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

被引:127
作者
Tanemura, M
Yin, DP
Chong, AS
Galili, U
机构
[1] Rush Univ, Xenotransplantat Res Lab, Dept Cardiovasc Thorac Surg, Chicago, IL 60612 USA
[2] Rush Univ, Dept Gen Surg, Chicago, IL 60612 USA
[3] Rush Univ, Dept Immunol, Chicago, IL 60612 USA
关键词
D O I
10.1172/JCI7358
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Xenograft recipients produce large amounts of high-affinity anti-Gal IgG in response to Gal alpha 1-3Gal beta 1-4GlcNAc-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 alpha 1,3galactosyltransferase 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 help er 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.
引用
收藏
页码:301 / 310
页数:10
相关论文
共 28 条
[1]  
ALEXANDRE GPJ, 1987, TRANSPLANT P, V19, P4538
[2]  
BACH FH, 1991, TRANSPL P, V23, P205
[3]   Accommodation of vascularized xenografts: Expression of ''protective genes'' by donor endothelial cells in a host Th2 cytokine environment [J].
Bach, FH ;
Ferran, C ;
Hechenleitner, P ;
Mark, W ;
Koyamada, N ;
Miyatake, T ;
Winkler, H ;
Badrichani, A ;
Candinas, D ;
Hancock, WW .
NATURE MEDICINE, 1997, 3 (02) :196-204
[4]   Transgenic pigs expressing human CD59 and decay-accelerating factor produce an intrinsic barrier to complement-mediated damage [J].
Byrne, G ;
McCurry, KR ;
Martin, MJ ;
McClellan, SM ;
Platt, JL ;
Logan, JS .
TRANSPLANTATION, 1997, 63 (01) :149-155
[5]  
Cozzi E, 1997, XENOTRANSPLANTATION, P665
[6]  
DECASTRO JAL, 1982, P NATL ACAD SCI-BIOL, V79, P3813
[7]  
Desnick R.J., 1995, The Metabolic and Molecular Bases of Inherited Disease, P2741
[8]  
EGGE H, 1985, J BIOL CHEM, V260, P4927
[9]  
GALILI U, 1988, J BIOL CHEM, V263, P17755
[10]   A sensitive assay for measuring α-gal epitope expression on cells by a monoclonal anti-Gal antibody [J].
Galili, U ;
LaTemple, DC ;
Radic, MZ .
TRANSPLANTATION, 1998, 65 (08) :1129-1132