Transgenic expression of a CD46 (membrane cofactor protein) minigene: Studies of xenotransplantation and measles virus infection
Corresponding Author
Bruce R. Thorley
The Austin Research Institute, Heidelberg, Australia
Austin Research Institute, Studley Road, Heidelberg, Victoria 3084, Australia Fax: +61-3-9287-0666Search for more papers by this authorJulie Milland
The Austin Research Institute, Heidelberg, Australia
Search for more papers by this authorDale Christiansen
The Austin Research Institute, Heidelberg, Australia
Search for more papers by this authorMarc B. Lanteri
The Austin Research Institute, Heidelberg, Australia
Search for more papers by this authorBeth McInnes
The Austin Research Institute, Heidelberg, Australia
Search for more papers by this authorIngrid Moeller
University of Melbourne Department of Medicine, Austin and Repatriation Medical Centre, Heidelberg, Australia
Search for more papers by this authorPierre Rivailler
Laboratoire d'Immunobiologie Moléculaire, Ecole Supérieure de Lyon, UMR 49, CNRS, Lyon, France
Search for more papers by this authorBranka Horvat
Laboratoire d'Immunobiologie Moléculaire, Ecole Supérieure de Lyon, UMR 49, CNRS, Lyon, France
Search for more papers by this authorChantal Rabourdin-Combe
Laboratoire d'Immunobiologie Moléculaire, Ecole Supérieure de Lyon, UMR 49, CNRS, Lyon, France
Search for more papers by this authorDenis Gerlier
Immunité et Infections Virales, IVMC, CNRS-UCBL, UMR 5537, Faculté de Médecine Lyon-RTH Laënnec, Lyon, France
Search for more papers by this authorIan F. C. McKenzie
The Austin Research Institute, Heidelberg, Australia
Search for more papers by this authorBruc. E. E. Loveland
The Austin Research Institute, Heidelberg, Australia
Search for more papers by this authorCorresponding Author
Bruce R. Thorley
The Austin Research Institute, Heidelberg, Australia
Austin Research Institute, Studley Road, Heidelberg, Victoria 3084, Australia Fax: +61-3-9287-0666Search for more papers by this authorJulie Milland
The Austin Research Institute, Heidelberg, Australia
Search for more papers by this authorDale Christiansen
The Austin Research Institute, Heidelberg, Australia
Search for more papers by this authorMarc B. Lanteri
The Austin Research Institute, Heidelberg, Australia
Search for more papers by this authorBeth McInnes
The Austin Research Institute, Heidelberg, Australia
Search for more papers by this authorIngrid Moeller
University of Melbourne Department of Medicine, Austin and Repatriation Medical Centre, Heidelberg, Australia
Search for more papers by this authorPierre Rivailler
Laboratoire d'Immunobiologie Moléculaire, Ecole Supérieure de Lyon, UMR 49, CNRS, Lyon, France
Search for more papers by this authorBranka Horvat
Laboratoire d'Immunobiologie Moléculaire, Ecole Supérieure de Lyon, UMR 49, CNRS, Lyon, France
Search for more papers by this authorChantal Rabourdin-Combe
Laboratoire d'Immunobiologie Moléculaire, Ecole Supérieure de Lyon, UMR 49, CNRS, Lyon, France
Search for more papers by this authorDenis Gerlier
Immunité et Infections Virales, IVMC, CNRS-UCBL, UMR 5537, Faculté de Médecine Lyon-RTH Laënnec, Lyon, France
Search for more papers by this authorIan F. C. McKenzie
The Austin Research Institute, Heidelberg, Australia
Search for more papers by this authorBruc. E. E. Loveland
The Austin Research Institute, Heidelberg, Australia
Search for more papers by this authorAbstract
CD46 (membrane cofactor protein) is a human cell-surface regulator of activated complement and a receptor for the measles virus. A CD46 transgenic mouse line with an expression pattern similar to that of human tissues has been produced, to develop an animal model of (i) the control of complement activation by complement regulators in hyperacute rejection of xenografts, and (ii) measles virus infection. The mouse line was made using a CD46 minigene that includes promoter sequence and the first two introns of genomic CD46, which was coinjected into mouse ova with chicken lysozyme matrix attachment region DNA. A high level of CD46 expression in homozygotic transgenic mice was obtained with spleen cells having approximately 75% of the level found on human peripheral blood mononuclear cells. CD46 was detected in all tissues examined by immunohistochemistry, radioimmunoassay and Western blotting, showing that these mice were suitable for transplantation and measles virus infection studies. It also indicated that the transgene included the important regulatory elements of the CD46 promoter. Transgenic spleen cells were significantly protected in vitro from human complement activated by either the classical or alternative pathways and from alternative pathway rat complement. Furthermore, transgenic mouse hearts transplanted to rats regulated complement deposition in an in vivo model of antibody-dependent hyperacute xenograft rejection. Similar to human lymphocytes, transgenic lymphoblasts could be infected in vitro with measles virus; infected cells expressed viral proteins and produced infectious viral particles. The data demonstrate the suitability of this minigene for obtaining high-level CD46 expression sufficient for enhanced resistance of transgenic cells to complement attack and for obtaining wide tissue distribution of CD46, analogous to human tissues and, therefore, useful for comparative studies.
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