Immune response, accommodation, and tolerance to transplantation carbohydrate antigens

Abstract

The carbohydrate antigens, blood groups A and B, and the alpha-gal epitope (Galalpha1-3Gal) are major risk factors in transplantation. Transplantation across ABO barriers may result in rejection by elicited anti-blood group antibodies, accommodation where elicited anti-blood group antibodies do not reject the graft, or tolerance where no anti-blood group antibodies are produced and the graft is not rejected. alpha1,3Galactosyltransferase knockout mice that lack alpha-gal epitopes but produce the anti-Gal antibody serve as a model for studying these immune responses. Knockout mice underwent transplantation heterotopically with wild-type mouse heart expressing alpha-gal epitopes and subsequently received lymphocytes including naive and memory anti-Gal B cells. The type of elicited immune response was found to be associated with the period that anti-Gal B cells were exposed to alpha-gal epitopes of the graft in the absence of T-cell help. Immediate T-cell help induced production of cytolytic anti-Gal antibodies that reject the graft, whereas delayed T-cell help induced production of accommodating anti-Gal antibodies. In the absence of T-cell help for prolonged periods, anti-Gal B cells exposed to alpha-gal epitopes were deleted, resulting in tolerance. Similar variations in the extent of T-cell help may determine the B-cell response to incompatible A or B antigens. The experimental model further suggests that active tolerance induction before transplantation may be achieved by gene therapy with autologous bone marrow cells or autologous lymphocytes manipulated to express the incompatible transplantation carbohydrate antigen by introduction of the corresponding glycosyltransferase gene into these cells.