the substance to the cells (30). Complement-mediated EC activation and damage have also been demonstrated in the pathophysiology of acute vascular rejection in xenotransplantation (31).…”

Section: Discussionmentioning

confidence: 97%

Protection of Endothelial Cells by Dextran Sulfate in Rats with Thrombotic Microangiopathy

Eto

Kojima

Uesugi

et al. 2005

Journal of the American Society of Nephrology

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The characteristic features of thrombotic microangiopathy (TMA) include glomerular and peritubular capillary endothelial cell injury in association with loss of heparan sulfate proteoglycans on the cell surface and thrombus formation, followed by subsequent ischemic tubulointerstitial damage. It therefore was hypothesized that dextran sulfate (DXS) may protect the kidney against endothelial damage in a model of TMA. TMA was induced in rats by renal artery perfusion of an antiglomerular endothelial antibody, followed by the administration of DXS or vehicle. Renal damage was assessed by histologic analysis and measurements of blood urea nitrogen and creatinine. Whereas control rats developed severe renal failure with extensive glomerular and tubular injury, administration of DXS significantly protected renal function and preserved the glomerular endothelium and peritubular capillaries. The beneficial effect of DXS could be attributed to the ability of DXS to protect endothelial cells from coagulation and complement activation, as demonstrated by the histologic analysis. In addition, binding of the administered DXS to the surface of the glomerular endothelium was confirmed in TMA rats, suggesting that DXS acts as a "repair coat" of injured glomerular endothelium. In conclusion, DXS protects the kidney from experimental TMA. This protection may be mediated by DXS's binding directly to the surface of glomerular endothelium and amelioration of coagulation, complement activation, and cellular matrix loss.

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Development of a bead‐based multiplex assay for the simultaneous detection of porcine inflammation markers using xMAP technology

et al. 2013

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Commercially available assays for the simultaneous detection of multiple inflammatory and cardiac markers in porcine blood samples are currently lacking. Therefore, this study was aimed at developing a bead-based, multiplexed flow cytometric assay to simultaneously detect porcine cytokines [interleukin (IL)-1b, IL-6, IL-10, and tumor necrosis factor alpha], chemokines (IL-8 and monocyte chemotactic protein 1), growth factors [basic fibroblast growth factor (bFGF), vascular endothelial growth factor, and platelet-derived growth factor-bb], and injury markers (cardiac troponin-I) as well as complement activation markers (C5a and sC5b-9). The method was based on the Luminex xMAP technology, resulting in the assembly of a 6-and 11-plex from the respective individual singleplex situation. The assay was evaluated for dynamic range, sensitivity, cross-reactivity, intra-assay and interassay variance, spike recovery, and correlation between multiplex and commercially available enzyme-linked immunosorbent assay as well as the respective singleplex. The limit of detection ranged from 2.5 to 30,000 pg/ml for all analytes (6-and 11-plex assays), except for soluble C5b-9 with a detection range of 2-10,000 ng/ml (11-plex). Typically, very low cross-reactivity (\3% and \1.4% by 11-and 6-plex, respectively) between analytes was found. Intra-assay variances ranged from 4.9 to 7.4% (6-plex) and 5.3 to 12.9% (11-plex). Interassay variances for cytokines were between 8.1 and 28.8% (6-plex) and 10.1 and 26.4% (11-plex). Correlation coefficients with singleplex assays for 6-plex as well as for 11-plex were high, ranging from 0.988 to 0.997 and 0.913 to 0.999, respectively. In this study, a bead-based porcine 11-plex and 6-plex assay with a good assay sensitivity, broad dynamic range, and low intra-assay variance and cross-reactivity was established. These assays therefore represent a new, useful tool for the analysis of samples generated from experiments with pigs. ' 2013 International Society for Advancement of Cytometry

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Dextran sulfate acts as an endothelial cell protectant and inhibits human complement and natural killer cell-mediated cytotoxicity against porcine cells

Abstract: DXS binds to porcine cells and protects them from complement- and NK cell-mediated injury in vitro. It might therefore be used as a novel therapeutic strategy to prevent xenograft rejection and has potential for clinical application as an "EC protectant."

Cited by 58 publications

References 24 publications

Endothelial Cell Protection by Dextran Sulfate: A Novel Strategy to Prevent Acute Vascular Rejection in Xenotransplantation

Endothelial Cell Protection by Dextran Sulfate: A Novel Strategy to Prevent Acute Vascular Rejection in Xenotransplantation

Protection of Endothelial Cells by Dextran Sulfate in Rats with Thrombotic Microangiopathy

Development of a bead‐based multiplex assay for the simultaneous detection of porcine inflammation markers using xMAP technology

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