Gene transfer of RANTES and MCP-1 chemokine antagonists prolongs cardiac allograft survival
Details
Serval ID
serval:BIB_4189063AD207
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Gene transfer of RANTES and MCP-1 chemokine antagonists prolongs cardiac allograft survival
Journal
Gene Therapy
ISSN
0969-7128 (Print)
Publication state
Published
Issued date
07/2006
Volume
13
Number
14
Pages
1104-9
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Jul
Research Support, Non-U.S. Gov't --- Old month value: Jul
Abstract
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.
Keywords
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
Create date
15/02/2008 12:28
Last modification date
20/08/2019 14:42