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 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) 8 alpha(+) and T-cell receptor alpha beta(+) 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.