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

Abstract

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.

The Complement Inhibitor Low Molecular Weight Dextran Sulfate Prevents TLR4-Induced Phenotypic and Functional Maturation of Human Dendritic Cells

“…It should be noted that the used concentrations of DXS did not affect viability and metabolic activity of the cells, which is consistent with previously published in vitro and in vivo observations in which concentrations up to 25 mg/ml were used (5,6). Recently, the maximum tolerated doses of DXS were determined in vivo in cynomolgus monkeys and i.v.…”

“…In addition, DXS has been shown to act as an endothelial cell protectant (3,4). It prevents human complement-and NK cell-mediated cytotoxicity in vitro (3) and, in combination with cyclosporin A, induces long-term graft survival in a hamster-to-rat cardiac xenotransplantation model in vivo (5). Moreover, DXS is very effective in protecting vasculature and tissue from ischemia/reperfusion injury, as recently shown in a porcine model of acute myocardial infarction (6).…”

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

“…DXS inhibits complement in vitro experiments using human serum and porcine cells (32). Similarly, DXS inhibited complement in vivo by preventing hamster cardiac xenografts from undergoing acute vascular rejection, and DXS in combination with cyclosporin A significantly prolonged xenograft survival rate (33). Taken together, we postulate that DXS ameliorated renal injury in our study by inhibiting the coagulation cascade and by inhibiting complement activation.…”

Recombinant IL-33 prolongs leflunomide-mediated graft survival by reducing IFN-γ and expanding CD4+Foxp3+ T cells in concordant heart transplantation

“…3 The combined use of IL-33 and Lef thus allowed us to study the impact of IL-33 on AVR. 13 Graft survival was determined in separate animals, and the activation and infiltration of immune cells were studied separately by flow cytometry. Furthermore, we report the novel observation that administering the combination of IL-33 and Lef to cardiac-transplanted rats also expanded suppressive CD4 + Foxp3 + Tregs while reducing Th1 responses and IFN-γ levels.…”