Role of anti-Gal alpha 1,3Gal and anti-platelet antibodies in hyperacute rejection of pig lung by human blood

Background. Previous work has shown that antibodies against porcine antigen s are an important trigger of hyperacute lung rejection (HALR). The relativ e importance of Gal alpha1,3Gal epitopes and other antigens, such as those expressed on pig platelet membranes or lung itself, has not been defined. T his study compares the efficiency of three anti-pig antibody depletion stra tegies, and their efficacy with regard to attenuation of HALR. Methods. Plasma pooled from three human donors was adsorbed against Gal alp ha1,3Gal disaccharide or porcine platelet extract (PPE), or passed through pig lung vasculature. Whole blood reconstituted using adsorbed plasma was t hen used to perfuse piglet lung, and results were compared with unmodified human blood. Results. Depletion of lung-reactive anti-Gal alpha1-3Gal antibodies was mos t efficient with the alpha Gal column (99% +/- 0.5% vs 87% to 93% +/- 11% f or PPE and 92% to 95% +/- 8% for lung, p < 0.01 vs aGal column). PPE column tended to be more efficient (77% to 84% +/- 12%) in removing anti-PPE anti bodies than pig lung (66% to 70% +/- 14%) or the aGal column (56% to 63% +/ - 16%, P < 0.05). Lung survival and function with each antibody depletion s trategy was improved relative to unmodified controls (mean survival greater than or equal to 146 minutes vs 8 minutes for controls). Although alpha Ga l and lung adsorption yielded more consistent lung protection (survival bey ond 2 hours) than did PPE, no approach proved significantly superior. Compl ement C3a. elaboration at 10 minutes was attenuated > 80% by each adsorptio n strategy, an effect that was most pronounced in the lung adsorption group (95%, p < 0.01). Histamine elaboration was blunted significantly by PPE ad sorption but not in other groups (p < 0.05). Platelet but not leukocyte seq uestration was decreased with antibody depletion compared with the nondeple ted group (44% to 50% vs 82%, p < 0.01). Conclusions. Each antibody depletion strategy tested significantly prolongs lung xenograft survival and function compared with unmodified human blood, but none was sufficient to reliably prevent HALR. Depletion of antibodies against both aGal and additional cell membrane antigens, or control of anti body-independent pathogenic pathways, may be necessary to consistently prev ent HALR. (C) 2001 by The Society of Thoracic Surgeons.