title: A recombinant soluble chimeric complement inhibitor composed of human CD46 and CD55 reduces acute cardiac tissue injury in models of pig-to-human heart transplantation.
abstract: BACKGROUND
  Inasmuch as complement plays a critical role in many pathological processes and in xenograft rejection, efficient complement inhibitors are of great interest. Because the membrane-associated complement inhibitors are very effective, recombinant soluble molecules have been generated.
  
  
  METHODS
  We tested the efficacy of complement activation blocker-2 (CAB-2), a recombinant soluble chimeric protein derived from human decay accelerating factor (DAF, CD55) and membrane cofactor protein (MCP, CD46), in two models of pig-to-human xenotransplantation in which tissue injury is complement mediated. The in vitro model consisted of porcine aortic endothelial cells and human serum, and the ex vivo model consisted of a porcine heart perfused with human blood.
  
  
  RESULTS
  In vitro, addition of CAB-2 to serum inhibited cytotoxicity and the deposition of C4b and iC3b on the endothelial cells. Ex vivo, addition of CAB-2 to human blood prolonged organ survival from 17.3 +/- 6.4 min in controls to 108 +/- 55.6 min with 910 nM (100 microg/ml) CAB-2 and 219.8 +/- 62.7 min with 1820 nM (200 microg/ml) CAB-2. CAB-2 also retarded the onset of increased coronary vascular resistance. The complement activity of the perfusate was reduced by CAB-2, as was the generation of C3a and SC5b-9. The myocardial tissues had similar deposition of IgG, IgM, and Clq; however, CAB-2 reduced the deposition of C3, C4, and C9. Hearts surviving >240 min demonstrated trace to no deposition of C9 and normal histologic architecture.
  
  
  CONCLUSIONS
  These results indicate that CAB-2 can function as an inhibitor of complement activation and markedly reduce tissue injury in models of pig-to-human xenotransplantation and thus may represent a useful therapeutic agent for xenotransplantation and other complement-mediated conditions.
authors.affiliation: Department of Surgery and Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Kroshus
authors.forename: C T
authors.initials: CT
authors.lastname: Salerno
authors.forename: C G
authors.initials: CG
authors.lastname: Yeh
authors.forename: P J
authors.initials: PJ
authors.lastname: Higgins
authors.forename: R M
authors.initials: RM
authors.lastname: Bolman
authors.forename: A P
authors.initials: AP
authors.lastname: Dalmasso
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000494:pharmacology*; D001769:Blood / Q000187:drug effects; D018958:CD55 Antigens / Q000235:genetics; D002678:Chimera / Q000235:genetics; D003169:Complement Inactivator Proteins / Q000235:genetics / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects; D006321:Heart / Q000503:physiopathology; D016027:Heart Transplantation; D006801:Humans; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000235:genetics; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D009206:Myocardium / Q000473:pathology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013552:Swine; D014183:Transplantation, Heterologous
chemical_list: D015703:Antigens, CD; C497857:CD46 protein, human; D018958:CD55 Antigens; D003169:Complement Inactivator Proteins; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C410468:complement activation blocker 2, human