Gene transfer of RANTES and MCP-1 chemokine antagonists prolongs cardiac allograft survival

Détails

ID Serval
serval:BIB_4189063AD207
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Gene transfer of RANTES and MCP-1 chemokine antagonists prolongs cardiac allograft survival
Périodique
Gene Therapy
Auteur⸱e⸱s
Fleury  S., Li  J., Simeoni  E., Fiorini  E., von Segesser  L. K., Kappenberger  L., Vassalli  G.
ISSN
0969-7128 (Print)
Statut éditorial
Publié
Date de publication
07/2006
Volume
13
Numéro
14
Pages
1104-9
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Jul
Résumé
Vascularized organ allografts are rapidly destroyed by host immune cells that are recruited along chemokine gradients. Among chemokines, Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES) CC chemokine ligand (CCL5) and monocyte chemoattractant protein (MCP)-1 (CCL2) are upregulated in rejecting cardiac allografts. To antagonize these chemokines, we constructed adenoviral vectors expressing NH(2)-terminal deletion (8ND) mutants of the respective genes. Using the F344-to-LEW rat model, intragraft gene transfer of chemokine analogs prolonged cardiac allograft survival from 10.1+/-0.7 and 10.4+/-0.7 days using non-coding adenovirus and vehicle alone, respectively, to 17.0+/-0.7 days for 8ND-RANTES (P<0.001) and 14.2+/-0.8 days for 8ND-MCP-1 (P<0.01). 8ND-RANTES reduced graft infiltration by monocytes/macrophages, cluster of differentiation (CD) 8alpha(+) and T-cell receptor alphabeta(+) cells, while 8ND-MCP-1 reduced monocytes/macrophages. In mixed leukocyte reactions in vitro, proliferation of host lymphocytes from regional lymph nodes in response to donor splenocytes was unaffected by 8ND-RANTES gene transfer. Using a two-gene approach, the contribution of 8ND-MCP-1 was negligible, consistent with available evidence that 8ND-RANTES inhibits both RANTES and MCP-1 activities. 8ND-RANTES gene transfer and a short course of low-dose cyclosporine A synergistically prolonged graft survival to 37.8+/-5.5 vs 15.4+/-0.5 days with cyclosporine alone (P<0.001). These results suggest a role for anti-chemokine gene therapy as an adjuvant therapy in heart transplantation.
Mots-clé
Animals Chemokine CCL2/*antagonists & inhibitors/genetics Combined Modality Therapy Coronary Vessels Cyclosporine/therapeutic use Cytokines/genetics/immunology Gene Deletion Gene Therapy/*methods Graft Survival Heart Transplantation/*immunology Immunosuppressive Agents/therapeutic use Infusions, Intravenous Male Models, Animal RANTES/*antagonists & inhibitors/genetics Rats Rats, Inbred F344 Rats, Inbred Lew Reverse Transcriptase Polymerase Chain Reaction Transgenes Transplantation, Homologous
Pubmed
Web of science
Création de la notice
15/02/2008 11:28
Dernière modification de la notice
20/08/2019 13:42
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