A membrane cofactor protein transgenic mouse model for the study of discordant xenograft rejection.
BACKGROUND
In recent years, interest has been revived in the possibility of transplanting organs into humans from a phylogenetically disparate species such as the pig (xenotransplantation). Such discordant xenografts, however, are subject to hyperacute rejection (HAR) and activation of host complement plays a major role in this rejection. This problem may be solved through the use of transgenic technology by providing the grafted tissue with molecules that down-regulate the action of host complement.


RESULTS
Transgenesis with a yeast artificial chromosome (YAC) was used to produce transgenic mice with the complete genomic gene of the human complement regulator membrane cofactor protein (MCP). Transgenic mice were obtained that exhibit full regulation of MCP as normally observed in humans. Hearts from these mice were shown to be significantly protected from HAR caused by human serum in an in vivo experimental procedure.


CONCLUSIONS
We conclude that MCP can protect discordant xenografts from HAR caused by human serum and that transgenic mice can be used effectively as in vivo models for the study of the role of human complement regulatory molecules in xenotransplantation.
Yannoutsos
N
N
Department of Cell Biology and Genetics, Erasmus University, Rotterdam, The Netherlands.
Ijzermans
J N
JN
Harkes
C
C
Bonthuis
F
F
Zhou
C Y
CY
White
D
D
Marquet
R L
RL
Grosveld
F
F
D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D015152:Blotting, Northern; D002874:Chromosome Mapping; D018244:Chromosomes, Artificial, Yeast; D003001:Cloning, Molecular; D003169:Complement Inactivator Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D015870:Gene Expression; D005809:Genes, Regulator; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D012313:RNA / Q000302:isolation & purification; D014183:Transplantation, Heterologous / Q000276:immunology*
D015703:Antigens, CD; C497857:CD46 protein, human; D003169:Complement Inactivator Proteins; C497859:Mcp protein, mouse; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D012313:RNA