Elimination of anti-Gal B cells by alpha-Gal ricin1.
Elimination of anti-Gal B cells by alpha-Gal ricin1.
复制标题
α-Gal ricin1 消除抗 Gal B 细胞。
DOI：
10.1097/00007890-200206270-00002
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发表时间：
2002
期刊：
影响因子：
6.2
通讯作者：
Galili,Uri
中科院分区：
文献类型：
--
作者：
Tanemura,Masahiro;Ogawa,Haruko;Yin,Deng-Ping;Chen,Zhao-Chun;DiSesa,VerdiJ;Galili,Uri
背景：人抗Gal抗体与猪细胞上的α-gal表位（Galα1-3Galβ1-4GlcNAc-R）的结合是猪向人器官移植的主要障碍，导致猪异种移植物的超急性和急性血管排斥反应。此外，异种移植物受体中的免疫系统被这些表位激活以产生高亲和力抗Gal，这也对异种移植物有害。通过特异性消除抗Gal B细胞可以防止抗Gal的产生。这是用蓖麻毒素A实现的，蓖麻毒素A与经修饰携带α-gal表位的人α1-酸性糖蛋白偶联。这种复合物称为α-半乳糖蓖麻毒素，在体内通过与这些细胞上的免疫球蛋白分子（即B细胞受体）相互作用而靶向抗-Gal B细胞。将该分子与蓖麻毒素A生物素化并通过抗生物素蛋白偶联以产生α-半乳糖蓖麻毒素。在α1，3 GT基因敲除（KO）小鼠实验模型上研究了α-半乳糖蓖麻毒素（α-gal ricin）对抗Gal B细胞的清除作用。当用猪肾膜免疫时，这些小鼠产生大量的抗Gal免疫球蛋白G，如通过ELISA用与牛血清白蛋白（BSA）连接的α-gal表位测量的。在抗Gal B细胞缺乏的情况下，这些小鼠缺乏产生抗Gal.Results.的能力，反复给药α-半乳糖蓖麻毒素到α1，3 GT KO小鼠导致消除抗Gal B细胞，从而防止产生抗Gal免疫球蛋白G后，免疫与猪肾膜。α-半乳糖蓖麻毒素的剂量对小鼠无毒性，也不影响其他特异性抗体的产生。结论：α-半乳糖蓖麻毒素的给药导致α1，3 GT KO小鼠中抗Gal B细胞的特异性消除。消除这些B细胞可能有助于在灵长类动物中实现对α-gal表位的免疫耐受。
Background.A major barrier in pig to human organ transplantation is the binding of human anti-Gal to α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R) on pig cells, resulting in hyperacute and acute vascular rejection of pig xenografts. Moreover, the immune system in xenograft recipients is activated by these epitopes to produce high affinity anti-Gal, which is also detrimental to xenografts. Production of anti-Gal can be prevented by specific elimination of anti-Gal B cells. This was achieved with the toxin ricin A, coupled to human α1-acid glycoprotein modified to carry α-gal epitopes. This complex, designated α-gal ricin, is targeted in vivo to anti-Gal B cells by interaction with the immunoglobulin molecules (ie, B cell receptors) on these cells.Methods.Carbohydrate chains on α1-acid glycoprotein were converted to carry α-gal epitopes by enzymatic treatment with recombinant α1, 3 galactosyltransferase (α1, 3GT). This molecule and ricin A were biotinylated and coupled by avidin to generate α-gal ricin. The efficacy of α-gal ricin in eliminating anti-Gal B cells was studied in the experimental model of α1, 3GT knockout (KO) mice. These mice produce large amounts of anti-Gal immunoglobulin G when immunized with pig kidney membranes, as measured by ELISA with α-gal epitopes linked to bovine serum albumin (BSA). In the absence of anti-Gal B cells, these mice lack the ability to produce anti-Gal.Results.Repeated administration of α-gal ricin into α1, 3GT KO mice resulted in elimination of anti-Gal B cells, thereby preventing production of anti-Gal immunoglobulin G after immunization with pig kidney membranes. This prevention of anti-Gal production occurred with doses of α-gal ricin that were not toxic to the mice and did not affect production of antibodies with other specificities.Conclusions.Administration of α-gal ricin results in specific elimination of anti-Gal B cells in α1, 3GT KO mice. The elimination of these B cells may prove to be helpful in attempts to achieve immune tolerance to α-gal epitopes in primates.