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J Thorac Cardiovasc Surg 2000;119:690-699
© 2000 The American Association for Thoracic Surgery

CARDIOTHORACIC TRANSPLANTATION

TRANSGENIC SWINE LUNGS EXPRESSING HUMAN CD59 ARE PROTECTED FROM INJURY IN A PIG-TO-HUMAN MODEL OF XENOTRANSPLANTATION

From the Departments of Surgery^a and Laboratory Medicine and Pathology,^b University of Minnesota, Minneapolis, the Veterans Affairs Medical Center,^c Minneapolis, Minn, and Alexion Pharmaceuticals,^d New Haven, Conn.

Supported by the US Department of Commerce, National Institute of Standards and Technology/Advanced Technology Program Cooperative Agreement, DVA Medical Research, and the Minnesota Medical Foundation.

Address for reprints: David M. Kulick, MD, University of Minnesota, Department of Surgery, UMHC Box 1, 420 Delaware St SE, Minneapolis, MN 55455 (E-mail: kuli0004{at}tc.umn.edu ).

Background: Pulmonary xenotransplantation is currently limited by hyperacute rejection mediated in part by xenoreactive natural antibody and complement. Transgenic swine organs that express the human complement regulatory protein CD59 have demonstrated improved survival in models of pig-to-primate xenotransplantation.
Objective: The purpose of this study was to evaluate transgenic swine lungs that express the human complement regulatory protein CD59 in a model of pig-to-human xenotransplantation.
Methods: Transgenic swine lungs (n = 5, experimental group) and outbred swine lungs (n = 6, control group) were perfused with fresh, whole human blood through a centrifugal pump on an ex vivo circuit. Functional data were collected throughout perfusion. Immunoglobulin and complement studies were performed on perfusate samples, and both histologic and immunofluorescent analyses were performed on tissue sections.
Results: Mean lung survival for the experimental group was increased when compared with controls, 240 ± 0 minutes versus 35.3 ± 14.5 minutes, respectively, with a P value of less than .01. A decreased rise in pulmonary vascular resistance at 15 minutes was observed in the experimental group (343 ± 87 mm Hg · L^–1 · min^–1, in contrast to the control group (1579 ± 722 mm Hg · L^–1 · min^–1; P < .01). Pulmonary compliance at 15 minutes was improved for the experimental group versus control group (9.31 ± 1.41 mL · cm^–2 H₂O and 4.11 ± 2.84 mL · cm^–2 H₂O, respectively; P < .01). SC5b-9 generation in the plasma perfusate was delayed for the experimental group versus the control group. Immunofluorescent examination of tissue sections demonstrated equivalent deposition of immunoglobulin G, immunoglobulin M, C1q, and C3 in both groups, with reduced deposition of C9 in the experimental group.
Conclusions: Transgenic swine pulmonary xenografts that express the human complement regulatory protein CD59 demonstrated improved function and survival in an ex vivo model of pig-to-human xenotransplantation.

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