title: Human decay-accelerating factor expressed on rat hearts inhibits leukocyte adhesion.
abstract: In xenotransplantation the use of donors transgenic for recipient-type complement regulatory protein decay-accelerating factor (DAF/CD55) or membrane co-factor protein (MCP/CD46) protects grafts against hyperacute rejection (HAR), which is primarily mediated by xenoreactive natural antibodies and complement. In the Langendorff model, we previously demonstrated that rat hearts transgenic for human CD55 (hCD55), perfused with human serum, were protected against HAR. However, ex vivo, these hearts were found to be destroyed by a process occurring after the period of HAR. The question arose as to whether hearts transgenic for hCD55 are also protected against adhesion and infiltration by cells implicated in the early phases of xenograft rejection. The aim of the present study was to analyze this process in the ex vivo heart perfusion model. hCD55-transgenic rat hearts and their controls were perfused with either heat-inactivated or normal human blood solutions for 60 min. Although most of the hearts had stopped beating within the 60-min perfusion period, the perfusion was not stopped to enable adhesion of cells during a fixed period identical for all groups. Independent of the presence of complement, H&E-stained tissues of hCD55-transgenic hearts revealed fewer PMN leukocytes adhering to the endothelium than the controls (mean: 31% vs 60%). Standard histology and immunohistochemistry showed that hCD55-transgenic hearts exhibited less interstitial edema, hemorrhage, microthrombosis, fibrin deposition, and leukocyte infiltration than did the controls. All hearts showed mild to moderate levels of P-selectin and similar levels of ICAM-1, C3c, C9, IgA, IgG, and IgM deposition. hCD55 expressed on rat hearts not only inhibits complement activation, but also human leukocyte adhesion and apparently functions as an anti-adhesion molecule. hCD55 is an efficient factor in protecting grafts against HAR and protects the graft against adhesion of leukocytes as well.
authors.affiliation: Laboratory for Experimental Surgery, Room Ee 102c, Erasmus Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands. carolineverbakel@hotmail.com
authors.forename: Caroline A E
authors.initials: CA
authors.lastname: Verbakel
authors.forename: Suzanne
authors.initials: S
authors.lastname: van Duikeren
authors.forename: Ron W F
authors.initials: RW
authors.lastname: de Bruin
authors.forename: Richard L
authors.initials: RL
authors.lastname: Marquet
authors.forename: Jan N M
authors.initials: JN
authors.lastname: IJzermans
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D018958:CD55 Antigens / Q000032:analysis / Q000235:genetics*; D002448:Cell Adhesion / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000032:analysis; D005260:Female; D006321:Heart / Q000502:physiology*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D007962:Leukocytes / Q000276:immunology / Q000502:physiology*; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000276:immunology*; D051381:Rats
chemical_list: D018958:CD55 Antigens; D015815:Cell Adhesion Molecules