Chapter 5 - Anti-Gal B Cells Are Tolerized by α-Gal Epitopes in the Absence of T Cell Help

Abstract

The immune response to large (complex) carbohydrate antigens such as the α-gal epitope differs from the immune response to protein antigens in that these carbohydrate antigens are not capable of activating T cells. Therefore, activation of both naïve and memory anti-Gal B cells requires Th cell help from T cells that are activated by immunogenic peptide antigens (e.g., xeno-peptides). However, in vivo exposure of naïve and memory anti-Gal B cells to α-gal epitopes without T cell help for prolonged periods (2–4 weeks) results in the deletion of these B cells and induction of immune tolerance to the α-gal epitope. Thus, administration into GT-KO mice of syngeneic WT bone marrow cells, WT lymphocytes, or WT heart grafts, all presenting multiple α-gal epitopes, results within 2–4 weeks in tolerance induction to this epitope. The tolerized mice do not produce anti-Gal even after several immunizations with PKM homogenates. Anti-Gal B cells exposed in vivo to α-gal epitopes for a period of ~7 days prior to T cell activation, are induced to produce noncytolytic accommodating anti-Gal antibodies that bind to α-gal epitopes on endothelial cells of WT syngeneic heart but do not reject the graft. The tolerance induction also can be achieved by autologous cells engineered to present α-gal epitopes. Transduction of GT-KO mouse lymphocytes with replication defective adenovirus containing the α1,3GT gene (AdαGT) results in presentation of α-gal epitopes on these lymphocytes. Administration of AdαGT transduced GT-KO lymphocytes into GT-KO mice tolerizes both naïve and memory anti-Gal B cells. It is suggested that this method may be applicable for tolerance induction to blood group antigens in patients receiving ABO incompatible allografts. Such tolerance induction may be performed with autologous mononuclear cells transduced by replication-defective adenovirus containing the gene of the glycosyltransferase synthesizing the corresponding incompatible blood group antigen. In such a hypothetical protocol, the transduced mononuclear cells may be administered several times to the patient only after effective removal of the antibody to the incompatible blood group antigen and under T cell suppression.