Expression of a functional human complement inhibitor in a transgenic pig as a model for the prevention of xenogeneic hyperacute organ rejection

William L. Fodor, Barry L. Williams, Louis A. Matis, Joseph A. Madri, Scott A. Rollins, James W. Knight, William H Velander, Stephen P. Squnito

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Abstract

The serious shortage of human organs available for transplantation has engendered a heightened interest in the use of animal organs (xenografts) for transplantation. However, the major barrier to successful discordant xenogeneic organ transplantation is the phenomenon of hyperacute rejection. Hyperacute rejection results from the deposition of high-titer preformed antibodies that activate serum complement on the luminal surface of the vascular endothelium, leading to vessel occlusion and graft failure within minutes to hours. Although endogenous membrane-associated complement inhibitors normally protect endothelial cells from autologous complement, they are species restricted and thus confer limited resistance to activated xenogeneic complement. To address the pathogenesis of hyperacute rejection in xenotransplantation, transgenic mice and a transgenic pig were engineered to express the human terminal complement inhibitor hCD59. High-level cell surface expression of hCD59 was achieved in a variety of murine and porcine cell types, most importantly on both large vessel and capillary endothelium. hCD59-expressing porcine cells were significantly resistant to challenge with high-titer anti-porcine antibody and human complement. These experiments demonstrate a strategy for developing a pig-to-primate xenogeneic transplantation model to test whether the expression of a human complement inhibitor in transgenic pigs could render xenogeneic organs resistant to hyperacute rejection.

Original languageEnglish (US)
Pages (from-to)11153-11157
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number23
DOIs
StatePublished - Nov 8 1994

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Complement Inactivating Agents
Swine
Organ Transplantation
Heterologous Transplantation
Vascular Endothelium
Animal Structures
Primates
Transgenic Mice
Anti-Idiotypic Antibodies
Endothelial Cells
Transplantation
Transplants

ASJC Scopus subject areas

  • General

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Expression of a functional human complement inhibitor in a transgenic pig as a model for the prevention of xenogeneic hyperacute organ rejection. / Fodor, William L.; Williams, Barry L.; Matis, Louis A.; Madri, Joseph A.; Rollins, Scott A.; Knight, James W.; Velander, William H; Squnito, Stephen P.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 91, No. 23, 08.11.1994, p. 11153-11157.

Research output: Contribution to journalArticle

Fodor, William L. ; Williams, Barry L. ; Matis, Louis A. ; Madri, Joseph A. ; Rollins, Scott A. ; Knight, James W. ; Velander, William H ; Squnito, Stephen P. / Expression of a functional human complement inhibitor in a transgenic pig as a model for the prevention of xenogeneic hyperacute organ rejection. In: Proceedings of the National Academy of Sciences of the United States of America. 1994 ; Vol. 91, No. 23. pp. 11153-11157.
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