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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.

AbstractBACKGROUND:
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.
CONCLUSION:
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.
AuthorsT J Kroshus, C T Salerno, C G Yeh, P J Higgins, R M Bolman 3rd, A P Dalmasso
JournalTransplantation (Transplantation) Vol. 69 Issue 11 Pg. 2282-9 (Jun 15 2000) ISSN: 0041-1337 [Print] United States
PMID10868627 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antigens, CD
  • CD46 protein, human
  • CD55 Antigens
  • Complement Inactivator Proteins
  • Membrane Cofactor Protein
  • Membrane Glycoproteins
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • complement activation blocker 2, human
Topics
  • Animals
  • Antigens, CD (genetics, pharmacology)
  • Blood (drug effects)
  • CD55 Antigens (genetics)
  • Chimera (genetics)
  • Complement Inactivator Proteins (genetics, pharmacology)
  • Endothelium, Vascular (cytology, immunology)
  • Graft Survival (drug effects)
  • Heart (physiopathology)
  • Heart Transplantation
  • Humans
  • Membrane Cofactor Protein
  • Membrane Glycoproteins (genetics)
  • Myocardial Reperfusion Injury (prevention & control)
  • Myocardium (pathology)
  • Recombinant Fusion Proteins (genetics, pharmacology)
  • Recombinant Proteins (chemistry, pharmacology)
  • Solubility
  • Swine
  • Transplantation, Heterologous

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