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Vaccinia virus complement control protein inhibits hyperacute xenorejection in a guinea pig-to-rat heterotopic cervical cardiac xenograft model by blocking both xenoantibody binding and complement pathway activation

Posted by on in 2003
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 Transplant Immunology, Volume 11, Issue 2 , April-June 2003, Pages 129-135
Jaime B. Anderson (a), Scott A. Smith (a), Rochelle van Wijk (b), Sufan Chien (c) and Girish J. Kotwal (a)(d)
(a) Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA
(b) Department of Anatomical Pathology, University of Cape Town, Cape Town, South Africa
(c) Department of Surgery, University of Louisville School of Medicine, Louisville, KY, USA
(d) Division of Medical Virology, University of Cape Town, Cape Town, South Africa
Received 24 April 2002; accepted 23 July 2002; Available online 11 September 2002.

Abstract

Vaccinia virus complement control protein (VCP) binds the activated third and fourth complement components and inhibits both alternative and classical pathways of activation. The ability of VCP to bind heparan sulfate allows the protein to attach itself to the cell surface, enabling it with many additional activities. Altogether, the many functions of VCP have been shown to suppress the inflammatory response of the host, helping the vaccinia virus to evade immune destruction. VCP has recently been shown to inhibit human anti-Gal 1-3 Gal antibody attachment to cultured porcine endothelial cells and reduce human neutrophil and NK killing of pig aortic endothelial cells through its ability to bind heparan sulfate. Here we demonstrate that in an in vivo guinea pig-to-rat heterotopic cervical cardiac xenograft model, recombinant VCP (rVCP) is able to block hyperacute xenograft rejection, significantly prolonging graft survival. Histopathological examination of transplanted hearts from rats receiving rVCP revealed a significant reduction in cardiac tissue damage as compared to control hearts. Finally, rVCP treated recipients demonstrated marked rVCP deposition on the endothelium and significantly less C3, IgG and IgM deposition in the tissue. rVCP is therefore able to inhibit hyperacute xenorejection by binding the endothelial surface, blocking complement fixation and activation, and preventing xenoantibody attachment.

Author Keywords: Hyperacute rejection; Vaccinia virus complement control protein; Complement; Xenotransplantation

Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; C4b-BP, C4b binding protein; CH50, complement hemolytic activity at 50%; DAF, decay accelerating factor; IV, intravenous; MCP, membrane cofactor protein; PAECs, pig aortic endothelial cells; sCR1, soluble complement receptor 1; VCP, vaccinia virus complement control protein.

Corresponding author. Tel.: +1-502-852-5359.

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