Abstract
Background: Galactosyl transferase gene knock-out (GalTKO) swine offer a unique tool to evaluate the role of the Gal antigen in xenogenic lung hyperacute rejection. Methods: We perfused GalTKO miniature swine lungs with human blood. Results were compared with those from previous studies using wild-type and human decay-accelerating factor-transgenic (hDAF+/+) pig lungs. Results: GalTKO lungs survived 132 ± 52 min compared to 10 ± 9 min for wild-type lungs (P = 0.001) and 45 ± 60 min for hDAF+/+ lungs (P = 0.18). GalTKO lungs displayed stable physiologic flow and pulmonary vascular resistance (PVR) until shortly before graft demise, similar to autologous perfusion, and unlike wild-type or hDAF+/+ lungs. Early (15 and 60 min) complement (C3a) and platelet activation and intrapulmonary platelet deposition were significantly diminished in GalTKO lungs relative to wild-type or hDAF+/+ lungs. However, GalTKO lungs adsorbed cytotoxic anti-non-Gal antibody and elaborated high levels of thrombin; their demise was associated with increased PVR, capillary congestion, intravascular thrombi and strong CD41 deposition not seen at earlier time points. Conclusions: In summary, GalTKO lungs are substantially protected from injury but, in addition to anti-non-Gal antibody and complement, platelet adhesion and non-physiologic intravascular coagulation contribute to Gal-independent lung injury mechanisms.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 94-107 |
| Number of pages | 14 |
| Journal | Xenotransplantation |
| Volume | 18 |
| Issue number | 2 |
| DOIs | |
| State | Published - Mar 1 2011 |
| Externally published | Yes |
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Keywords
- Xenotransplantation
- alphaGal
- antibodies
- ex vivo lung perfusion
- genetically engineered
- hyperacute rejection
- lung
- swine
ASJC Scopus subject areas
- Immunology
- Transplantation
Cite this
Absence of Gal epitope prolongs survival of swine lungs in an ex vivo model of hyperacute rejection. / Nguyen, Bao Ngoc H.; Azimzadeh, Agnes M.; Schroeder, Carsten; Buddensick, Thomas; Zhang, Tianshu; Laaris, Amal; Cochrane, Megan; Schuurman, Henk Jan; Sachs, David H.; Allan, James S.; Pierson, Richard N.
In: Xenotransplantation, Vol. 18, No. 2, 01.03.2011, p. 94-107.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Absence of Gal epitope prolongs survival of swine lungs in an ex vivo model of hyperacute rejection
AU - Nguyen, Bao Ngoc H.
AU - Azimzadeh, Agnes M.
AU - Schroeder, Carsten
AU - Buddensick, Thomas
AU - Zhang, Tianshu
AU - Laaris, Amal
AU - Cochrane, Megan
AU - Schuurman, Henk Jan
AU - Sachs, David H.
AU - Allan, James S.
AU - Pierson, Richard N.
PY - 2011/3/1
Y1 - 2011/3/1
N2 - Background: Galactosyl transferase gene knock-out (GalTKO) swine offer a unique tool to evaluate the role of the Gal antigen in xenogenic lung hyperacute rejection. Methods: We perfused GalTKO miniature swine lungs with human blood. Results were compared with those from previous studies using wild-type and human decay-accelerating factor-transgenic (hDAF+/+) pig lungs. Results: GalTKO lungs survived 132 ± 52 min compared to 10 ± 9 min for wild-type lungs (P = 0.001) and 45 ± 60 min for hDAF+/+ lungs (P = 0.18). GalTKO lungs displayed stable physiologic flow and pulmonary vascular resistance (PVR) until shortly before graft demise, similar to autologous perfusion, and unlike wild-type or hDAF+/+ lungs. Early (15 and 60 min) complement (C3a) and platelet activation and intrapulmonary platelet deposition were significantly diminished in GalTKO lungs relative to wild-type or hDAF+/+ lungs. However, GalTKO lungs adsorbed cytotoxic anti-non-Gal antibody and elaborated high levels of thrombin; their demise was associated with increased PVR, capillary congestion, intravascular thrombi and strong CD41 deposition not seen at earlier time points. Conclusions: In summary, GalTKO lungs are substantially protected from injury but, in addition to anti-non-Gal antibody and complement, platelet adhesion and non-physiologic intravascular coagulation contribute to Gal-independent lung injury mechanisms.
AB - Background: Galactosyl transferase gene knock-out (GalTKO) swine offer a unique tool to evaluate the role of the Gal antigen in xenogenic lung hyperacute rejection. Methods: We perfused GalTKO miniature swine lungs with human blood. Results were compared with those from previous studies using wild-type and human decay-accelerating factor-transgenic (hDAF+/+) pig lungs. Results: GalTKO lungs survived 132 ± 52 min compared to 10 ± 9 min for wild-type lungs (P = 0.001) and 45 ± 60 min for hDAF+/+ lungs (P = 0.18). GalTKO lungs displayed stable physiologic flow and pulmonary vascular resistance (PVR) until shortly before graft demise, similar to autologous perfusion, and unlike wild-type or hDAF+/+ lungs. Early (15 and 60 min) complement (C3a) and platelet activation and intrapulmonary platelet deposition were significantly diminished in GalTKO lungs relative to wild-type or hDAF+/+ lungs. However, GalTKO lungs adsorbed cytotoxic anti-non-Gal antibody and elaborated high levels of thrombin; their demise was associated with increased PVR, capillary congestion, intravascular thrombi and strong CD41 deposition not seen at earlier time points. Conclusions: In summary, GalTKO lungs are substantially protected from injury but, in addition to anti-non-Gal antibody and complement, platelet adhesion and non-physiologic intravascular coagulation contribute to Gal-independent lung injury mechanisms.
KW - Xenotransplantation
KW - alphaGal
KW - antibodies
KW - ex vivo lung perfusion
KW - genetically engineered
KW - hyperacute rejection
KW - lung
KW - swine
UR - http://www.scopus.com/inward/record.url?scp=79955029439&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79955029439&partnerID=8YFLogxK
U2 - 10.1111/j.1399-3089.2011.00633.x
DO - 10.1111/j.1399-3089.2011.00633.x
M3 - Article
C2 - 21496117
AN - SCOPUS:79955029439
VL - 18
SP - 94
EP - 107
JO - Xenotransplantation
JF - Xenotransplantation
SN - 0908-665X
IS - 2
ER -