Differential immune responses to α-gal epitopes on xenografts and allografts:: implications for accommodation in xenotransplantation
Differential immune responses to α-gal epitopes on xenografts and allografts:: implications for accommodation in xenotransplantation
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DOI：
10.1172/jci7358
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发表时间：
2000-02-01
影响因子：
15.9
通讯作者：
Galili, U
中科院分区：
文献类型：
--
作者：
Tanemura, M;Yin, DP;Galili, U
异种移植受体对移植物上的Galα1-3Galβ1-4GlcNAc-R(α-Gal)表位产生大量高亲和力的抗Gal-Ig G。相比之下，ABO不相合的同种异体移植受者会经历“适应”，即对ABO抗原的免疫反应非常弱的状态。在α-1，3-半乳糖基转移酶基因敲除小鼠中研究了这些抗碳水化合物免疫反应的差异。给这些小鼠注射猪肾膜可广泛产生抗Gal-Ig G，而表达α-Gal表位的同种异体肾膜仅引起微弱的抗Gal Ig M反应。抗CD40L抗体抑制抗Gal-Ig G反应依赖于辅助性T细胞的激活。这些T细胞被异源多肽激活，而不是被阿尔法-半乳糖表位激活。此外，操控表达异种蛋白的异体细胞膜也能诱导抗Gal免疫球蛋白反应。具有α-半乳糖表位的异糖蛋白由抗半乳糖B细胞处理。这些细胞呈递的异肽能激活大量的辅助T细胞，使抗GalB细胞分化为分泌抗GalIg的细胞。具有α-半乳糖表位的同种异体糖蛋白具有极少的免疫原肽，并且不能激活辅助T细胞。同样，无效的辅助T细胞激活阻止了ABO血型不合的同种异体移植受者对血型抗原的强烈免疫反应，从而使调节的发展成为可能。
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.