Transgenic swine lungs expressing human CD59 are protected from injury in a pig-to-human model of xenotransplantation.
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) H(2)O and 4.11 +/- 2.84 mL. cm(-2) H(2)O, 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.
Kulick
D M
DM
Department of Surgery, University of Minnesota, Minneapolis 55455, USA. kuli0004@tc.umn.edu
Salerno
C T
CT
Dalmasso
A P
AP
Park
S J
SJ
Paz
M G
MG
Fodor
W L
WL
Bolman
R M
RM
D000818:Animals; D018957:CD59 Antigens / Q000032:analysis*; D015926:Complement C3a / Q000032:analysis; D015941:Complement Hemolytic Activity Assay; D005455:Fluorescent Antibody Technique; D006085:Graft Survival / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D066298:In Vitro Techniques; D008168:Lung / Q000276:immunology / Q000473:pathology; D008170:Lung Compliance; D016040:Lung Transplantation / Q000276:immunology*; D011652:Pulmonary Circulation; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*; D014655:Vascular Resistance
D018957:CD59 Antigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D015926:Complement C3a