Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Low molecular weight dextran sulfate prevents complement activation and delays hyperacute rejection in pig‐to‐human xenotransplantation models

Low molecular weight dextran sulfate prevents complement activation and delays hyperacute... Abstract: Dextran sulfate of 5000 molecular weight (DXS 5000) is known to block complement activation as well as the intrinsic coagulation cascade by potentiation of C1 inhibitor. The effect of DXS 5000 on hyperacute rejection (HAR) was tested in pig‐to‐human xenotransplantation models. For in vitro testing, a cytotoxicity assay was used with the pig kidney cell line PK15 as target cells and fresh, undiluted human serum as antibody and complement source. Ex vivo pig lung perfusion was chosen to assess DXS 5000 in a physiologic model. Pig lungs were perfused with fresh, citrate‐anticoagulated whole human blood to which 1 or 2 mg/ml DXS 5000 were added; the lungs were ventilated and the blood de‐oxygenated. Pulmonary vascular resistance (PVR) and blood oxygenation (ΔpO2) were monitored throughout the experiment. Autologous pig blood and human blood without DXS 5000 served as controls. In the PK15 assay DXS 5000 led to a complete, dose‐dependent inhibition of human serum cytotoxicity with an average IC50 of 43 ± 18 µg/ml (n = 8). Pig lungs perfused with untreated human blood (n = 2) underwent HAR within 105 ± 64 min, characterized by increased PVR, decrease of ΔpO2, and generalized edema. Microscopically, capillary bleeding as well as deposition of human antibodies, complement and fibrin could be observed. Addition of DXS 5000 (n = 4) prolonged lung survival to 170 ± 14 min for 1 mg/ml and 250 ± 42 min for 2 mg/ml, and PVR values as well as edema formation were comparable to control lungs that were perfused with autologous pig blood (n = 2). Activation of complement (activation products in serum, deposition on lung tissue) and the coagulation system (fibrin monomers) were significantly diminished as compared to human blood without DXS 5000. Binding of anti‐Gal antibodies was not influenced, and in vitro experiments showed no evidence of complement depletion by DXS 5000. In conclusion, DXS 5000 is an efficient complement inhibitor in pig‐to‐human xenotransplantation models and therefore a candidate for complement‐inhibitory/anti‐inflammatory therapy – either alone or in combination with other substances – and warrants further investigation. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Xenotransplantation Wiley

Low molecular weight dextran sulfate prevents complement activation and delays hyperacute rejection in pig‐to‐human xenotransplantation models

Download PDF
12 pages

Loading next page...
 
/lp/wiley/low-molecular-weight-dextran-sulfate-prevents-complement-activation-jhxG8vEbiE

References (36)

Publisher
Wiley
Copyright
Copyright © 2001 Wiley Subscription Services, Inc., A Wiley Company
ISSN
0908-665X
eISSN
1399-3089
DOI
10.1046/j.0908-665X.2000.00088.x
Publisher site
See Article on Publisher Site

Abstract

Abstract: Dextran sulfate of 5000 molecular weight (DXS 5000) is known to block complement activation as well as the intrinsic coagulation cascade by potentiation of C1 inhibitor. The effect of DXS 5000 on hyperacute rejection (HAR) was tested in pig‐to‐human xenotransplantation models. For in vitro testing, a cytotoxicity assay was used with the pig kidney cell line PK15 as target cells and fresh, undiluted human serum as antibody and complement source. Ex vivo pig lung perfusion was chosen to assess DXS 5000 in a physiologic model. Pig lungs were perfused with fresh, citrate‐anticoagulated whole human blood to which 1 or 2 mg/ml DXS 5000 were added; the lungs were ventilated and the blood de‐oxygenated. Pulmonary vascular resistance (PVR) and blood oxygenation (ΔpO2) were monitored throughout the experiment. Autologous pig blood and human blood without DXS 5000 served as controls. In the PK15 assay DXS 5000 led to a complete, dose‐dependent inhibition of human serum cytotoxicity with an average IC50 of 43 ± 18 µg/ml (n = 8). Pig lungs perfused with untreated human blood (n = 2) underwent HAR within 105 ± 64 min, characterized by increased PVR, decrease of ΔpO2, and generalized edema. Microscopically, capillary bleeding as well as deposition of human antibodies, complement and fibrin could be observed. Addition of DXS 5000 (n = 4) prolonged lung survival to 170 ± 14 min for 1 mg/ml and 250 ± 42 min for 2 mg/ml, and PVR values as well as edema formation were comparable to control lungs that were perfused with autologous pig blood (n = 2). Activation of complement (activation products in serum, deposition on lung tissue) and the coagulation system (fibrin monomers) were significantly diminished as compared to human blood without DXS 5000. Binding of anti‐Gal antibodies was not influenced, and in vitro experiments showed no evidence of complement depletion by DXS 5000. In conclusion, DXS 5000 is an efficient complement inhibitor in pig‐to‐human xenotransplantation models and therefore a candidate for complement‐inhibitory/anti‐inflammatory therapy – either alone or in combination with other substances – and warrants further investigation.

Journal

Xenotransplantation – Wiley

Published: Feb 1, 2001

There are no references for this article.