Endothelial cell protection by dextran sulfate: a novel strategy to prevent acute vascular rejection in xenotransplantation

Am J Transplant. 2004 Feb;4(2):181-7. doi: 10.1046/j.1600-6143.2003.00306.x.

Abstract

We showed recently that low molecular weight dextran sulfate (DXS) acts as an endothelial cell (EC) protectant and prevents human complement- and NK cell-mediated 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Heterophile / blood
  • Cricetinae
  • Cyclosporine / therapeutic use
  • Dextran Sulfate / therapeutic use*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / transplantation*
  • Graft Survival / drug effects*
  • Heart Transplantation / immunology*
  • Immunosuppression
  • Male
  • Mesocricetus
  • Rats
  • Rats, Inbred Lew
  • Transplantation, Heterologous / physiology*

Substances

  • Antibodies, Heterophile
  • Cyclosporine
  • Dextran Sulfate