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Regulation of rejection against zenotransplantation by gene transfer of guinea pig species-specific complement regulatory molecules

通过豚鼠物种特异性补体调节分子的基因转移调节异种移植排斥反应

基本信息

批准号：
09670234
负责人：
OKADA Noriko
金额：
$ 1.92万
依托单位：
Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670234/
关键词：
complement regulation species-specific guinea pig DAF MCP zenotransplantation transgene

项目摘要

To protect complement activation on self cell membranes, membrane inhibitors of complement restrict complement activation of homologous serum (Okada et al. 1983). In xenotransplantation, regulation of complement activation on donor organ is very important to overcome hyperacute rejection. Transgenic pigs that express human complement regulatory membrane inhibitors which include decay accelerating factor (DAF), membrane cofactor protein (MCP) and HRF2O (2OkDa homologous restriction factor), have been generated, and being used as models of transplantation of organs from pig to primates. Recently, for the purpose of identifying regulatory molecules among the experimental animals, we have cloned the cDNAs of guinea pig(gp) DAF and gpMCP, and rat 512 antigen (rat Crry) and rat DAF and rat MCP.Furthermore we also analyzed the gene orientation of rat DAF and rat MCP which shows close linkage between the mouse Mcp and Cr2 genes on distal chromosome 1.gpDAF consists of multiple isoforms generated by alternative splicing from a single copy gene. The isoforms are mainly comprised of a glycosylphosphatidylinositol anchored form and a transmenbrane form that are not present in human DAF.We have transfected cDNA of the six major isoforms and the functional differences were evaluated to choose the best candidate to transgene into the experimental animals.

为了保护自身细胞膜上的补体激活，补体膜抑制剂限制同源血清的补体激活（Okada 等人，1983）。在异种移植中，供体器官上补体激活的调节对于克服超急性排斥反应非常重要。表达人类补体调节膜抑制剂（包括腐烂加速因子（DAF）、膜辅因子蛋白（MCP）和HRF2O（2OkDa同源限制因子））的转基因猪已经被生产出来，并被用作从猪到灵长类动物的器官移植模型。最近，为了鉴定实验动物中的调控分子，我们克隆了豚鼠（gp）DAF和gpMCP、大鼠512抗原（rat Crry）、大鼠DAF和大鼠MCP的cDNA。此外，我们还分析了大鼠DAF和大鼠MCP的基因方向，显示远端染色体上的小鼠Mcp和Cr2基因之间存在紧密连锁。 1.gpDAF由单拷贝基因选择性剪接产生的多个亚型组成。该亚型主要由糖基磷脂酰肌醇锚定形式和跨膜形式组成，这两种形式在人DAF中不存在。我们转染了六种主要亚型的cDNA，并评估了功能差异，以选择最佳候选者转基因到实验动物中。