Assistant Professor of Surgery
University of Maryland
N-Glycolylneuraminic acid (Neu5Gc) knock-out in GalTKO.hCD46 pig lungs improves pulmonary function in a xenogeneic pig-to-human lung perfusion model
Lars Burdorf1, Franchesca Ali1, Jagdeece Ramsoondar2, Siamak Dahi1, Natalia Kubicki1, Tianshu Zhang1, Dawn Parsell1, Beth French1, Evan Schwartz1, Xiangfei Cheng1, Evelyn Sievert1, Elizabeth Kang1, Gheorghe Braileanu1, Nan Cheng1, Carol J Phelps2, David L Ayares2, Agnes M Azimzadeh1, Richard N Pierson III1.
1Department of Surgery, University of Maryland, Baltimore, MD, United States; 2Revivicor, Inc., Blacksburg, VA, United States
Background: Due to a gene mutation, humans cannot synthesize the Neu5Gc form of sialic acid. Anti-Neu5Gc antibodies are often found in human sera, and have been associated with xeno-inflammation. Here we describe effects associated with a Neu5Gc knock-out in GalTKO.hCD46 lungs in an ex vivo perfusion model.
Methods: 5 GalTKO.hCD46.Neu5GcKO pig lungs were perfused for 6h with fresh heparinized human blood. 7 GalTKO.hCD46 lungs without additional KO served as a reference. Functional parameters as well as blood and tissue samples were collected at pre-defined time points. Plasma cytokines and inflammatory markers were measured by Luminex.
Results: All Neu5GcKO organs kept adequate blood oxygenation and “survived” until elective termination whereas one of the “reference” lungs failed prior to the 4h time point. An immediate temporary drop in platelet counts at the 5 min time point in both study groups recovered to more than 90% of pre-perfusion baseline after 4 hours in the Neu5GcKO group, but to only about 60% in the reference group (p=0.017). Thromboxane (TBX) elaboration was significantly lower with additional Neu5GcKO (e.g. 51.9 vs. 14.1 ng/ml at 4h; p=0.004). Pulmonary vascular resistance (PVR) rise was significantly attenuated in GalTKO.hCD46. Neu5GcKO lungs (e.g. 75±9 vs. 279±58 mmHg*min/L at 4h). MCP-1, ELA2, and LTF levels were blunted in Neu5GcKO perfusions (p<0.05 vs. reference at 1 and 4h). Further analyses of platelet, complement and coagulation pathway activation, antibody and histamine levels are in progress.
Conclusion: Neu5GcKO in GalTKO.hCD46 lungs significantly reduces TBX levels and PVR elevation and is associated with an almost complete “recovery” of the observed early platelet count drop. The findings suggest that the knock-out of the Neu5Gc sialic acid reduces the inflammation process, perhaps by blunting activation of pulmonary macrophages and platelets that elaborate TBX.
15:30 - 16:30
|Non-Gal Antibodies||N-Glycolylneuraminic acid (Neu5Gc) knock-out in GalTKO.hCD46 pig lungs improves pulmonary function in a xenogeneic pig-to-human lung perfusion model.||Room 109|
11:00 - 12:30
|Solid Organ Xenotransplantation (2)||New multi-transgenic donor pigs and targeted drug treatments extended life-supporting xenogeneic lung function||Room 109|
11:00 - 12:30
|Solid Organ Xenotransplantation (2)||Effect of C5a inhibition on GalTKO.hCD46 pig lung xenograft perfusion||Room 109|
17:30 - 18:30
|Joint Poster Session||Effects of a thromboxane synthase inhibitor, 1-BIA, on eicosanoid metabolism in a GalTKO.hCD46 xenogeneic lung perfusion model||Main Foyer 1 & 2|