Xenograft recipients produce large amounts of high-affinity anti-Gal IgG in response to Galα13Galβ1- 4GlcNAc-R (α-gal) epitopes on the graft. In contrast, ABO-mismatched allograft recipients undergo 'accommodation,' a state of very weak immune response to ABO antigens. These differences in anti-carbohydrate immune response were studied in α1,3galactosyltransferase knock-out mice. Pig kidney membranes administered to these mice elicited extensive production of anti-Gal IgG, whereas allogeneic kidney membranes expressing α-gal epitopes elicited only a weak anti-Gal IgM response. Anti- Gal IgG response to xenograft membranes depended on helper T cell activation and was inhibited by anti-CD40L antibody. These T cells were activated by xenopeptides and not by α-gal epitopes. Moreover, allogeneic cell membranes manipulated to express xenoproteins also induced anti-Gal IgG response. Xenoglycoproteins with α-gal epitopes are processed by anti-Gal B cells. Xenopeptides presented by these cells activate a large repertoire of helper T cells required for the differentiation of anti-Gal B cells into cells secreting anti-Gal IgG. Alloglycoproteins with α-gal epitopes have very few immunogenic peptides and fail to activate helper T cells. Similarly, ineffective helper T-cell activation prevents a strong immune response to blood group antigens in ABO-mismatched allograft recipients, thus enabling the development of accommodation.
Tanemura, M., Yin, D., Chong, A. S., & Galili, U. (2000). Differential immune responses to α-gal epitopes on xenografts and allografts: Implications for accommodation in xenotransplantation. Journal of Clinical Investigation, 105(3), 301–310. https://doi.org/10.1172/JCI7358