Antibody-mediated accommodation of heart grafts expressing an incompatible carbohydrate antigen

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Abstract
Background. Accommodation in patients transplanted with ABO incompatible allografts describes a state in which antibodies are produced against the incompatible blood group carbohydrate antigen; however, the graft is not rejected. The present study describes an experimental model for antibody-mediated accommodation of organs expressing incompatible carbohydrate antigens. Methods. The model includes α1,3galactosyltransferase knockout mice that lack the α-gal epitope (Galα1–3Galβ1–4GlcNAc-R), transplanted heterotopically with wild-type (WT) hearts expressing this epitope. The mice are irradiated and receive memory anti-Gal B cells by adoptive transfer. Immunization of these mice with pig-kidney membranes induces the production of large amounts of anti-Gal, which binds specifically to α-gal epitopes. Results. Under the described accommodation protocol, transplanted mice produce anti-Gal that binds to α-gal epitopes on endothelial cells of the grafted WT heart; however, the WT hearts continued to function for months. Second WT hearts transplanted into accommodating, anti-Gal producing mice, were not rejected. Anti-Gal in accommodating mice was not cytolytic, whereas anti-Gal in rejecting mice readily induced complement-mediated lysis of cells expressing α-gal epitopes. In addition, accommodating mice displayed a preferential increase in the anti-Gal immunoglobulin (Ig)G2b subclass. Conclusions. The immune system may be manipulated to accommodate grafts expressing incompatible carbohydrate antigens by preferential production of noncytolytic anticarbohydrate antibodies.