Alpha‐Gal on bioprostheses: xenograft immune response in cardiac surgery

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Abstract
Background The α-Gal (Galα1,3-Galβ1–4GlcNAc-R) epitope is the major xenoantigen causing hyperacute rejection of pig organs transplanted into primates. Porcine bioprostheses are utilized in cardiac surgery. However, premature degeneration of bioprostheses has limited utilization in younger patients and the immune response remains elusive. We sought to investigate whether a specific α-Gal immune response may play a role in this clinical scenario. Materials and methods We investigated the presence of α-Gal-epitope on native and fixed porcine valves by means of confocal laser scanning microscope (CLSM). ELISA was utilized to evidence whether implantation of bioprostheses elicits augmentation of pre-existing cytotoxic anti α-Gal IgM antibodies within 10 days of surgery. Patients who underwent coronary artery bypass grafting (CABG) or mechanical valve replacement served as controls (each group, n = 12). To corroborate the clinical relevance of the α-Gal immune response in vivo, we studied serum obtained before and after implantation of bioprostheses and its potency to lyse porcine α-Gal-bearing PK15 cells. Results We found the immunogenic α-Gal-epitope on fibrocytes interspersed in the connective tissue of porcine valves as determined by vimentin/IB4 lectin binding. Moreover, patients who were provided with a bioprostheses had developed a significant increase of naturally occurring cytotoxic IgM antibodies directed towards α-Gal after surgical intervention as compared with control patients (P < 0·0001, respectively). Sera obtained from the patients after the implantation of bioprostheses demonstrated an increased cytotoxicity against α-Gal-bearing PK-15 cells as compared with preoperative sera (P < 0·001). The specificity of the cytotoxic effects was proven as soluble Galα1–3Galβ1–4GlcNAc markedly inhibited cell death of α-Gal-bearing PK15 cells (P < 0·001). Conclusion Our data suggest that implantation of bioprostheses in cardiac surgery induces a xenograft-specific immune response. Procedures diminishing the presence of α-Gal on bioprostheses, such as utilization of genetically manipulated α-Gal-deficient xenograft or pretreatment with α-Galactosidase, might diminuate the immune response against bioprostheses and extend durability.