Differential immune responses to α-gal epitopes on xenografts and allografts: implications for accommodation in xenotransplantation
Masahiro Tanemura, … , Anita S. Chong, Uri Galili
Masahiro Tanemura, … , Anita S. Chong, Uri Galili
Published February 1, 2000
Citation Information: J Clin Invest. 2000;105(3):301-310. https://doi.org/10.1172/JCI7358.
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Article

Differential immune responses to α-gal epitopes on xenografts and allografts: implications for accommodation in xenotransplantation

Abstract

Xenograft recipients produce large amounts of high-affinity anti-Gal IgG in response to Galα1-3Galβ1- 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.

Authors

Masahiro Tanemura, Dengping Yin, Anita S. Chong, Uri Galili

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Figure 4

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Two-color FACS analysis of B cells with anti-Gal BCR in α1,3GT KO mice. ...
Two-color FACS analysis of B cells with anti-Gal BCR in α1,3GT KO mice. B cells were identified by the staining with PE-conjugated anti-mouse Ig, whereas cells with anti-Gal BCR were identified by the binding of biotinylated α-gal BSA, followed by avidin-FITC. The stained lymphocytes were from: (a) nonimmunized mice; (b) mice immunized with pig kidney membranes; (c) cells from mice immunized as in b and tested for binding of biotinylated N-acetyllactosamine (Galβ1-4GlcNAc-R)-BSA as specificity control; (d) mice immunized with WT mouse kidney membranes; (e) mice immunized with glycolipids from rabbit RBC. Proportion of double-positive stained cells is indicated. Data are from a representative mouse of 5 in each group.