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

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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.