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

Gene Ther. 2006 Jul;13(14):1104-9. doi: 10.1038/ Epub 2006 Mar 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemokine CCL2 / antagonists & inhibitors*
  • Chemokine CCL2 / genetics
  • Chemokine CCL5 / antagonists & inhibitors*
  • Chemokine CCL5 / genetics
  • Combined Modality Therapy
  • Coronary Vessels
  • Cyclosporine / therapeutic use
  • Cytokines / genetics
  • Cytokines / immunology
  • Gene Deletion
  • Genetic Therapy / methods*
  • Graft Survival
  • Heart Transplantation / immunology*
  • Immunosuppressive Agents / therapeutic use
  • Infusions, Intravenous
  • Male
  • Models, Animal
  • Rats
  • Rats, Inbred F344
  • Rats, Inbred Lew
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transgenes
  • Transplantation, Homologous


  • Ccl2 protein, rat
  • Chemokine CCL2
  • Chemokine CCL5
  • Cytokines
  • Immunosuppressive Agents
  • Cyclosporine