Life-supporting function of genetically modified swine lungs in baboons
Journal of Thoracic and Cardiovascular Surgery
Objective: During ex vivo perfusion with human blood, homozygous galactosyl transferase knockout swine lungs exhibit prolonged survival (∼2 hours) relative to wild-type (<15 minutes) and swine lungs expressing human decay accelerating factor (<1 hour). In this study, the in vivo behavior of galactosyl transferase knockout lungs was evaluated. Methods: Three galactosyl transferase knockout swine left lungs were transplanted into baboons in a life-supporting model. One baboon lung allograft and two swine lung xenografts transgenic for human membrane cofactor protein (CD46) served as controls. Results: Whereas two membrane cofactor protein lungs exhibited high pulmonary vascular resistance (>500 mm Hg · min/L) and failed to support life within 21 minutes, two of three galactosyl transferase knockout lungs supported life, for 90 and 215 minutes, and displayed low peripheral vascular resistance (48 ± 12 mm Hg · min/L at 60 minutes), similar to the allogeneic control. Complement activation (delta C3a < 250 ng/mL through 60 minutes) and C5b-9 deposition were minimal in both galactosyl transferase knockout and membrane cofactor protein lungs. Neutrophils, monocytes, and platelets were rapidly sequestered in galactosyl transferase knockout and human membrane cofactor protein lung recipients, unlike the allogeneic control (<20%); and thrombin formation (delta plasma fraction 1+2 > 0.5 nmol/L) was seen in the galactosyl transferase knockout recipients. Platelet activation (β-thromboglobulin rise > 200) and appearance of capillary congestion and vessel thrombosis confirmed coagulation activation associated with galactosyl transferase knockout lung failure. Conclusions: Galactosyl transferase knockout swine lungs are significantly protected in vivo from the physiologic consequences (increased pulmonary vascular resistance, capillary leak) associated with hyperacute lung rejection. As during ex vivo perfusion, dysregulated coagulation-thrombin elaboration, platelet activation, and intravascular thrombosis-mediates galactosyl transferase knockout lung xenograft injury. © 2007 The American Association for Thoracic Surgery.
Nguyen, B., Azimzadeh, A., Zhang, T., Wu, G., Shuurman, H., Sachs, D., Ayares, D., Allan, J., & Pierson, R. (2007). Life-supporting function of genetically modified swine lungs in baboons. Journal of Thoracic and Cardiovascular Surgery, 133 (5). http://dx.doi.org/10.1016/j.jtcvs.2006.11.043