Xenotransplantation and ABO incompatible transplantation: the similarities they share.

Abstract Transplantation of kidney allografts across the ABO barrier has been feasible with the development of technologies for removal of anti-blood group antibodies from the circulation of the recipent. The recipients of ABO incompatible grafts display tolerance, accommodation or rejection of the graft. Understanding the factors that determine the outcome of the immune response against incompatible blood group antigens has required the study of an appropriate experimental animal model. The model used is that of knockout (KO) mice for the α1,3galactosyltransferase gene, lacking the α-gal epitopes and transplanted with wild type mouse heart expressing the α-gal epitope. The α-gal epitope (Galα1-3Galβ1-(3)4GlcNAc-R) is one of the most abundant carbohydrate epitopes on cells of non-primate mammals and New World monkeys, where it is synthesized by the glycosylation enzyme α1,3galactosyltransferase. In humans, apes and Old World monkeys, this epitope is absent due to an evolutionary event that led to the inactivation of the α1,3galactosyltransferase gene in ancestral Old World primates. Instead, humans, apes and Old World monkeys produce a natural antibody, the anti-Gal antibody, that is the most abundant natural antibody in humans (∼1% of circulating immunoglobulins) and which specifically interacts with α-gal epitopes. The interaction between anti-Gal and α-gal epitopes is a major immunologic barrier in xenotransplantation, preventing transplantation of pig organs or tissues (i.e. xenografts) into humans. Anti-Gal antibodies also comprise a large proportion of anti-blood group B activity in A and O individuals. Moreover, in recipients of ABO incompatible grafts, much of the elicited anti-A and anti-B antibodies are in fact anti-Gal antibodies capable of binding also to the incompatible blood group antigens. Since the α-gal epitope is very similar in its structure to blood groups A and B, understanding anti-Gal response to α-gal epitopes is likely to provide information on the immune response to ABO incompatible antigens. Studies on the immune response to α-gal epitopes in KO mice have indicated that this epitope can not activate T cells. Anti-Gal B cells engaging α-gal epitopes on transplated wild type mouse heart can be activated to produce their antibodies only if they receive help from T cells that are activated by allogeneic or xenogeneic peptides. If T cell help is not available for several days the B cells are induced to differentiate into cells capable of producing accommodating antibodies. Accommodating anti-Gal antibodies bind to the incompatible carbohydrate antigen but do not induce rejection. Prolonged exposure of anti-Gal B cells to the incompatible α-gal epitope on the wild type mouse heart graft induces tolerance due to the deletion of these B cells. These studies imply that similar variation in the availability of T cell help in recipients of ABO incompatible grafts result in rejection, accommodation or tolerance, to the blood group antigen. The studies on immune response to incompatible α-gal epitopes have further indicated that tolerance to incompatible blood group antigens can be achieved by gene therapy with autologous bone marrow cells or autologous lymphocytes engineered to express the incompatible blood group antigen. Studies in the mouse model suggest that administration into the patient such autologous cells engineered to express the incompatible transplantation carbohydrate antigen induces deletion of anti-blood group B cells and induction of tolerance, provided that the anti-blood group antibodies are removed. Such tolerance is perpetuated indefinitely by the subsequent transplantation of the organ expressing the incompatible blood group antigen.