Differential immune responses to alpha-gal epitopes on xenografts and allografts: implications for accommodation in xenotransplantation.
Xenograft recipients produce large amounts of high-affinity anti-Gal IgG in response to Galalpha1-3Galbeta1- 4GlcNAc-R (alpha-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 alpha1,3galactosyltransferase knock-out mice. Pig kidney membranes administered to these mice elicited extensive production of anti-Gal IgG, whereas allogeneic kidney membranes expressing alpha-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 alpha-gal epitopes. Moreover, allogeneic cell membranes manipulated to express xenoproteins also induced anti-Gal IgG response. Xenoglycoproteins with alpha-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 alpha- 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
M
Departments of Cardiovascular-Thoracic Surgery, General Surgery, and Immunology, Rush University, Chicago, Illinois 60612, USA.
Yin
D
D
Chong
A S
AS
Galili
U
U
D000818:Animals; D001788:Blood Grouping and Crossmatching; D002462:Cell Membrane / Q000276:immunology / Q000637:transplantation; D000939:Epitopes / Q000276:immunology; D007109:Immunity; D016030:Kidney Transplantation; D051379:Mice; D018345:Mice, Knockout; D013552:Swine; D014181:Transplantation Immunology; D014183:Transplantation, Heterologous / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology; D014312:Trisaccharides / Q000276:immunology*
D000939:Epitopes; D014312:Trisaccharides; C076569:alpha-galactosyl epitope