Gene transfer of RANTES and MCP-1 chemokine antagonists prolongs cardiac allograft survival.
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.
Department of Cardiology, University Hospital, Lausanne, Switzerland.
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S
Fleury
J
J
Li
E
E
Simeoni
E
E
Fiorini
L K
LK
von Segesser
L
L
Kappenberger
G
G
Vassalli
D000818:Animals; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors* / Q000235:genetics; D003131:Combined Modality Therapy; D003331:Coronary Vessels; D016572:Cyclosporine / Q000627:therapeutic use; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D017353:Gene Deletion; D015316:Genetic Therapy / Q000379:methods*; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007262:Infusions, Intravenous; D008297:Male; D023421:Models, Animal; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes; D014184:Transplantation, Homologous
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D016207:Cytokines; D007166:Immunosuppressive Agents; D016572:Cyclosporine