Strategies for tolerance induction among B cells responding transplantation-associated carbohydrate antigens (with the aim of success in clinical ABO-incompatible transplantation and xenotransplantation

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The specific and persistent inhibition of antibody (Ab) production against blood group A or B carbohydrate determinants would be required to succeed ABO-incompatible transplantation. We here demonstrated a novel strategy for specific elimination of B cells responding to A-carbohydrates. Resembling to human blood group O or B individuals, mice had naturally occurring Abs against human blood group A-carbohydrates in their sera. By surface staining with fluoresceine-labeled synthetic A-carbohydrates (GalNAcα1-3 Fucα1-2Gal) conjugated to bovine serum albumin (BSA), we have demonstrated that B cells bearing receptors recognizing A-carbohydrates in mice belong to CD5^+ CD11b^+ B-1a subset, similarly to the phenotypic property of those in humans. Such B cells could be temporarily eliminated by single injection of synthetic A-carbohydrates conjugated with BSA and anti-BSA Abs. Administration of such A-carbohydrates into the circulation resulted in its specific binding to the corresponding B cell receptors, and consequently depleted the B cells with the anti-A-carbohydrates specificity via the interaction with the cytotoxic constituent without affecting B cell clones with other specificity. Subsequent treatment with cyclosporin A, which could block differentiation to B-1a, completely inhibited reappearance of B cells bearing receptor for A-carbohydrates. This strategy thereby prevented production of anti-A Abs even after immunization with human group A erythrocytes, while maintaining total serum IgM and IgG levels.