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Accommodation using synthetic Gal Antigen in xenotransplantation

在异种移植中使用合成 Gal 抗原进行调节

基本信息

批准号：
07671284
负责人：
SATOMI Susumu
金额：
$ 1.47万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

Transplantation between members of discordant species, such as pig to human, result in hyperacute rejection in unmodified recipient. The extremely rapid rejection process is associated with codeposition of recipient xenoreactive natural antibody named anti-Galalpha (1,3) Gal antibody and complement on the endothelium of the donor organ. In some cases the temporary depletion of antidonor antibody from the circulation of a graft recipient and perhaps other manipulations allows the prolonged survivl of a vascularized graft even after the antibody return to the circulation and the complement system is restored. This condition is called accommodation.Though the mechanism underlyning accommodation is not known, if accommodation can be achieved which is an issue of importance in the clinical application of xenotransplantation. We tried to absorb anti Gal antibody from human serum using the pig thyroglobulin affinity chromatography colum and then bounded antibodies were eluted from the colum. In the histological examination, pig islets were stained with human serum clearly, but not anti Gal antibody. Therefore, we concluded that there is an another antigen except Gal antigen which is recognized by anti Gal antibody on the surface of pig islets.While not a method to remove antibodies, adoministration of the target epitopes (Gal antigen) in vivo is an useful method to block the binding of natural antibody to their targets. We attempted to synthesis Gal antigen by two methods using chemical agents or alpha-galactosidase. Synthetic Gal antigen neutralized anti Gal antibody from human serum effectively resulted blocking to bind to antigen in ELISA assay. Since the cost of Gal antigen synthesis is very expensive we can not try to use in vivo. Immunoadsorption using syntetic antigen and antigen adoministration in solible form have an ability to come an effective therapy to prevent hyperacute rejection in clinical xenotransplantation.

不协调物种成员之间的移植，如猪到人，导致未修饰受体的超急性排斥反应。极快的排斥过程与受体异种反应性天然抗体（称为抗Galalpha（1，3）Gal抗体）和补体在供体器官内皮上的共沉积有关。在某些情况下，从移植物受体的循环中暂时耗尽抗供体抗体以及可能的其他操作允许延长血管化移植物的存活，即使在抗体返回循环和补体系统恢复之后。尽管调节的机制尚不清楚，但能否实现调节是异种移植临床应用中的一个重要问题。用猪甲状腺球蛋白亲和层析柱吸附人血清中的抗Gal抗体，然后将结合的抗体从层析柱上洗脱下来。在组织学检查中，猪胰岛可被人血清清楚地染色，但抗Gal抗体不能染色。因此，我们认为，猪胰岛表面除Gal抗原外，还存在另一种抗原，该抗原可被抗Gal抗体识别，而体内给药靶表位（Gal抗原）是一种有效的方法，可阻断天然抗体与其靶点的结合，但不是去除抗体的方法。我们尝试用化学试剂和α-半乳糖苷酶两种方法合成Gal抗原。在ELISA检测中，人工合成的Gal抗原中和了人血清中的抗Gal抗体，有效地阻断了与抗原的结合。由于Gal抗原合成的成本非常昂贵，我们无法尝试在体内使用。合成抗原免疫吸附和可溶性抗原给药是预防异种移植超急性排斥反应的有效方法。