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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2006-03-16

AUTHORS

S Fleury, J Li, E Simeoni, E Fiorini, L K von Segesser, L Kappenberger, G Vassalli

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 NH2-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) 8α+ and T-cell receptor αβ+ 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. More... »

PAGES

1104-1109

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.gt.3302765

DOI

http://dx.doi.org/10.1038/sj.gt.3302765

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1010018928

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/16541117


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