title: An in vivo model of hyperacute rejection: characterization and evaluation of the effect of transgenic human complement inhibitors.
abstract: Hyperacute rejection (HAR) occurring after transplantation within phylogenetically distant species is a severe reaction triggered by preexisting xenoreactive antibodies and complement activation, leading to the destruction of the donor organ. Expression of human complement inhibitors in transgenic pig organs prolongs the survival of xenograft in experimental models. Moreover, the extent of protection from hyperacute rejection is dependent on the level and site of expression of the transgenic molecules and, probably, on the combination of different molecules. In this regard a small animal model to test the efficacy of expression vectors and different human molecules could be very advantageous. A murine model developed in our laboratory was characterized by measurement of several parameters characteristic of HAR in the livers of control and transgenic mice expressing transgenic human DAF (CD55) or MCP (CD46) at the end of 2 h of perfusion with human plasma and after I day. The parameters studied were heamatological values of hepatic functions (GOT and GPT), induction of pro-inflammatory molecules and histopathological evaluation. Cytokines (IL-1alpha, IL-1beta, IL-6) induction and exposure of P-selectin on the endothelial cell surface, was only observed in control animals after 2 h of perfusion, as an early event. GOT and GPT values increase dramatically after 2 h perfusion and 1 day after the treatment according to the histopathological observation of liver damage. On the contrary, the livers of hDAF or hMCP transgenic mice, under the same treatment were significantly protected although the extent of this protection is dependent on the level of expression of transgenic human molecules.
authors.affiliation: Consorzio Interuniversitario per i Trapianti d'Orgazno Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mora
authors.forename: M
authors.initials: M
authors.lastname: Lazzer
authors.forename: G
authors.initials: G
authors.lastname: Marsicano
authors.forename: L C
authors.initials: LC
authors.lastname: Mulder
authors.forename: L
authors.initials: L
authors.lastname: Carraresi
authors.forename: A
authors.initials: A
authors.lastname: Pieri
authors.forename: A
authors.initials: A
authors.lastname: Benanchi
authors.forename: D
authors.initials: D
authors.lastname: Grifoni
authors.forename: S
authors.initials: S
authors.lastname: Nuti
authors.forename: P
authors.initials: P
authors.lastname: Bruzzone
authors.forename: M
authors.initials: M
authors.lastname: Comporti
authors.forename: R
authors.initials: R
authors.lastname: Cortesini
authors.forename: M
authors.initials: M
authors.lastname: Rossini
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics*; D001219:Aspartate Aminotransferases / Q000097:blood; D018958:CD55 Antigens / Q000096:biosynthesis / Q000235:genetics*; D015932:Complement C3c / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000235:genetics*; D017931:DNA Primers / Q000737:chemistry; D019084:Fluorescent Antibody Technique, Indirect; D015870:Gene Expression; D006084:Graft Rejection / Q000378:metabolism / Q000517:prevention & control*; D006085:Graft Survival; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D019007:P-Selectin / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015703:Antigens, CD; C497857:CD46 protein, human; D018958:CD55 Antigens; D003169:Complement Inactivator Proteins; D017931:DNA Primers; D007378:Interleukins; C497859:Mcp protein, mouse; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D019007:P-Selectin; D012333:RNA, Messenger; D015932:Complement C3c; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase