Evaluation of the carbohydrate antigen-mediated donor rejection in xenotransplantation

异种移植中碳水化合物抗原介导的供体排斥反应的评价

• 批准号: 11557182
• 负责人: KOZUTSUMI Yasunori
• 金额: $ 7.74万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557182/
• 关键词: sialic acid; xenotransplantation; NeuGc; Siglec; CD22; 臓器移植; CMP-NeuAC水酸化酵素; B細胞; N-グリコリルノイラミン酸; N-アセチルノイラミン酸; シアル酸水酸化酵素; ノックアウトマウス; ヒト化マウス

During the grant period, we conducted a research to evaluate the carbohydrate antigen-medi-ated donor organ rejection in the proposed xenoplantation procedure. Recently, shortage of donor organs from human source for the transplantation made xenoplantation (non-human to human transplantation) a rationale source of donor organ to be transplanted to meet the demand. Here, porcine is expected as the logical choice of animal for the preparation of donor organs because of their similarity in size and relative higher amino- acid sequence homology between human. However these two animal species considerably differ for their expression of the carbohydrate antigens in their cell surface. To verify the antigenicty of the N-glycolylneuraminic acid (NeuGc) which human lacks, we developed the mouse line lacking functional CMP-N-acetylneuraminic acid hydroxylase gene. Major achie- vements in this study are as follows.(1) The targeted mutagenesis of CMP-NeuAc hydroxylase re-created the lack of NeuGc in human that is known to lack active hydroxylase and its product NeuGc in cells.(2) We analyzed the immune system development in these mice that may affect the point of organ rejection and found that this mouse line has normal immune system in steady state.(3) We backcrossed this ES-based germline mutation to C57Black/6 line to prepare the donor organ for organ transplantation. Now the number of generations backcrossed is 17 and back- ground similarity between donor and recipient is expected to be quite strong concerning types of MHC and other protein-based antigens.

在赠款期间，我们进行了一项研究，以评估拟议中的盐含量程序中的碳水化合物抗原剂量器官排斥。最近，从人类来源的供体器官短缺进行移植的短缺（非人类移植到人移植）是供体器官的基本原理来源，以满足需求。在这里，由于人类之间的相似性和相对较高的氨基酸序列同源性，因此预计猪是动物制备供体器官的逻辑选择。但是，这两种动物物种在细胞表面表达了碳水化合物抗原的表达有很大差异。为了验证人类缺乏的N-糖胆基神经氨酸（Neugc）的抗原性，我们开发了缺乏功能性CMP-N-乙基神经氨氧化物酸羟化酶基因的小鼠系。这项研究中的主要成就如下。（1）CMP-NEUAC羟化酶的靶向诱变重新创建了人类中缺乏neugc，该诱变缺乏活性羟化酶及其在细胞中的产物。（2）我们分析了我们分析了这些小鼠的免疫系统发育可能会影响器官排斥的点，并发现该小鼠线的免疫系统正常。用于器官移植。现在，回击的几代人数为17，供体和受体之间的背景相似性预计将非常有力，因为MHC的类型和其他基于蛋白质的抗原类型。

项目成果

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