Abstract | BACKGROUND: 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.
|
Authors | T J Kroshus, C T Salerno, C G Yeh, P J Higgins, R M Bolman 3rd, A P Dalmasso |
Journal | Transplantation
(Transplantation)
Vol. 69
Issue 11
Pg. 2282-9
(Jun 15 2000)
ISSN: 0041-1337 [Print] United States |
PMID | 10868627
(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
|