Potential implications of ABO blood group for vascular rejection in pig to human kidney xenotransplantation

Abstract: Background: A substantial hurdle for successful xenotransplantation is to negate the effect of xenoreactive natural antibodies [mainly Galα1–3Galβ1–4GlcNAc (α‐Gal) specific] that cause hyperacute xenograft rejection. Galα1–3Gal molecules (α‐Gal) have close structural homology with human ABO blood groups and therefore an individual's blood group might influence the formation of α‐Gal specific antibodies. Genetic heterogeneity controlling α‐Gal specific antibody formation could have important implications for future pig to human xenotransplantation clinical trials. We have investigated the relationship between ABO blood group and immunoglobulin M (IgM) and immunoglobulin G (IgG) α‐Gal specific antibody titres in sera obtained from renal dialysis patients and healthy blood donors. Methods: Serially diluted sera (n = 166) obtained from renal dialysis patients awaiting kidney transplantation (n = 116) and healthy blood donors (n = 50) were tested for IgM and IgG α‐Gal antibodies using an enzyme‐linked immunosorbent assay (ELISA) specific for α‐Gal. The study cohort comprised 62, 48, 36 and 20 sera obtained from blood group O, A, B and AB individuals, respectively. Reciprocal α‐Gal specific antibody titres were calculated from ELISA titration curves and stratified by individual blood group. Results: No significant heterogeneity was found in IgM α‐Gal specific antibody titres across ABO blood groups. In contrast, marked heterogeneity was observed in IgG α‐Gal specific antibody titres when stratified by blood group. IgG α‐Gal specific antibody titres were higher in sera obtained from blood group O renal dialysis patients [median titre 40, interquartile range (IQR) 14 to 72], compared with blood group A (median titre 18, IQR 7 to 54, P = 0.05), blood group B (median titre 6, IQR 0 to 15, P < 0.001) and blood group AB patients (median titre 3.5, IQR 0 to 16, P = 0.002). A similar correlation was found for IgG α‐Gal specific antibody titres in sera obtained from healthy blood donors with median titres of 20 (IQR 12 to 34), 37 (10 to 91), 9 (0 to 20), and 5.5 (0 to 12) in blood groups O, A, B and AB individuals, respectively. There was a strong interrelationship between α‐Gal specific antibody class and blood group, with both IgM and IgG α‐Gal specific antibodies found in 84% of the blood group O sera, 73% of blood group A sera, 50% of blood group B sera and 40% of blood group AB sera (P < 0.001). In a subgroup of 39 renal dialysis patients, IgM and IgG α‐Gal specific antibody titres were measured in two serum samples obtained at different time‐points (median time interval 581 days, range 42 to 4414), and showed a high degree of stability (correlation coefficient 0.88 and 0.90 for IgM and IgG, respectively). Conclusion: IgG α‐Gal specific antibody titres are significantly higher in the sera of blood group O and A renal dialysis patients and healthy individuals compared with blood groups B and AB. These data indicate that future clinical trials of pig to human xenotransplantation may be more problematic for non‐blood group B patients who are likely to have high levels of IgG α‐Gal specific antibodies that are associated with acute vascular rejection.