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Enhanced Immunogenicity of Gal+ Bioprosthetic Heart Valves
Guerard W. Byrne, Ph.D., Heide Kogelberg, Ph.D, Neha Passi,
Christopher GA McGregor, MB, FRCS.
University College London, London, United Kingdom.

OBJECTIVE: The objective of this study was to compare the immunogenicity of bioprosthetic heart valves (BHVs) produced from either wild type (WT) galactose alpha 1,3 galactose (Gal) positive and Gal-free (GTKO) porcine heart valves in a clinically relevant nonhuman primate model. Commercial BHVs contain the major xenogeneic antigen Gal and patients treated with heart valve replacement show an induced anti-Gal antibody (Ab) response.
METHODS: Baboons had mitral valve replacement (MVR) with commercial BHVs produced from Gal+ (n=4) and Gal-free (GTKO) (n=3) pigs. Recipients were immunized prior to BHV implant to increase anti-Gal Ab titers to human levels. Serum anti-Gal Ab levels were monitored by ELISA. Non-Gal Ab responses were measured by Ab binding to GTKO porcine aortic endothelial cells (PAECs) using flow cytometry. Immunofluorescence microscopy was used to detect serum IgG binding to fixed GTKO porcine endothelial cells and to fresh frozen GTKO pig valves.
RESULTS: Immunization resulted in high anti-Gal IgG levels prior to BHV implantation in all recipients. Anti-Gal IgG levels fell rapidly after MVR in GTKO BHV recipients, returning to baseline in approximately 60 days. GT+ BHV recipients maintained significantly elevated levels of anti-Gal IgG for at least the first year post implantation. GT+ BHV recipients also showed increased IgG reactivity to GTKO pig endothelial cells 3 weeks after MVR which was not evident in GTKO recipients.
CONCLUSIONS: Chronic elevated anti-Gal IgG levels during the first year post MVR in GT+ BHV recipients, but not in GTKO BHV recipients is indicative of the expected increase Gal immunogenicity of glutaraldehyde fixed Gal+ BHV's. Increased IgG reactivity to GTKO endothelial cells further indicates that Gal+ BHVs also appear to have increased overall immunogenicity compared to GTKO BHVs. Enhanced immunogenicity of GT+ BHVs may be due to the adjuvant-like effect of the Gal epitope which can act to enhance immune presentation of non-Gal antigens. These data illustrate the range of immunogenicity of commercial Gal+ BHVs in a clinically relevant nonhuman primate model and support the hypothesis that more durable BHVs might be achieved using low antigenicity tissues from GTKO pigs.

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