Sharma A, Okabe J, Birch P, McClellan S B, Martin M J, Platt J L, Logan J S
Nextran, Princeton, NJ 08540, USA.
Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7190-5. doi: 10.1073/pnas.93.14.7190.
Hyperacute rejection of a porcine organ by higher primates is initiated by the binding of xenoreactive natural antibodies of the recipient to blood vessels in the graft leading to complement activation. The majority of these antibodies recognize the carbohydrate structure Gal(alphal,3)Gal (gal epitope) present on cells of pigs. It is possible that the removal or lowering of the number of gal epitopes on the graft endothelium could prevent hyperacute rejection. The Gal(alpha1,3) Gal structure is formed by the enzyme Galbeta1,4GlcNAc3-alpha-D-galactosyltransferase [alpha(1,3)GT; EC 2.4.1.51], which transfers a galactose molecule to terminal N-acetyllactosamine (N-lac) present on various glycoproteins and glycolipids. The N-lac structure might be utilized as an acceptor by other glycosyltransferases such as Galbeta1,4GlcNAc 6-alpha-D-sialyltransferase [alpha(2,6)ST], Galbeta1,4GlcNAc 3-alpha-D-Sialyltransferase [alpha(2,3)ST], or Galbeta 2-alpha-L-fucosyltransferase [alpha(1,2)FT; EC 2.4.1.691, etc. In this report we describe the competition between alpha(1,2)FT and alpha(1,3)GT in cells in culture and the generation of transgenic mice and transgenic pigs that express alpha(1,2)Fr leading to synthesis of Fucalpha,2Galbeta- (H antigen) and a concomitant decrease in the level of Gal(alpha1,3)Gal. As predicted, this resulted in reduced binding of xenoreactive natural antibodies to endothelial cells of transgenic mice and protection from complement mediated lysis.
高等灵长类动物对猪器官的超急性排斥反应是由受体的异种反应性天然抗体与移植物中的血管结合引发的，进而导致补体激活。这些抗体中的大多数识别猪细胞上存在的碳水化合物结构Gal(α1,3)Gal（半乳糖表位）。移植物内皮细胞上半乳糖表位数量的去除或减少有可能预防超急性排斥反应。Gal(α1,3)Gal结构由Galβ1,4GlcNAc3-α-D-半乳糖基转移酶[α(1,3)GT；EC 2.4.1.51]形成，该酶将一个半乳糖分子转移到各种糖蛋白和糖脂上存在的末端N-乙酰乳糖胺（N-乳糖）上。N-乳糖结构可能被其他糖基转移酶用作受体，如Galβ1,4GlcNAc 6-α-D-唾液酸转移酶[α(2,6)ST]、Galβ1,4GlcNAc 3-α-D-唾液酸转移酶[α(2,3)ST]或Galβ2-α-L-岩藻糖基转移酶[α(1,2)FT；EC 2.4.1.691]等。在本报告中，我们描述了培养细胞中α(1,2)FT和α(1,3)GT之间的竞争，以及表达α(1,2)FT的转基因小鼠和转基因猪的产生，这导致Fucα2Galβ-（H抗原）的合成以及Gal(α1,3)Gal水平的相应降低。正如所预测的，这导致异种反应性天然抗体与转基因小鼠内皮细胞的结合减少，并使其免受补体介导的裂解。
