Protective Effects of Transgenic Human Endothelial Protein C Receptor Expression in Murine Models of Transplantation
Identifieur interne : 005977 ( Main/Exploration ); précédent : 005976; suivant : 005978Protective Effects of Transgenic Human Endothelial Protein C Receptor Expression in Murine Models of Transplantation
Auteurs : K. F. E. Lee [Australie] ; B. Lu [Australie] ; J. C. Roussel [France] ; L. J. Murray-Segal [Australie] ; E. J. Salvaris [Australie] ; S. J. Hodgkinson [Australie] ; B. M. Hall [Australie] ; A. J. F. D'Apice [Australie] ; P. J. Cowan [Australie] ; H. Gock [Australie]Source :
- American journal of transplantation : (Print) [ 1600-6135 ] ; 2012.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
Abstract
Thrombosis and inflammation are major obstacles to successful pig-to-human solid organ xenotransplantation. A potential solution is genetic modification of the donor pig to overexpress molecules such as the endothelial protein C receptor (EPCR), which has anticoagulant, anti-inflammatory and cytoprotective signaling properties. Transgenic mice expressing human EPCR (hEPCR) were generated and characterized to test this approach. hEPCR was expressed widely and its compatibility with the mouse protein C pathway was evident from the anticoagulant phenotype of the transgenic mice, which exhibited a prolonged tail bleeding time and resistance to collagen-induced thrombosis. hEPCR mice were protected in a model of warm renal ischemia reperfusion injury compared to wild type (WT) littermates (mean serum creatinine 39.0 ± 2.3 μmol/L vs. 78.5 ± 10.0 μmol/L, p < 0.05; mean injury score 31 ± 7% vs. 56 ± 5%, p < 0.05). Heterotopic cardiac xenografts from hEPCR mice showed a small but significant prolongation of survival in C6-deficient PVG rat recipients compared to WT grafts (median graft survival 6 vs. 5 days, p < 0.05), with less hemorrhage and edema in rejected transgenic grafts. These data indicate that it is possible to overexpress EPCR at a sufficient level to provide protection against transplant-related thrombotic and inflammatory injury, without detrimental effects in the donor animal.
Affiliations:
- Australie, France
- Nouvelle-Galles du Sud, Pays de la Loire, Victoria (État)
- Melbourne, Nantes, Sydney
- Université de Melbourne
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Lee</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Immunology Research Centre, St. Vincent's Hospital</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Medicine, The University of Melbourne</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region><settlement type="city">Melbourne</settlement></placeName><orgName type="university">Université de Melbourne</orgName></affiliation></author><author><name sortKey="Lu, B" sort="Lu, B" uniqKey="Lu B" first="B." last="Lu">B. 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F. E." last="Lee">K. F. E. Lee</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Immunology Research Centre, St. Vincent's Hospital</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Medicine, The University of Melbourne</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region><settlement type="city">Melbourne</settlement></placeName><orgName type="university">Université de Melbourne</orgName></affiliation></author><author><name sortKey="Lu, B" sort="Lu, B" uniqKey="Lu B" first="B." last="Lu">B. Lu</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Immunology Research Centre, St. Vincent's Hospital</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Roussel, J C" sort="Roussel, J C" uniqKey="Roussel J" first="J. C." last="Roussel">J. C. Roussel</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Department of Cardiothoracic Surgery, Nantes Hospital University</s1><s2>Nantes</s2><s3>FRA</s3><sZ>3 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Pays de la Loire</region><region type="old region">Pays de la Loire</region><settlement type="city">Nantes</settlement></placeName></affiliation></author><author><name sortKey="Murray Segal, L J" sort="Murray Segal, L J" uniqKey="Murray Segal L" first="L. J." last="Murray-Segal">L. J. Murray-Segal</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Immunology Research Centre, St. Vincent's Hospital</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Salvaris, E J" sort="Salvaris, E J" uniqKey="Salvaris E" first="E. J." last="Salvaris">E. J. Salvaris</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Immunology Research Centre, St. Vincent's Hospital</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Hodgkinson, S J" sort="Hodgkinson, S J" uniqKey="Hodgkinson S" first="S. J." last="Hodgkinson">S. J. Hodgkinson</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Faculty of Medicine, South Western Sydney Clinical School, The University of New South Wales</s1><s2>Sydney</s2><s3>AUS</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Hall, B M" sort="Hall, B M" uniqKey="Hall B" first="B. M." last="Hall">B. M. Hall</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Faculty of Medicine, South Western Sydney Clinical School, The University of New South Wales</s1><s2>Sydney</s2><s3>AUS</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="D Apice, A J F" sort="D Apice, A J F" uniqKey="D Apice A" first="A. J. F." last="D'Apice">A. J. F. D'Apice</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Immunology Research Centre, St. Vincent's Hospital</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Medicine, The University of Melbourne</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region><settlement type="city">Melbourne</settlement></placeName><orgName type="university">Université de Melbourne</orgName></affiliation></author><author><name sortKey="Cowan, P J" sort="Cowan, P J" uniqKey="Cowan P" first="P. J." last="Cowan">P. J. Cowan</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Immunology Research Centre, St. Vincent's Hospital</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Medicine, The University of Melbourne</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region><settlement type="city">Melbourne</settlement></placeName><orgName type="university">Université de Melbourne</orgName></affiliation></author><author><name sortKey="Gock, H" sort="Gock, H" uniqKey="Gock H" first="H." last="Gock">H. Gock</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Immunology Research Centre, St. Vincent's Hospital</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Medicine, The University of Melbourne</s1><s2>Melbourne</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region><settlement type="city">Melbourne</settlement></placeName><orgName type="university">Université de Melbourne</orgName></affiliation></author></analytic><series><title level="j" type="main">American journal of transplantation : (Print)</title><title level="j" type="abbreviated">Am. j. transplant. : (Print)</title><idno type="ISSN">1600-6135</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">American journal of transplantation : (Print)</title><title level="j" type="abbreviated">Am. j. transplant. : (Print)</title><idno type="ISSN">1600-6135</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animal model</term><term>Cold</term><term>Endothelial cell protein C receptor</term><term>Gene expression</term><term>Heart</term><term>Heterotransplantation</term><term>Homotransplantation</term><term>Inflammation</term><term>Ischemia</term><term>Mouse</term><term>Protection</term><term>Protective factor</term><term>Protein C</term><term>Reperfusion</term><term>Thrombosis</term><term>Transplantation</term><term>Treatment</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Homotransplantation</term><term>Facteur de protection</term><term>Protection</term><term>Hétérotransplantation</term><term>Protéine C</term><term>Expression génique</term><term>Ischémie</term><term>Modèle animal</term><term>Souris</term><term>Thrombose</term><term>Traitement</term><term>Transplantation</term><term>Coeur</term><term>Inflammation</term><term>Reperfusion</term><term>Froid</term><term>Récepteur EPCR</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Thrombosis and inflammation are major obstacles to successful pig-to-human solid organ xenotransplantation. A potential solution is genetic modification of the donor pig to overexpress molecules such as the endothelial protein C receptor (EPCR), which has anticoagulant, anti-inflammatory and cytoprotective signaling properties. Transgenic mice expressing human EPCR (hEPCR) were generated and characterized to test this approach. hEPCR was expressed widely and its compatibility with the mouse protein C pathway was evident from the anticoagulant phenotype of the transgenic mice, which exhibited a prolonged tail bleeding time and resistance to collagen-induced thrombosis. hEPCR mice were protected in a model of warm renal ischemia reperfusion injury compared to wild type (WT) littermates (mean serum creatinine 39.0 ± 2.3 μmol/L vs. 78.5 ± 10.0 μmol/L, p < 0.05; mean injury score 31 ± 7% vs. 56 ± 5%, p < 0.05). Heterotopic cardiac xenografts from hEPCR mice showed a small but significant prolongation of survival in C6-deficient PVG rat recipients compared to WT grafts (median graft survival 6 vs. 5 days, p < 0.05), with less hemorrhage and edema in rejected transgenic grafts. These data indicate that it is possible to overexpress EPCR at a sufficient level to provide protection against transplant-related thrombotic and inflammatory injury, without detrimental effects in the donor animal.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li></country><region><li>Nouvelle-Galles du Sud</li><li>Pays de la Loire</li><li>Victoria (État)</li></region><settlement><li>Melbourne</li><li>Nantes</li><li>Sydney</li></settlement><orgName><li>Université de Melbourne</li></orgName></list><tree><country name="Australie"><region name="Victoria (État)"><name sortKey="Lee, K F E" sort="Lee, K F E" uniqKey="Lee K" first="K. F. E." last="Lee">K. F. E. Lee</name></region><name sortKey="Cowan, P J" sort="Cowan, P J" uniqKey="Cowan P" first="P. J." last="Cowan">P. J. Cowan</name><name sortKey="Cowan, P J" sort="Cowan, P J" uniqKey="Cowan P" first="P. J." last="Cowan">P. J. Cowan</name><name sortKey="D Apice, A J F" sort="D Apice, A J F" uniqKey="D Apice A" first="A. J. F." last="D'Apice">A. J. F. D'Apice</name><name sortKey="D Apice, A J F" sort="D Apice, A J F" uniqKey="D Apice A" first="A. J. F." last="D'Apice">A. J. F. D'Apice</name><name sortKey="Gock, H" sort="Gock, H" uniqKey="Gock H" first="H." last="Gock">H. Gock</name><name sortKey="Gock, H" sort="Gock, H" uniqKey="Gock H" first="H." last="Gock">H. Gock</name><name sortKey="Hall, B M" sort="Hall, B M" uniqKey="Hall B" first="B. M." last="Hall">B. M. Hall</name><name sortKey="Hodgkinson, S J" sort="Hodgkinson, S J" uniqKey="Hodgkinson S" first="S. J." last="Hodgkinson">S. J. Hodgkinson</name><name sortKey="Lee, K F E" sort="Lee, K F E" uniqKey="Lee K" first="K. F. E." last="Lee">K. F. E. Lee</name><name sortKey="Lu, B" sort="Lu, B" uniqKey="Lu B" first="B." last="Lu">B. Lu</name><name sortKey="Murray Segal, L J" sort="Murray Segal, L J" uniqKey="Murray Segal L" first="L. J." last="Murray-Segal">L. J. Murray-Segal</name><name sortKey="Salvaris, E J" sort="Salvaris, E J" uniqKey="Salvaris E" first="E. J." last="Salvaris">E. J. Salvaris</name></country><country name="France"><region name="Pays de la Loire"><name sortKey="Roussel, J C" sort="Roussel, J C" uniqKey="Roussel J" first="J. C." last="Roussel">J. C. Roussel</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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